MONONITROPHENOLS - WHO | World Health Organization · purpose of the IOMC is to promote...

This report contains the collective views of an international group of experts and does notnecessarily represent the decisions or the stated policy of the United Nations EnvironmentProgramme, the International Labour Organisation, or the World Health Organization.

Concise International Chemical Assessment Document 20

MONONITROPHENOLS

First draft prepared by Dr A. Boehncke, Dr G. Koennecker, Dr I. Mangelsdorf, andDr A. Wibbertmann, Fraunhofer Institute for Toxicology and Aerosol Research,Hanover, Germany

Please note that the layout andpagination of this pdf file are not identicalto those oftheprinted CICAD

Published under the joint sponsorship of the United Nations Environment Programme, theInternational Labour Organisation, and the World Health Organization, and produced within theframework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health OrganizationGeneva, 2000

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint ventureof the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO),and the World Health Organization (WHO). The overall objectives of the IPCS are to establish thescientific basis for assessment of the risk to human health and the environment from exposure tochemicals, through international peer review processes, as a prerequisite for the promotion of chemicalsafety, and to provide technical assistance in strengthening national capacities for the sound managementof chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) wasestablished in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO,the United Nations Industrial Development Organization, the United Nations Institute for Training andResearch, and the Organisation for Economic Co-operation and Development (ParticipatingOrganizations), following recommendations made by the 1992 UN Conference on Environment andDevelopment to strengthen cooperation and increase coordination in the field of chemical safety. Thepurpose of the IOMC is to promote coordination of the policies and activities pursued by the ParticipatingOrganizations, jointly or separately, to achieve the sound management of chemicals in relation to humanhealth and the environment.

WHO Library Cataloguing-in-Publication Data

Mononitrophenols.

(Concise international chemical assessment document ; 20)

1.Nitrophenols - toxicity 2.Risk assessment 3.Environmental exposureI.International Programme on Chemical Safety II.Series

ISBN 92 4 153020 0 (NLM classification: QD 341.P5) ISSN 1020-6167

The World Health Organization welcomes requests for permission to reproduce or translate itspublications, in part or in full. Applications and enquiries should be addressed to the Office of Publications,World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information onany changes made to the text, plans for new editions, and reprints and translations already available.

©World Health Organization 2000

Publications of the World Health Organization enjoy copyright protection in accordance with theprovisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.

The designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the Secretariat of the World Health Organizationconcerning the legal status of any country, territory, city, or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital letters.

The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany,provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

iii

TABLE OF CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . . . . 8

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

7.1 2-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117.2 4-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . 11

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.3 Short-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

8.3.1 Oral exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128.3.2 Inhalation exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.3.2.1 2-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.3.2.2 4-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.3.3 Dermal exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.4 Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

8.4.1 Subchronic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138.4.2 Chronic exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

8.5 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

8.6 Reproductive and developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.6.1 Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148.6.2 Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

8.6.2.1 2-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188.6.2.2 4-Nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

8.7 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188.8 Methaemoglobin formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1910.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20


iv

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 11.1.2 Criteria for setting guidance values for 2- and 4-nitrophenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

APPENDIX 1 — 3-NITROPHENOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

APPENDIX 2 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

APPENDIX 3 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

APPENDIX 4 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Mononitrophenols

1

FOREWORD

Concise International Chemical AssessmentDocuments (CICADs) are the latest in a family ofpublications from the International Programme onChemical Safety (IPCS) — a cooperative programme ofthe World Health Organization (WHO), the InternationalLabour Organisation (ILO), and the United NationsEnvironment Programme (UNEP). CICADs join theEnvironmental Health Criteria documents (EHCs) asauthoritative documents on the risk assessment ofchemicals.

CICADs are concise documents that providesummaries of the relevant scientific informationconcerning the potential effects of chemicals uponhuman health and/or the environment. They are basedon selected national or regional evaluation documents oron existing EHCs. Before acceptance for publication asCICADs by IPCS, these documents undergo extensivepeer review by internationally selected experts to ensuretheir completeness, accuracy in the way in which theoriginal data are represented, and the validity of theconclusions drawn.

The primary objective of CICADs ischaracterization of hazard and dose–response fromexposure to a chemical. CICADs are not a summary of allavailable data on a particular chemical; rather, theyinclude only that information considered critical forcharacterization of the risk posed by the chemical. Thecritical studies are, however, presented in sufficientdetail to support the conclusions drawn. For additionalinformation, the reader should consult the identifiedsource documents upon which the CICAD has beenbased.

Risks to human health and the environment willvary considerably depending upon the type and extentof exposure. Responsible authorities are stronglyencouraged to characterize risk on the basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverpossible. These examples cannot be considered asrepresenting all possible exposure situations, but areprovided as guidance only. The reader is referred to EHC1701 for advice on the derivation of health-basedguidance values.

While every effort is made to ensure that CICADsrepresent the current status of knowledge, newinformation is being developed constantly. Unlessotherwise stated, CICADs are based on a search of thescientific literature to the date shown in the executivesummary. In the event that a reader becomes aware ofnew information that would change the conclusionsdrawn in a CICAD, the reader is requested to contactIPCS to inform it of the new information.

Procedures

The flow chart shows the procedures followed toproduce a CICAD. These procedures are designed totake advantage of the expertise that exists around theworld — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and otherdata that are necessary for assessing risks to humanhealth and/or the environment.

The first draft is based on an existing national,regional, or international review. Authors of the firstdraft are usually, but not necessarily, from the institutionthat developed the original review. A standard outlinehas been developed to encourage consistency in form.The first draft undergoes primary review by IPCS toensure that it meets the specified criteria for CICADs.

The second stage involves international peerreview by scientists known for their particular expertiseand by scientists selected from an international rostercompiled by IPCS through recommendations from IPCSnational Contact Points and from IPCS ParticipatingInstitutions. Adequate time is allowed for the selectedexperts to undertake a thorough review. Authors arerequired to take reviewers’ comments into account andrevise their draft, if necessary. The resulting second draftis submitted to a Final Review Board together with thereviewers’ comments.

The CICAD Final Review Board has severalimportant functions:

– to ensure that each CICAD has been subjected toan appropriate and thorough peer review;

– to verify that the peer reviewers’ comments havebeen addressed appropriately;

– to provide guidance to those responsible for thepreparation of CICADs on how to resolve anyremaining issues if, in the opinion of the Board, theauthor has not adequately addressed all commentsof the reviewers; and

– to approve CICADs as international assessments.

Board members serve in their personal capacity, not asrepresentatives of any organization, government, or

1 International Programme on Chemical Safety (1994)Assessing human health risks of chemicals: derivationof guidance values for health-based exposure limits.Geneva, World Health Organization (EnvironmentalHealth Criteria 170).


2

S E L E C T I O N O F H I G H Q U A L I T YN A T I O N A L / R E G I O N A L

A S S E S S M E N T D O C U M E N T ( S )

CICAD PREPARATION FLOW CHART

F I R S T D R A F T

P R E P A R E D

REVIEW BY IPCS CONTACT POINTS/SPECIALIZED EXPERTS

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

SELECTION OF PRIORITY CHEMICAL

1 Taking into account the comments from reviewers.2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments.3 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER),PREPARATION

OF SECOND DRAFT 1

P R I M A R Y R E V I E W B Y I P C S

( REVISIONS AS NECESSARY)

Mononitrophenols

3

industry. They are selected because of their expertise inhuman and environmental toxicology or because of theirexperience in the regulation of chemicals. Boards arechosen according to the range of expertise required for ameeting and the need for balanced geographicrepresentation.

Board members, authors, reviewers, consultants,and advisers who participate in the preparation of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects underdiscussion at any stage of the process. Representativesof nongovernmental organizations may be invited toobserve the proceedings of the Final Review Board.Observers may participate in Board discussions only atthe invitation of the Chairperson, and they may notparticipate in the final decision-making process.


4

1. EXECUTIVE SUMMARY

This CICAD on the isomers 2-, 3-, and 4-nitro-phenol was prepared by the Fraunhofer Institute forToxicology and Aerosol Research, Hanover, Germany. Itwas based on reviews compiled by the German AdvisoryCommittee on Existing Chemicals of EnvironmentalRelevance (BUA, 1992) and the US Agency for ToxicSubstances and Disease Registry (ATSDR, 1992) toassess the potential effects of 2- and 4-nitrophenol onthe environment and on human health. Data identified upto 1992 were considered in these reviews. A compre-hensive literature search of several databases was con-ducted in 1998 to identify any relevant references on 2-and 4-nitrophenol published subsequent to those in thesource documents and to identify all references contain-ing relevant data on the isomer 3-nitrophenol. Informa-tion found on 3-nitrophenol was very scarce, precludinga meaningful assessment. As a result, data on thisisomer are summarized in Appendix 1. Information on thenature of the peer review and the availability of thesource documents is presented in Appendix 2. Informa-tion on the peer review of this CICAD is presented inAppendix 3. This CICAD was approved as an interna-tional assessment at a meeting of the Final ReviewBoard, held in Washington, DC, USA, on 8–11 December1998. Participants at the Final Review Board meeting arelisted in Appendix 4. The International Chemical SafetyCard (ICSC 1342) for mononitrophenols, produced by theInternational Programme on Chemical Safety (IPCS,1998), has also been reproduced in this document.

The nitrophenol isomers are water-soluble solidsthat are moderately acidic in water as a result of dissoci-ation. 2-Nitrophenol and 4-nitrophenol are used as inter-mediates in the synthesis of a number of organophos-phorus pesticides and some medical products. Releasesinto the environment are primarily emissions into air,water, and soil from diffuse sources, such as vehicletraffic and hydrolytic and photolytic degradation of therespective pesticides. Further releases into the hydro-sphere and the geosphere are caused by the dry and wetdeposition of airborne nitrophenols from the atmos-phere. The photo-oxidative formation of 2- and 4-nitro-phenol in the atmosphere is still under discussion.

From the available data, only a slow rate of volati-lization of 2-nitrophenol and no significant volatilizationof 4-nitrophenol from water to air are to be expected.2-Nitrophenol is enriched in the liquid phase of clouds,whereas more 4-nitrophenol than expected from physico-chemical data can be found in the gas phase owing toextensive binding to particles. In view of the watersolubilities and the expected occurrence in the vapour

phase, wet deposition of nitrophenols from air to surfacewaters and soil is to be expected. The majortransformation pathway for 2-nitrophenol emitted to thetroposphere should be rapid nitration to 2,4-dinitro-phenol, whereas the major portion of airborne 4-nitro-phenol is expected to be particle bound and thereforeonly to a minor extent available for photochemicalreactions. Most of the 4-nitrophenol should be washedout from air by wet and dry deposition. Nitrophenols arenot considered to contribute directly to the depletion ofthe stratospheric ozone layer or to global warming.Measured half-lives for the photochemical decomposi-tion of 4-nitrophenol in water ranged from 2.8 to13.7 days. Numerous studies on the biodegradation of2- and 4-nitrophenol indicate the isomers to be inher-ently biodegradable in water under aerobic conditions.Mineralization of nitrophenols under anaerobic condi-tions requires extended adaptation of microbial commu-nities.

Measured coefficients of soil sorption (Koc) in therange of 44–530 indicate a low to moderate potential forsoil sorption. Nitrophenols released to soil should bebiodecomposed under aerobic conditions. Infiltrationinto groundwater is expected only under conditionsunfavourable to biodegradation. For 2- and 4-nitrophe-nol, measured bioconcentration factors ranging from 11to 76 indicate a low potential for bioaccumulation.

There is only limited information concerning thetoxicological profiles of 2- and 4-nitrophenol. In experi-mental animals given 4-nitrophenol orally, intravenously,or intraperitoneally, most of the applied dose wasexcreted via the urine within 24–48 h as glucuronide andsulfate conjugates, while only very small amounts wereexcreted via faeces or as unchanged 4-nitrophenol. Thepercentages of glucuronide and sulfate conjugates wereshown to be species and dose dependent. After oraldosing in rabbits, 4-nitrophenol undergoes reduction top-aminophenol as well as glucuronidation and sulfation.The available data from in vivo and in vitro studies givean indication for dermal uptake of 4-nitrophenol. Thedata for 2-nitrophenol are very limited. However, basedon the available data, a comparable metabolic transfor-mation is assumed. Bioaccumulation of 2- and 4-nitro-phenol in organisms is not to be expected owing to theirrapid metabolism and excretion.

In acute studies, 4-nitrophenol is harmful after oraluptake and was found to be more toxic than 2-nitrophe-nol. A dose-dependent increase in the formation ofmethaemoglobin was seen in cats after oral exposure to2-nitrophenol and in rats after exposure by inhalation to4-nitrophenol. After repeated exposure to 4-nitrophenol,the formation of methaemoglobin was shown to be the

Mononitrophenols

5

most critical end-point for exposure by inhalation and isassumed to be relevant for oral exposure too. Othernoted effects included decreases in body weight gain,differences in organ weights, focal fatty degeneration ofthe liver, and haematological changes. For these effects,it was not possible to identify a clear dose–response orreliable no-observed-(adverse-)effect levels (NO(A)ELs).

2-Nitrophenol is slightly irritating to the skin butnon-irritating to the eye. The substance proved to haveno sensitizing effects in a Buehler test. Based on validstudies with experimental animals, irritating effects onskin and eye are assumed for 4-nitrophenol. In a guinea-pig maximization test, 4-nitrophenol was considered asslightly sensitizing. In humans, a possible sensitizationafter contact with 4-nitrophenol cannot be excluded,especially as skin sensitization has been found in patchtests on factory workers who may have been exposed to4-nitrophenol.

Neither of the two isomers of nitrophenol has beenfully tested for genotoxicity. Insufficient data are avail-able on 2-nitrophenol to allow any conclusions to bemade about its possible mutagenicity. More mutageni-city studies are available for 4-nitrophenol, althoughsome were inadequately reported. There is evidence tosuggest that 4-nitrophenol can cause chromosomalaberrations in vitro . In the absence of any in vivomutagenicity studies in mammals, it is not possible toconclude whether or not the mutagenic potential of 4-nitrophenol is expressed in vivo.

In mice, the dermal application of 4-nitrophenol for78 weeks gave no indication of carcinogenic effects. Inanother study with mice, which has several limitations,no skin tumours were noted after dermal application of 2-or 4-nitrophenol over 12 weeks. Carcinogenicity studiesusing the oral or inhalation routes were not available foreither of the isomers.

For 4-nitrophenol, the available data gave noevidence of specific or statistically significant reproduc-tive or developmental toxicity effects after dermal or oralapplication to rats and mice. In an oral study with rats, 2-nitrophenol induced developmental effects in theoffspring only at doses that also produced maternaltoxicity. However, in these studies, the fetuses were notexamined for internal malformations.

The database for 2-nitrophenol is extremely limited,and the database for 4-nitrophenol is insufficient forderiving reliable NO(A)EL values. Therefore, at present,no tolerable daily intakes (TDIs) or tolerable con-centrations (TCs) can be derived for either 2- or 4-nitro-phenol.

From valid test results available on the toxicity of2- and 4-nitrophenol to various aquatic organisms,nitrophenols can be classified as substances exhibitingmoderate to high toxicity in the aquatic compartment.The lowest effect concentrations found in chronicstudies with freshwater organisms (Scenedesmussubspicatus, 96-h EC50: 0.39 mg 2-nitrophenol/litre;Entosiphon sulcatum, 72-h minimum inhibitory concen-tration, or MIC: 0.83 mg 4-nitrophenol/litre) were 40–50 times higher than maximum levels determined in adensely populated and highly industrialized Asian riverbasin (0.0072 mg 2-nitrophenol/litre and 0.019 mg 4-nitrophenol/litre). Therefore, despite biotic and photo-chemical decomposition, nitrophenols emitted to watercould pose some risk to sensitive aquatic organisms,particularly under surface water conditions not favour-ing both elimination pathways. Because of their usepatterns and release scenarios, it is likely that nitrophe-nols pose only a minor risk to aquatic organisms.

The available data indicate only a moderate toxicitypotential of nitrophenols in the terrestrial environment.From calculations of the toxicity exposure ratio (TER) ofnitrophenols from the degradation of pesticides, only aminor risk for organisms in this compartment is to beexpected, even under a worst-case scenario.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

2-Nitrophenol (CAS No. 88-75-5; 2-hydroxy-1-nitrobenzene, o-nitrophenol) and 4-nitrophenol (CASNo. 100-02-7; 4-hydroxy-1-nitrobenzene, p-nitrophenol)share the empirical formula C6H5NO3. Their structuralformulas are shown below.

OH

NO2

OH

NO2

2-nitrophenol 4-nitrophenol

Technical-grade 2- and 4-nitrophenol from theGerman producer have a typical purity of >99%. Namedimpurities are the corresponding isomer for each product(0.3%) and traces of 3-nitrochlorobenzene (<0.05%).Polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/


6

PCDF) and tetrachlorodibenzo-p-dioxin/dibenzofuran(TCDD/TCDF) isomers were not detected at detectionlimits between 0.1 and 0.4 :g/kg product (BUA, 1992).

The pure nitrophenol isomers form pale yellow toyellow crystals at room temperature. The substances arecharacterized by the physicochemical properties given inTable 1 (Sax & Lewis, 1987).

Table 1: Physicochemical properties of 2- and 4-nitrophenol.

Parameter 2-Nitrophenol 4-Nitrophenol

Molecular mass(g/mol)

139.11 139.11

Melting point (°C) 44–45 (1)(2)(3) 113–114 (1)(2)(3)

Boiling point (°C) 214–217 (1) 279(decomposition) (3)

Vapour pressure(kPa)

6.8 × 10–3 (19.8 °C) (4)

3.2 × 10–6

(20 °C) (5)

Water solubility(g/litre)

1.26(20 °C) (4)

12.4(20 °C) (6)

n-Octanol/waterpartition coefficient(log Kow)

1.77–1.89 (7) 1.85–2.04 (7)

Dissociation constant(pKa)

7.23 (21.5 °C) (8)

7.08(21.5 °C) (8)

Ultraviolet spectrum 8max (water):230; 276 nm;log ,max: 3.57;3.80 (9)

8max (methanol):no absorptionmaxima #290 nm(9)

Conversion factors 1 mg/m3 = 0.173 ppmv1 ppmv = 5.78 mg/m3

References: (1) Budavari et al. (1996); (2) Booth (1991);(3) Verschueren (1983); (4) Koerdel et al. (1981);(5) Sewekow (1983); (6) Andrae et al. (1981); (7) BUA (1992);(8) Schwarzenbach et al. (1988); (9) Weast (1979)

Additional physicochemical properties formononitrophenols are presented in the InternationalChemical Safety Card (ICSC 1342) reproduced in thisdocument.

3. ANALYTICAL METHODS

The nitrophenol isomers are usually determined bygas chromatography combined with mass spectrometricdetection, flame ionization detection, electron capturedetection, or nitrogen-sensitive detection, which aregenerally applied after derivatization (BUA, 1992; Nick &Schoeler, 1992; Geissler & Schoeler, 1994; Harrison et al.,

1994; Luettke & Levsen, 1994; Mussmann et al., 1994).For liquid samples (water, urine, blood), high-performance liquid chromatography in combination withconcentration-gradient elution (acetonitrile/methanol orammonium acetate, acetic acid with potassium chloride/methanol) and ultraviolet or electrochemical detection,which can be carried out without derivatization, is alsoused (BUA, 1992; Nasseredine-Sebaei et al., 1993; Ruanaet al., 1993; Paterson et al., 1996; Pocurull et al., 1996;Thompson et al., 1996). The separation of the differentisomers is carried out either by steam distillation (BUA,1992) or by the formation and subsequent extraction ofdifferent ion pairs (León-González et al., 1992).

The following enrichment techniques are used(BUA, 1992; see also review by Puig & Barcelo, 1996):

# solid-phase adsorption with thermal or liquidextraction for air and water samples (Luettke &Levsen, 1994; Mussmann et al., 1994)

# liquid/liquid extraction after derivatization for watersamples (initial purification by acid/basefractionation of highly polluted samples, increasedrecovery rates with continuous extractionmethods) (León-González et al., 1992; Nick &Schoeler, 1992; Geissler & Schoeler, 1994; Harrisonet al., 1994)

# liquid extraction with acid/base fractionation orsolid-phase enrichment and subsequentdesorption following aqueous extraction for soilsamples (Vozñáková et al., 1996)

# acid hydrolysis of the glucuronide withsubsequent derivatization for blood and urinesamples or denaturation (Nasseredine-Sebaei et al.,1993; Thompson et al., 1996).

The detection limits are <10 ng/m3 for air, 0.03–10 :g/litre for water, and 200–1600 :g/kg for soil. Adetection limit for the determination of the nitrophenolisomers in biological materials was given only for ratliver perfusate (0.5–1 mg/litre; Thompson et al., 1996).

4. SOURCES OF HUMAN AND

There are no known natural sources of the nitro-phenol isomers.

Mononitrophenols

7

Within the European Union, 2- and 4-nitrophenolare produced mainly by three companies. Six other largemanufacturers are known in the USA and Japan (as of1989). In 1983, the production volume for WesternEurope was estimated at about 6400 t 2-nitrophenol andabout 20 500 t 4-nitrophenol. In 1988–89, the Germanproduction volumes originating from one manufacturerwere approximately 500 t 2-nitrophenol and about 2000 t4-nitrophenol, with about 20 t of each being exported.Both 2- and 4-nitrophenol are intermediates in thesynthesis of azo dyes and a number of pesticides, mainlyinsecticides (2-nitrophenol: carbofuran, phosalon; 4-nitrophenol: parathion, parathion-methyl, fluorodifen)and, to a lesser extent, herbicides (4-nitrophenol:nitrofen, bifenox). The corresponding aminophenols thatare gained by reduction are used as a photographicdeveloper (2-aminophenol) and as an intermediate in thesynthesis of the tuberculostatic 4-aminosalicylic acidand the analgesic 4-acetaminophenol (paracetamol) (4-aminophenol) (see also Booth, 1991). In the 1980s, theproduction volumes for 2- and 4-nitrophenol showed adecreasing tendency in Germany as a result of changesin and termination of the production of some organo-phosphorus pesticides.

The releases of 2- and 4-nitrophenol during pro-duction and processing at the only German manufacturerappear to be of minor importance. In 1988–89, about2.5 kg 2-nitrophenol and 10 kg 4-nitrophenol wereemitted to air, and #93 kg 2-nitrophenol and <64 kg 4-nitrophenol were emitted to surface water.

For 1996, the following releases of 2- and 4-nitro-phenol to the environment were reported by manufac-turers in the USA (TRI, 1998):

# 2-nitrophenol: from three manufacturers (oneproduction site each) with production volumesbetween 450 and 45 000 kg/year, total releases of 15kg to air and 23 kg into water were reported.

# 4-nitrophenol: from three manufacturers (sixproduction sites) with production volumes of45–450 kg/year up to 45 000–450 000 kg/year, atotal release of 420 kg to air was reported. Data onreleases into water were not given.

2-Nitrophenol and 4-nitrophenol have beendetected in the exhaust gases of light-duty gasoline anddiesel vehicles. Depending on the motor load, theexhaust concentrations of the isomers were <50 :g/m3

exhaust gas (idle) and about 1000 :g 4-nitrophenol/m3

and 2000 :g 2-nitrophenol/m3 (driving at constantvelocity) (Nojima et al., 1983; Tremp et al., 1993). Aregulated three-way catalytic converter reduced thenitrophenol emissions to about 8% at high motor load

and to about 2% at normal motor load (Tremp et al.,1993). A rough estimation combining the above-mentioned exhaust gas concentrations with estimationsof the total exhaust gas volumes from vehicle traffic forGermany resulted in an airborne nitrophenol load of atleast several tonnes per year from this source (BUA,1992). Data concerning nitrophenol releases from othercombustion processes (heating, burning of refuse) werenot identified.

From laboratory experiments, there is some

evidence that 2- and 4-nitrophenol are generated in theatmosphere during the photochemical degradation ofaromatic compounds such as benzene and toluene in thepresence of nitric oxide or hydroxyl radicals and nitrousdioxide. These results were at least partly obtained inmodel experiments with unrealistically high nitric oxideconcentrations, and there are competing reactions with-out nitrophenol formation for which the rate constant isnot known (BUA, 1992). However, smog chamberexperiments confirmed the formation of nitrophenolisomers during irradiation (Leone & Seinfeld, 1985;Leone et al., 1985). Recent cloud water model experi-ments showed that 2- and 4-nitrophenol are also formedfrom the reaction of phenol with nitrogen pentoxide ormonochloronitrogen dioxide, especially under alkalineconditions (Scheer et al., 1996). Estimations of thecontribution of photochemically formed nitrophenols tototal emissions into the atmosphere are not possible withthe available data.

Significant releases of 4-nitrophenol into thehydrosphere may occur from the hydrolytic degradationof the insecticides parathion and parathion-methyl and— although to a lesser extent — from the photolyticdegradation of the herbicides nitrofen and bifenox.Quantification of releases is not possible with the avail-able data. Furthermore, a considerable portion of air-borne nitrophenols, especially 4-nitrophenol, can bereleased to the hydrosphere and the geosphere by wetand dry deposition (see section 5) (Herterich & Herr-mann, 1990; Luettke et al., 1997). Numerous studiesconcerning the concentrations of 2- and 4-nitrophenol inwet deposition samples are available (see section 6.1).From precipitation data (average 746 mm rain per year forland masses, according to Baumgartner & Liebscher,1990) and the measured concentrations of 2- and 4-nitrophenol in rainwater, the release of nitrophenols viarain can be estimated to be at least in the order of severalthousand tonnes per year on a global basis.

The application of the herbicides nitrofen andbifenox, which are photolytically degraded to 4-nitro-phenol in aqueous solutions, may especially lead toemissions into the geosphere and the biosphere. Further,nitrophenol-contaminated rain, snow, and other wet and


8

dry deposition may contribute to nitrophenol levels insoils. Data concerning the release of nitrophenols intothe biosphere are not available.

5. ENVIRONMENTAL TRANSPORT,DISTRIBUTION, AND TRANSFORMATION

Environmental releases of nitrophenols are mostlyto ambient air, surface waters, and — to a smaller extent— soil. Using a non-steady-state equilibrium model, thefollowing distribution of 4-nitrophenol in different envi-ronmental compartments was predicted: air, 0.0006%;water, 94.6%; sediment, 4.44%; soil, 0.95%; biota,0.000 09% (Yoshida et al., 1983). The distribution pat-terns of 2- and 4-nitrophenol sprayed on a natural soil ina standardized terrestrial ecosystem were determined viaradiotracer technique (14C). Of the applied radioactivity(2-nitrophenol/4-nitrophenol), 49.45%/20.01% wasrecovered in air, 27.38%/40.21% in soil (includinganimals), 12.73%/7.57% in plants, and 0.05%/0.02% inleachate (Figge et al., 1985). Distribution of 4-nitrophenolin a terrestrial microcosm chamber with artificial soillargely corresponded to this result (Gile & Gillett, 1981).Owing to the expected decomposition within the incuba-tion periods of 30 and 28 days, respectively, it can beassumed that most of the recovered radioactivity referredto breakdown products of the applied nitrophenols.

In volatility experiments conducted according toOrganisation for Economic Co-operation and Develop-ment (OECD) guidelines, half-lives of 2-nitrophenol inwater ranged from 14.5 to 27.3 days, indicating a slowrate of volatilization (Koerdel et al., 1981; Rippen et al.,1984; Scheunert, 1984; Schoene & Steinhanses, 1984).Measurements concerning the partitioning between thegas and liquid phases of clouds during different rainevents showed that 2-nitrophenol is enriched in theliquid phase to a larger extent than would be predictedfrom its water solubility and vapour pressure. On theother hand, 4-nitrophenol is extensively adsorbed toparticles. Therefore, elevated levels of this isomer aredetected in the gaseous phase of clouds (Luettke et al.,1997). From the available data, a significant volatilizationof 4-nitrophenol from water to air is not expected. Sincenitrophenols dissociate in aqueous solution, volatiliza-tion may further decrease with increasing pH in surfacewaters. This leads to the conclusion that dry and wetdeposition of nitrophenols from air to surface waters andsoil are to be expected. The occurrence of this partitionmechanism is supported by the detection of 2- and 4-nitrophenol in rainwater and wet deposition samples (seesection 6.1).

From experimental results on direct photodegrada-tion (Koerdel et al., 1981) and the atmospheric photo-oxidation by hydroxyl radicals (Zetzsch et al., 1984), bothpathways were found to be of minor importance for theremoval of 2-nitrophenol emitted to the troposphere.Thus, the major degradation pathway for airborne 2-nitrophenol should be rapid nitration to 2,4-dinitrophe-nol (Herterich & Herrmann, 1990; Luettke et al., 1997).The major portion of airborne 4-nitrophenol is expectedto be particle bound and therefore only to a minor extentavailable for photochemical reactions. Thus, most of the4-nitrophenol can be washed out from air by wet and drydeposition. Measured half-lives for the photochemicaldecomposition of 4-nitrophenol in water exposed tosunlight ranged from 2.8 to 13.7 days (Hustert et al.,1981; Mansour, 1996), being longer with increasing pH(Hustert et al., 1981). Traces of 4-aminophenol werefound as a photoproduct in river water (Mansour, 1996).In experiments conducted according to OECD guide-lines, Andrae et al. (1981) and Koerdel et al. (1981) foundno hydrolysis of 2- or 4-nitrophenol under environmentalconditions.

Numerous studies on the biodegradation of 2- and4-nitrophenol have been conducted. Standardized testson ready or inherent biodegradability provide data oflarge variability, indicating 2- and 4-nitrophenol to beinherently biodegradable under aerobic conditions(depending on origin and density of inoculum and theapplied test method) (see Table 2). Results from differenttests point to a possible bacteriotoxic effect of 4-nitrophenol at concentrations above 300 mg/litre (Gerike& Fischer, 1979; Nyholm et al., 1984; Kayser et al., 1994).

Non-standardized experiments with differentinocula (e.g., natural water, soil, sediment) showed thatmicrobial decomposition of nitrophenols can occur indifferent environmental compartments after adaptation ofthe microflora (Rubin et al., 1982; Subba-Rao et al., 1982;Van Veld & Spain, 1983; Spain et al., 1984; Ou, 1985;Hoover et al., 1986; Aelion et al., 1987; Wiggins et al.,1987). Time for acclimation and degree of removaldepended mostly on substance concentration, microbialpopulation, climate, and additional substrates.

Biotic degradation of nitrophenols under anaerobicconditions requires extended acclimatization of microbialcommunities. In tests with sewage sludge and sludgefrom the primary anaerobic stage of a municipal sewagetreatment plant, respectively, initial 2- and 4-nitrophenolconcentrations in the range of 96.5–579 mg/litre were notdegraded at all within 7–60 days (Wagner & Braeutigam,1981; Battersby & Wilson, 1989). Boyd et al. (1983)found complete anaerobic removal of 50 mg/litre for allnitrophenol isomers within 1 week, but complete

Mononitrophenols

9

Table 2: Biotic degradation of nitrophenols under aerobic conditions.

Test SubstanceConcentration(mg/litre)

Additionalcarbon source

Test duration(days)

Removal(%) Reference

Tests on ready biodegradability

AFNOR test 2-NP 40 OC no 14 16 Gerike & Fischer (1979)

Sturm test 2-NP 10 no 28 32 Gerike & Fischer (1979)

MITI I 2-NP 10050

nono

1414

07

Urano & Kato (1986)Gerike & Fischer (1979)

Closed bottle test 4-NP 2 no 28 55 Rott et al. (1982)

Modified OECDscreening test

4-NP 20 DOC no 28 1 Rott et al. (1982)

Shake flask test 4-NP 20 OC no 21 50 Means & Anderson(1981)

AFNOR test 4-NP 40 OC no 14 97 Gerike & Fischer (1979)

Sturm test 4-NP 10 no 28 90 Gerike & Fischer (1979)

MITI I 4-NP 50100100

nonono

141414

104.3

Gerike & Fischer (1979)Urano & Kato (1986)CITI (1992)

Tests on inherent biodegradability

Zahn-Wellens test 2-NP 400 no 14 80 Gerike & Fischer (1979)

SCAS test 2-NP 20 TOC13.3 TOC

yesyes

2424

107110

Broecker et al. (1984)

Bunch & Chambers 2-NP 5–10 yes 28 100 Tabak et al. (1981)

Coupled units test 2-NP 12 OC yes 7 61 Gerike & Fischer (1979)

Batch test, aerated 2-NP 200 COD no 5 97 Pitter (1976)

Zahn-Wellens test 4-NP 300100 DOC

nono

1428

8100

Andrae et al. (1981)Pagga et al. (1982)

Activated sludge test 4-NP 50100

nono

1919

10090

Means & Anderson(1981)

SCAS test 4-NP 20 TOC yes 332725/3912–15

>90>97100100

Marquart et al. (1984)Scheubel (1984)Ballhorn et al. (1984)Koerdel et al. (1984)

Coupled units test 4-NP 12 OC yes 7 100 Gerike & Fischer (1979)

Batch test, aerated 4-NP 200 COD no 5 95 Pitter (1976)

Abbreviations used: 2-NP = 2-nitrophenol; 4-NP = 4-nitrophenol; OC = organic carbon; DOC = dissolved organic carbon; TOC = totalorganic carbon; COD = chemical oxygen demand.

mineralization was demonstrated only if the incubationperiod was extended to 10 weeks. Anaerobic degradationeven of high initial nitrophenol concentrations wasfound by Tseng & Lin (1994), who observed >90%removal of 2- and 4-nitrophenol (350–650 mg/litre) in abiological fluidized bed reactor with three different kindsof wastewater. From the available results, a slowdegradation of nitrophenols under anaerobic conditionsby adapted microorganisms can be expected.

Soil sorption coefficients (Koc) were found toincrease with increasing organic carbon content. Mea-sured Koc values ranged from 44 to 230 (2-nitrophenol)

and from 56 to 530 (4-nitrophenol) (Boyd, 1982; Broeckeret al., 1984; Koerdel et al., 1984; Løkke, 1984; Marquart etal., 1984). Nitrophenols emitted to soil are expected to bebiodecomposed under aerobic conditions. Infiltrationinto groundwater is expected only under conditionsunfavourable for biodegradation (e.g., anaerobicconditions). From the available experimental results,nitrophenols have to be classified as substances with alow to moderate potential for soil sorption.

A low potential for bioaccumulation is to beexpected from the available valid test results for 2- and 4-nitrophenol. Bioconcentration factors ranging from 14.6


10

to 24.4 were determined for 2-nitrophenol in a semistatictest system with zebra fish (Brachydanio rerio) (Koerdelet al., 1984); in a flow-through experiment,bioconcentration factors ranged from 30 to 76 forcommon carp (Cyprinus carpio), including possibleconjugates (Broecker et al., 1984). In static tests,accumulation factors for 4-nitrophenol of 11 for thegreen alga Chlorella fusca after 1 day (Geyer et al., 1981)and 57 for the freshwater golden orfe (Leuciscus idusmelanotus) after 3 days of exposure were determined(Freitag et al., 1982). Zebra fish exposed in tap and riverwater nearly completely eliminated the accumulated 14C-4-nitrophenol within 48 h (Ensenbach & Nagel, 1991).Star fish (Pisaster ochraceus) and sea urchin(Strongylocentrotus purpuratus) eliminated 89% and36%, respectively, of injected 14C-4-nitrophenol (3.48 and3.70 mg/kg body weight, respectively) within 8 h(Landrum & Crosby, 1981).

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

From the concentrations in rainwater, the totalatmospheric nitrophenol pollution in Switzerland isestimated at about 1 :g/m3 (Leuenberger et al., 1988).Recent measurements in the air of remote areas in Europe(German Alps, Fichtelgebirge, Germany; Mount Brocken,Germany; Great Dun Fell summit, United Kingdom) gave2-nitrophenol concentrations between 0.8 and 25 ng/m3

and 4-nitrophenol levels between 1.2 and 360 ng/m3

(Herterich & Herrmann, 1990; Luettke et al., 1997). Thehigher atmospheric 4-nitrophenol levels are apparentlydue to the higher photochemical stability of this isomer(see section 5). 2-Nitrophenol was found in 22 out of 27samples of air (range 1–140 ng/m3; detection limit 1ng/m3) in Japan in 1994, and 4-nitrophenol was detectedin 27 out of 27 air samples (range 1–71 ng/m3; detectionlimit 1 ng/m3) (Japan Environment Agency, 1995). Instreet dust samples from a Japanese city, up to 3.9 mg 2-nitrophenol/kg and up to 42 mg 4-nitrophenol/kg weredetected (Nojima et al., 1983).

Numerous studies deal with the distribution, depo-sition, and degradation behaviour of airborne 2- and 4-nitrophenol in clouds and rainwater. 2-Nitrophenol levelsin rainwater and snow between 0.03 and 5.7 :g/litre and4-nitrophenol concentrations from <0.5 to 19 :g/litre aregiven in reports mainly from Germany and the USA(BUA, 1992). The recent measurements in rainwater,cloud water, and “fog” (water vapour; not further char-acterized) from rural and urban areas in Europe confirm

these concentration ranges (Herterich & Herrmann, 1990;Levsen et al., 1990; Richartz et al., 1990; Capel et al., 1991;Geissler & Schoeler, 1993; Levsen et al., 1993; Luettke etal., 1997). The 2-nitrophenol levels are mostly below orslightly above the detection limit (i.e., <0.1 :g/litre),whereas mean 4-nitrophenol concentrations of about 5:g/litre rainwater and cloud water and 20 :g/litre fogwater were detected. The nitrophenol concentrations infog are significantly higher than those in rainwater orcloud water owing to the higher droplet surface andlonger residence times of the droplets in air comparedwith rain. The lower concentrations of 2-nitrophenol inthe deposition samples compared with 4-nitrophenol arepresumably due to the lower photochemical stability ofthis compound (see section 5).

In the 1970s and early 1980s, the 2- and 4-nitro-phenol concentrations in the German and Dutch parts ofthe river Rhine and some of its tributaries were between0.1 and 1 :g/litre (BUA, 1992). 2-Nitrophenol and 4-nitrophenol were not detected in 177 samples of Japa-nese surface waters (detection limits 0.04–10 :g/litre) orin 177 sediment samples (detection limits between 0.002and 0.8 :g/kg) in 1978, 1979, and 1994 (Japan Environ-ment Agency, 1979, 1980, 1995). Whereas 4-nitrophenolwas not detected in 129 fish samples (detection limits0.005–0.2 :g/kg) in Japan in 1979 and 1994, 2-nitro-phenol was detected in 1 out of 129 saltwater fishsamples (detection limits 0.005–0.3 :g/kg) in 1994 (JapanEnvironment Agency, 1980, 1995). 2-Nitrophenolconcentrations between <0.15 :g/litre (detection limit)and 7.2 :g/litre and 4-nitrophenol levels between <0.1and 18.8 :g/litre were reported for the densely populatedand highly industrialized Malaysian Klang river basin in1990 and 1991 (Tan & Chong, 1993).

6.2 Human exposure

Workers may be exposed to 2- and 4-nitrophenolvia inhalation and skin contact during production andprocessing (mainly in the manufacturing of pesticides).However, data on nitrophenol concentrations at theworkplace were not identified.

Based on the measured concentrations given insection 6.1, an exposure of the general population tonitrophenols via the environment — predominantlythrough ambient air and drinking-water — cannot beexcluded.

4-Nitrophenol accumulates in fog, whereas 2-nitrophenol is rapidly photochemically transformed (seesections 5 and 6.1). The mean measured level of 4-nitrophenol in fog water is about 20 :g/litre.

Mononitrophenols

11

In Dutch drinking-water samples, maximum con-centrations of 1 :g 2-nitrophenol/litre and <0.1 :g4-nitrophenol/litre were reported in 1988 (BUA, 1992).Further data are not available.

7. COMPARATIVE KINETICS ANDMETABOLISM IN LABORATORY ANIMALS

AND HUMANS

Studies providing quantitative information on theabsorption, metabolism, or elimination of 2- or 4-nitro-phenol in humans were not identified.

7.1 2-Nitrophenol

There is only very limited information available for2-nitrophenol. In rabbits given a single dose of200–330 mg/kg body weight via gavage, most of theapplied dose (o80%) was excreted via the urine within 24h. About 71% was conjugated with glucuronic acid andabout 11% with sulfate, whereas about 3% was reducedto aminophenols (Robinson et al., 1951).

Skin permeation for 2-nitrophenol was shown inseveral in vitro experiments (Huq et al., 1986; Jetzer et al.,1986; Ohkura et al., 1990).

Although the information is limited, bioaccumula-tion of 2-nitrophenol in organisms is not to be expectedowing to its rapid metabolism and excretion.

7.2 4-Nitrophenol

After oral, dermal, intravenous, or intraperitonealapplication of 4-nitrophenol to several test species (rats,mice, dogs, or rabbits), most of the applied dose (up to95%) was excreted as glucuronide and sulfate conjugatesof 4-nitrophenol via the urine within 24–48 h. Only smallamounts were excreted via faeces (about 1%) or asunchanged 4-nitrophenol (about 2–7%). Thepercentages of glucuronide and sulfate conjugates wereshown to be species, sex, and dose dependent.Although sulfate conjugation dominates at lower 4-nitrophenol concentrations, the percentage ofglucuronide conjugates increases at higher dosages(Robinson et al., 1951; Gessner & Hamada, 1970;Machida et al., 1982; Rush et al., 1983; Snodgrass, 1983;Tremaine et al., 1984; Meerman et al., 1987). As shown inrabbits after oral dosing, 4-nitrophenol undergoesreduction to 4-aminophenol as well as glucuronidationand sulfation. Up to 14% of the administered dose wasdetected as amino compounds in the urine (Robinson etal., 1951). After intraperitoneal administration in mice, 4-

nitrophenyl glucoside was identified as a minormetabolite of 4-nitrophenol (about 1–2% of theadministered dose) (Gessner & Hamada, 1970).

For 4-nitrophenol, the pretreatment of laboratoryanimals with ethanol (induction of cytochrome P-450)resulted in a marked increase in hepatic microsomalhydroxylation. The 4-nitrocatechol then formed com-peted with 4-nitrophenol for the glucuronidation andsulfation pathways (Reinke & Moyer, 1985; Koop, 1986;McCoy & Koop, 1988; Koop & Laethem, 1992).

Specific investigations on dermal resorption undernon-occlusive conditions showed dermal uptake ofabout 35% and 11% of the applied dose of 14C-4-nitro-phenol within 7 days in rabbits and dogs, respectively.Skin permeation for 4-nitrophenol was also shown inseveral in vitro experiments (Huq et al., 1986; Jetzer et al.,1986; Ohkura et al., 1990).

Owing to its rapid metabolism and excretion,bioaccumulation of 4-nitrophenol in organisms is not tobe expected.

8. EFFECTS ON LABORATORYMAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

For 2-nitrophenol, the oral LD50 is in the range of2830–5376 mg/kg body weight in rats (BASF AG, 1970;Vasilenko et al., 1976; Vernot et al., 1977; Koerdel et al.,1981) and 1300–2080 mg/kg body weight in mice(Vasilenko et al., 1976; Vernot et al., 1977). Clinical signsfollowing oral exposure were unspecific and includeddyspnoea, staggering, trembling, somnolence, apathy,and cramps. The macroscopic examination performed insome studies revealed congestion in liver and kidneysand ulcers of the stomach in high-dose rats. Theinhalation exposure of rats to an atmosphere saturatedwith the test substance at 20 °C for 8 h (no furtherinformation available) resulted in no mortality and nosigns of toxicity (BASF AG, 1970). In a limit test, thedermal LD50 for the rat was >5000 mg/kg body weight(Koerdel et al., 1981). In cats (two animals per dosegroup), the oral application of 2-nitrophenol (50, 100, or250 mg/kg body weight; no controls) resulted in a dose-dependent increase in methaemoglobin (6, 44, and 57%,respectively).1 One animal dosed with 250 mg/kg body

1 Methaemoglobin formation is discussed in greaterdetail in section 8.8.


12

weight died. No formation of methaemoglobin wasdetected after dermal application of a 50% solution of 2-nitrophenol in water to rabbits (dose not specified,exposure time 1 min to 20 h on the back or 20 h on theear) (BASF AG, 1970).

The oral LD50 of 4-nitrophenol is in the range of220–620 mg/kg body weight in rats (BASF AG, 1969;Vasilenko et al., 1976; Hoechst AG, 1977a; Vernot et al.,1977; Andrae et al., 1981) and 380–470 mg/kg bodyweight in mice (Vasilenko et al., 1976; Vernot et al., 1977).Clinical signs following oral exposure of rats wereunspecific and included tachypnoea and cramps, and themacroscopic examination performed in some studiesrevealed a greyish discoloration with dark red patches ofthe lungs. No mortality was observed in rats after singleexposure (head only) to 4700 mg/m3 (application as dust[sodium salt]; particle size not given) for 4 h. In four ofsix rats, a corneal opacity was observed at the end ofexposure, which persisted through the 14-dayobservation period. In two extra rats exposed to1510 mg/m3, the methaemoglobin concentrations werenot altered compared with controls. A determination ofmethaemoglobin concentrations after exposure to4700 mg/m3 was not performed (Smith et al., 1988). Inanother inhalation study with rats (exposure to anatmosphere saturated with the test substance at 20 °C for8 h; no further information available), no mortality andno signs of toxicity were seen (BASF AG, 1969). Thedermal LD50 for rats and guinea-pigs is $1000 mg/kgbody weight (Hoechst AG, 1977b; Eastman Kodak Co.,1980; Andrae et al., 1981). In contrast to 2-nitrophenol,no formation of methaemoglobin was noted in cats (twoanimals per dose group) after oral dosing with 100, 200,or 500 mg 4-nitrophenol/kg body weight. The mortalityrate was 0/2, 1/2, and 2/2, respectively (BASF AG, 1969).

8.2 Irritation and sensitization

From studies comparable to OECD Guidelines 404and 405, it can be concluded that 2-nitrophenol isslightly irritating to the skin but not to the eye (scoresnot given). In a Buehler test with guinea-pigs compa-rable to OECD Guideline 406, the substance showed noskin-sensitizing effects (Koerdel et al., 1981).

In a study performed according to US Food andDrug Administration (FDA) guidelines, non-dissolved 4-nitrophenol was slightly irritating to the skin (score 2 of8) (Hoechst AG, 1977c); in another study comparable toOECD Guideline 404, however, the non-dissolvedsubstance showed no skin-irritating effects (score 0 of 4)(Andrae et al., 1981). 4-Nitrophenol applied as a 10%solution to the eyes was slightly irritating in a testconducted according to FDA guidelines (scores not

given; Hoechst AG, 1977c). Results with the non-dissolved substance were either strongly irritating in atest conducted according to FDA guidelines (scores notgiven; Hoechst AG, 1977c) or slightly irritating in a testcomparable to OECD Guideline 405 (score 1–2 of 4;Andrae et al., 1981).

In a guinea-pig maximization test comparable toOECD Guideline 406, skin sensitization was shown in 5of 20 animals (Andrae et al., 1981).

Data on respiratory tract sensitization for 2- and 4-nitrophenol were not identified in the literature.

8.3 Short-term exposure

8.3.1 Oral exposure

The effect of 2-nitrophenol in rats was studied in a28-day study to evaluate OECD Guideline 407 (fiveanimals per sex per dose group; daily oral doses of 0, 22,67, or 200 mg/kg body weight via gavage). Food intakedecreased in high-dose males and in mid- and high-dosefemales, and final body weight decreased non-signifi-cantly in all dosed animals. The absolute liver and kid-ney weights were decreased in mid-dose animals, andthe relative testes weight increased in low- and mid-dosemales and decreased in high-dose males. In all dosedanimals, the relative and absolute weights of the adrenalglands increased. The haematological examination,clinical chemistry, and histopathological examination ofthe major organs and tissues did not give any indicationof a substance-related toxic effect in comparison withcontrols (Koerdel et al., 1981). Owing to insufficientdocumentation and the fact that there were minor effects(weight of adrenal glands) shown by all exposed animals,a reliable NO(A)EL cannot be deduced.

In a 28-day study that was also conducted to eval-uate OECD Guideline 407, Sprague-Dawley rats (10 persex per dose group) received daily oral doses of 0, 70,210, or 630 mg 4-nitrophenol/kg body weight via gavage.After dosing, locomotor inhibition, which lasted forabout 2 h, was seen in mid- and high-dose animals. Inmid-dose animals, 1/10 males died; in high-dose malesand females, the mortality rate was 4/10 and 6/10, respec-tively (specific signs of intoxication were not given). Inthe lowest dose group, the macroscopic examinationrevealed seven cases of pale liver, and the histo-pathological examination showed 14 cases of finelydispersed fatty degeneration. A focal fatty degenerationof the liver was also observed in 13/20 rats of the mid-dose group, but not in high-dose animals. However, itmust be noted that finely dispersed fatty degenerationwas also seen in 6/20 control animals. In 4/10 high-dose

Mononitrophenols

13

males but not females, a hydropic liver cell swelling wasnoted, and all high-dose rats that died before the end ofthe study showed vascular congestion of the liver. Aslight increase in the leukocyte count was seen at 210and 630 mg/kg body weight in males and females; theincrease was significant in high-dose females. In high-dose males, the alanine aminotransferase (ALAT)activity was significantly increased. Other substance-related effects in high-dose animals included increasednephrosis (two males and five females), testicularatrophy and inhibition of spermatogenesis (one and twomales, respectively), and follicular atresia in the ovaries(four females) (Andrae et al., 1981). Because of uncleareffects in the liver, a NO(A)EL cannot be deduced.

8.3.2 Inhalation exposure

8.3.2.1 2-Nitrophenol

In Sprague-Dawley rats (15 per sex per group), nomortality was observed after exposure to 0, 5, 30, or60 mg 2-nitrophenol vapour/m3 (“whole body” exposure;to generate the vapour, melted 2-nitrophenol was used)for 6 h/day, 5 days/week, over a period of 4 weeks.Except for squamous metaplasia of the epithelium liningthe maxilloturbinates and nasoturbinates in all high-doseanimals, the clinical and histopathological examinationsgave no consistent exposure-related effects. The met-haemoglobin values determined after the 11th exposurewere significantly increased only in low-dose animals(males: 1.0, 2.3, 1.8, and 1.6%; females: 2.0, 4.1, 2.1, and1.1%), but were within control values at the end of thestudy (Hazleton Lab., 1984).


No mortality was observed in male albino Crl:CDR

rats (10 per group) after exposure to 0, 340, or 2470 mg 4-nitrophenol dust/m3 (application as sodium salt; “headonly” exposure; mass median aerodynamic diameter[MMAD] 4.6–7.5 :m) for 6 h/day, 5 days/week, over aperiod of 2 weeks. Both exposure concentrationsresulted in signs of irritation (not further specified). Afterexposure to 340 and 2470 mg/m3, darker urine,proteinuria, elevated aspartate aminotransferase (ASAT)values, and a dose-dependent increase in methaemo-globin values were observed. These effects were stillevident after a 14-day recovery period; however, themethaemoglobin value was then still elevated in only 2/5high-dose animals. The methaemoglobin values were 0.2,0.87, and 1.53% after 10 exposures and 0.2, 0.13, and0.7% after 14 days’ recovery. The erythrocyte,haemoglobin, and haematocrit values decreased duringexposure but were elevated after the 14-day recoveryperiod. In treated rats, the urine volume decreased in adose-dependent manner during exposure and during the14-day recovery period. In high-dose animals, the

absolute spleen weight was significantly lower than thatof controls after 10 exposures, and the absolute/relativespleen and lung weights were significantly lower incomparison with controls at the end of the recoveryperiod. According to the authors, the biological signifi-cance of the changes in organ weights is unknownowing to the absence of corroborating pathologicaleffects (Smith et al., 1988).

In a second trial (exposure to 0, 30, or 130 mg/m3;MMAD 4.0–4.8 :m), both exposure concentrationsagain resulted in signs of irritation (not further speci-fied). Methaemoglobinaemia, an effect that was rever-sible within a 14-day recovery period, was seen only at130 mg/m3. The methaemoglobin values were 0.5, 0.3, and1.5% after 10 exposures and 0.4, 0.5, and 0.2% after 14days’ recovery. The gross and histopathologicalexamination revealed no adverse effects in any dosegroup. From these results, the authors of the studydecided upon a NO(A)EL of 30 mg/m3 (Smith et al., 1988).

Groups of Sprague-Dawley rats (15 per sex) wereexposed to 0, 1, 5, or 30 mg 4-nitrophenol dust/m3

(“whole body” exposure; MMAD 5.2–6.7 :m) for6 h/day, 5 days/week, over a period of 4 weeks. Theexposure resulted in no deaths, and no exposure-relatedeffects were noted in terms of haematology or clinicalchemistry values, gross examination, histopathology,and body or organ weights. In high-dose animals,unilateral and bilateral diffuse anterior capsular cataractswere observed. The methaemoglobin values determinedafter 2 weeks of exposure showed great variability andappeared to be unusually high (>3 %) in some unex-posed controls. However, the group total methaemo-globin value was increased at a concentration of5 mg/m3, which was significant in males and notsignificant in females (males: 0.8, 0.5, 2.2, and 1.1%;females: 1.3, 1.1, 2.0, and 1.0%) (Hazleton Lab., 1983).Therefore, a NO(A)EL of 5 mg/m3 can be derived for localeffects (cataracts), whereas the NO(A)EL for systemiceffects (formation of methaemoglobin) may be lower.

8.3.3 Dermal exposure

Data concerning short-term dermal exposure werenot identified in the literature.

8.4 Long-term exposure

In the literature, subchronic and chronic studiesare available only for 4-nitrophenol.

8.4.1 Subchronic exposure

In a 13-week gavage study with Sprague-Dawleyrats (20 per sex per dose group) given 0, 25, 70, or 140 mg4-nitrophenol/kg body weight in water 5 days/week,


14

premature deaths were seen in animals dosed with70 and 140 mg/kg body weight (1 male/1 female at70 mg/kg body weight and 15 males/6 females at140 mg/kg body weight); these were usually preceded byclinical signs, including pale appearance, languid behav-iour, prostration, wheezing, and dyspnoea, shortly afterdosing. The histopathological examination of theseanimals revealed minimal to moderately severe conges-tion in the lung, liver, kidney, adrenal cortex, and pitui-tary; in surviving animals, no treatment-related changescompared with controls were reported. A statementconcerning altered methaemoglobin values cannot begiven owing to a non-reliable analytical method (about13% in controls at week 7) (Hazleton Lab., 1989).Therefore, only a provisional NO(A)EL (changes in liver,kidneys, and lungs) of 25 mg/kg body weight can bederived from this study. The NO(A)EL based on theformation of methaemoglobin may be lower.

The dermal application of 4-nitrophenol to Swiss-Webster mice (10 per sex and dose group; given 0, 22,44, 88, 175, or 350 mg/kg body weight in acetone, 3 timesper week over 13 weeks) resulted in dose-dependentmortality as well as skin irritation/inflammation andnecrosis at $175 mg/kg body weight.1

8.4.2 Chronic exposure and carcinogenicity

In a long-term study with Swiss-Webster mice (50per sex per dose group), 4-nitrophenol in acetone wasapplied to the interscapular skin at doses of 0, 40, 80, or160 mg/kg body weight, 3 days/week for 78 weeks. Attermination of the study, the survival rates were 29/60,17/60, 26/60, and 24/60 for males and 35/60, 26/60, 33/60,and 27/60 for females. The increased mortality after 60weeks was due to a generalized amyloidosis (the severityof the amyloidosis was similar among dosed and controlanimals) and secondary kidney failure. The final meanbody weights of the dosed animals were similar to thoseof the controls. NTP (1993) stated that there were nosubstance-related neoplastic or non-neoplastic effectsassociated with the dermal administration of 4-nitro-phenol and that there was no evidence of a carcinogenicactivity of the substance in male or female mice.

In another study, which had several proceduraldeficiencies (only the skin was examined; only 12 weeksof exposure), no skin tumours were observed in31 female Sutter mice after dermal application of a 20%solution (25 :l of solution applied twice weekly) of 2- or4-nitrophenol in dioxane (Boutwell & Bosch, 1959).

8.5 Genotoxicity and related end-points

The available in vitro and in vivo genotoxicitystudies on 2- and 4-nitrophenol are summarized inTable 3.

2-Nitrophenol showed no mutagenicity in severallimited bacterial assays. From the available data, it is notpossible to draw any conclusions regarding its mutagen-icity.

For 4-nitrophenol, positive results were obtained inin vitro tests for chromosomal aberrations in mammaliancells. However, apart from one well-documented studypublished by NTP (1993), the other available assayswere inadequately reported. 4-Nitrophenol was shown tobe mutagenic in some but not all of the bacterial assays,whereas other studies (i.e., host-mediated bacterialassay, mouse lymphoma assay, unscheduled DNAsynthesis assay [apparently in vitro ], sister chromatidexchange assay, sex-linked recessive lethal [SLRL] assayin Drosophila) gave negative results. In the absence ofany in vivo mutagenicity studies in mammals, it is notpossible to conclude whether or not the mutagenicpotential of 4-nitrophenol is expressed in vivo.

8.6 Reproductive and developmentaltoxicity

8.6.1 Reproductive toxicity

In a valid two-generation study with groups of24 female and 12 male Sprague-Dawley rats carried outby Angerhofer (1985), 4-nitrophenol dissolved in ethanolwas applied dermally at doses of 0, 50, 100, or 250 mg/kgbody weight per day, 5 days/week. The F0 generationwas exposed over a period of 140 days before mating.Dosing of the F0 females continued throughoutbreeding, gestation, and lactation. Groups of 26 femalesand 13 males of the F1 generation were then exposed for168 days in the same manner as had been the F0 rats; thefemales were again exposed throughout breeding, gesta-tion, and lactation. Apart from dose-related signs of skinirritation (erythema, scaling, scabbing, and cracking) indosed animals, the gross and histopathological examina-tions provided no indication of significant adverseeffects. The calculated indices concerning fertility, gesta-tion, viability, and lactation were not different from thoseof controls. The testis to body weight ratios in the F0

generation were not affected, and histological lesionswere not observed in the testes. In a 28-day study in rats(see section 8.3.1), testicular atrophy and inhibition ofspermatogenesis were observed in some animals afteroral dosing at a level of 630 mg/kg body weight, but notat 210 mg/kg body weight.

1 Gulf South Research Institute, not dated; no furtherinformation available; results cited from NTP (1993).

Table 3: Genotoxicity of 2- and 4-nitrophenol in vitro and in vivo.

Resultsa

Species (test system) End-point Concentration range

Withoutmetabolicactivation

Withmetabolicactivation Remarks Reference

2-Nitrophenol (in vitro studies)

8 phage DNA Induction of DNA breakage 35 mg ! 0 Yamada et al. (1987)

Bacillus subtilis H17,M45

Recombination assay 0.01–0.5 mg/plate ! 0 Shimizu & Yano (1986)

SalmonellatyphimuriumTA1535, TA1537

Reverse mutations 0.003–2.5 mg/plate ! ! Koerdel et al. (1981); Haworth et al.(1983); Shimizu & Yano (1986)

SalmonellatyphimuriumTA1538

Reverse mutations 0.01–2.5 mg/plate ! ! Koerdel et al. (1981); Shimizu &Yano (1986)


Reverse mutations 0.0007–5 mg/plate ! ! Suzuki et al. (1983) also tested bothstrains in the presence of norharman,which also gave negative results

Chiu et al. (1978); Koerdel et al.(1981); Haworth et al. (1983); Suzukiet al. (1983); Shimizu & Yano(1986); Kawai et al. (1987); Dellarco& Prival (1989); Massey et al. (1994)

2-Nitrophenol (in vivo studies)

Drosophilamelanogaster

SLRL assay via feed (400 and 500ppm) or injection(2500 and 5000 ppm)

! Foureman et al. (1994)

4-Nitrophenol (in vitro studies)

8 phage DNA Induction of DNA breakage 35 mg ! 0 Yamada et al. (1987)


Recombination assay 0.01–5 mg/plate + 0 positive at 0.5 mg/plate Shimizu & Yano (1986)

Escherichia coliWP2uvrA

Gene mutation 0.001–2.5 mg/plate ! ! Hoechst AG (1980)

Escherichia coli K-12(Pol A1+/Pol1!), WP2(WP2, WP2uvrA,WP67, CM611,CM571)

Gene mutation 0.125–2 mg/plate ! 0 Rashid & Mumma (1986)

Escherichia coli Q13 DNA cell binding assay 7 or 70 mg + + positive at 70 mg Kubinski et al. (1981)

Saccharomycescerevisiaeade 2, trp 5

Mitotic gene conversion 2.9 mg/ml (+) 0 Fahrig (1974)

SalmonellatyphimuriumTA1535/pSK 1002

DNA damage (umu test) up to 0.75 mg/ml ! ! Nakamura et al. (1987)

Table 3 (Contd).

Resultsa





Reverse mutation 0.001–2.5 mg/plate + ! positive at $0.1 mg/plate Hoechst AG (1980)


Reverse mutation 0.01–5 mg/plate ! ! Andrae et al. (1981); Shimizu &Yano (1986)


Reverse mutation 0.125–2 mg/plate ! 0 Rashid & Mumma (1986)


Reverse mutation 0.0007– 5 mg/plate ! ! Suzuki et al. (1983) also tested bothstrains in the presence of norharman,which also gave negative results

McCann et al. (1975); Hoechst AG(1980); Andrae et al. (1981); Haworthet al. (1983); Suzuki et al. (1983);Shimizu & Yano (1986); Kawai et al.(1987); Dellarco & Prival (1989);Massey et al. (1994)


Reverse mutation 0.001–5 mg/plate ! ! McCann et al. (1975); Hoechst AG(1980); Andrae et al. (1981); Haworthet al. (1983); Shimizu & Yano (1986)

Rat hepatocytes DNA damage (alkalineelution)

42–417 mg (+) 0 Weakly positive at $97 mg Storer et al. (1996)

Rat hepatocytes DNA repair 4.2–417 mg ! 0 Andrae et al. (1981)

Chinese hamster ovary(CHO) cells

Chromosomal aberration without S9 mix:0.1–0.5 mg/mlwith S9 mix:1.25–2 mg/ml

! + NTP (1993)

Chinese hamster ovary(CHO) cells

Sister chromatid exchange without S9 mix:0.00017–0.025mg/mlwith S9 mix:0.05–1.5 mg/ml

! ! NTP (1993)

Mouse lymphomaassay L5178Y TK+/–

cells

Forward mutation without S9 mix:0.7–1.5 mg/mlwith S9 mix:0.0001–0.03 mg/ml

! ! Oberly et al. (1984)

Mouse lymphomaassay L5178Y TK+/–

cells

Forward mutation 0.06–0.78 mg/ml 0 ! Amacher & Turner (1982)

Rat hepatocytes Unscheduled DNAsynthesis

0.00007–0.14 mg/ml ! 0 Probst et al. (1981)

Human lymphocytes Chromosomal aberration not given + No data about metabolic activation;validity cannot be judged(documentation and study designinsufficient for assessment) lowest positive concentration: 1.4 mg/ml

Huang et al. (1996)

Table 3 (Contd).

Resultsa




Human lymphocytes Chromosomal aberration 0.001–0.3 mg/ml + No data about metabolic activation;validity cannot be judged(documentation and study designinsufficient for assessment)

Huang et al. (1995)

Human fibroblasts (WI-38)

DNA repair 0.14–139 mg + No data about metabolic activation;validity cannot be judged(documentation insufficient forassessment)positive at $13.9 mg

Poirier et al. (1975)

4-Nitrophenol (in vivo studies)

NMRI mice Host-mediated assay (testerstrains Salmonellatyphimurium G 46 andSerratia marcescens a 21Leu–)

single subcutaneousinjection of 75 mg/kgbody weight

! application of test substanceimmediately after the bacteria had beeninjected into the abdominal cavities; testduration 3 h

Buselmaier et al. (1972)

Drosophilamelanogaster

SLRL assay via feed (1000, 2500,6000, or 7500 ppm)or injection (1000 or1500 ppm)

! Zimmering et al. (1985); Fouremanet al. (1994)

a !, negative; +, positive; (+), weakly positive; 0, not tested.


18

8.6.2 Developmental toxicity


In a range-finding study with Charles River COBS©

CD© rats (five dams per group; application of 0, 50, 125,250, 500, or 1000 mg/kg body weight via gavage from day6 to day 15 of gestation; uterine examination on day 20),dose levels of 500 and 1000 mg/kg body weight causedsigns of maternal toxicity (transient but dose-relateddecrease in weight gain early during treatment). Onehigh-dose animal died, but no cause of death could bedetermined. Other clinical findings included darklycoloured urine at $250 mg/kg body weight and yellowstaining of haircoat (at the nose, mouth, anogenital area)at $125 mg/kg body weight; the necropsy findings gaveno biologically meaningful differences in survivingdams. At the highest dose level of 1000 mg/kg bodyweight, a slight but statistically significant (also com-pared with historical controls) increase in group meanpost-implantation losses (13.8% versus 8.2% in controls)and mean early resorptions (2.3 versus 1.2 in controls)was seen. No effects were observed on the number ofviable fetuses, implantations, or corpora lutea(International Research and Developmental Corporation,1983).


In both studies cited below, a complete examina-tion of the pups for possible teratogenic effects was notperformed. In addition, owing to limitations of thesestudies (i.e., use of only one dose group or exposure to amixture), reliable NO(A)EL values cannot be derived.

In a study performed by Booth et al. (1983), groupsof 50 female CD-1 mice received daily oral doses of400 mg 4-nitrophenol/kg body weight via gavage fromday 7 to day 14 of gestation. The survival rate inpregnant mice (n = 36) was 81% versus 100% in controls,and dosed animals showed less maternal weight gain. Nochanges were observed in the reproductive index (ratiobetween survivors delivered and pregnant survivors).The average number of live pups per litter was slightlydecreased, but 4-nitrophenol produced no grossabnormalities.

Kavlock (1990) studied the developmental toxicityof 4-nitrophenol in Sprague-Dawley rats. The substance(dissolved in a mixture of water, Tween 20, propyleneglycol, and ethanol [4:4:1:1]) was applied via gavage togroups of 12–13 animals at doses of 0, 100, 333, 667, or1000 mg/kg body weight on day 11 of gestation. End-points concerning maternal toxicity included signs oftoxicity, mortality, body weight gain, and the number ofimplantation scars in the uteri at weaning. In the off-spring, viability, body weight on postnatal days 1–6,

overt malformations, and perinatal loss were recorded. Indams, the mortality was increased at a dose level of$667 mg/kg body weight; at a dose level of $333 mg/kgbody weight, the litter size on postnatal days 1 and 6was non-significantly decreased.

8.7 Immunological and neurologicaleffects

There are no studies available dealing specificallywith immunological or neurological effects. There is anindication from an in vitro study that 4-nitrophenol mayact as a suppressor of cell-mediated immune response(Pruett & Chambers, 1988). However, the biologicalsignificance is uncertain.

8.8 Methaemoglobin formation

Methaemoglobin formation by 2-nitrophenol and4-nitrophenol has been tested in several studies usingdifferent species, routes, and durations of applications.An overview is given in Table 4.

2-Nitrophenol clearly leads to the formation ofmethaemoglobin in a dose-dependent manner in cats(BASF AG, 1970), the most sensitive species. The lowestdose tested, 50 mg/kg body weight, produced increasedmethaemoglobin levels. In inhalation experiments in rats,elevated methaemoglobin levels were observed at anexposure level of 5 mg/m3; methaemoglobin levels wereless elevated at exposure levels of 30 and 60 mg/m3

(Hazelton Lab., 1984).

4-Nitrophenol, in contrast, did not lead to methae-moglobin formation in cats at concentrations up to500 mg/kg body weight (BASF AG, 1969). In rats, at highconcentrations in inhalation experiments, the met-haemoglobin-forming capacity seemed to be very low(1.5% at 2470 mg/m3). In conclusion, 4-nitrophenol mayinduce methaemoglobin formation, but the effect seemsto be rather weak, without clear dose–response.

9. EFFECTS ON HUMANS

Naniwa (1979) performed patch tests with 4-nitrophenol, 4-aminophenol, 2-amino-4-chlorophenol, 3'-chlorodiphenylamine-2-carboxylic acid, and 4-dichloro-nitrobenzene (0.1, 0.5, or 1% in petrolatum) on31 employees probably exposed to these chemicals in achemical factory and on 5 control persons. In fouremployees, a positive reaction to 4-nitrophenol wasobserved, although none of these persons reactedpositively to all three tested concentrations. All four

Mononitrophenols

19

Table 4: Methaemoglobin formation by 2-nitrophenol and 4-nitrophenol.

Species(strain/number/dose/sex) Route

Frequency/duration Dose

Results(% metHb) Reference

2-Nitrophenol

cat2sex not given

oral 1 x 50 mg/kg body weight100250

64457

BASF AG (1970)

rabbitnumber and sexnot given

dermal 1 x 50% solutionin water

no increase BASF AG (1970)

ratSprague-Dawley15 m/15 f

inhalation 6 h/day5 days/week4 weeks

0 mg/m3

53060

m f

1.0 2.02.3 4.11.8 2.11.6 1.111th day of treatment

Hazleton Lab.(1984)

4-Nitrophenol

cat2sex not given

oral 1 x 100 mg/kg body weight200500

no increase BASF AG (1969)


oral 5 days/week13 weeks

0 mg/kg body weight2570140

analytical method notreliable (13% in controls)

Hazleton Lab.(1989)

ratCrl:CDR 10 m


0 mg/m3

3402470

0.2 0.20.87 0.131.53 0.7end of treatment andafter 14 days of recovery

Smith et al. (1988)

ratCrl:CDR 10 m


0 mg/m3

30130

0.5 0.40.3 0.51.5 0.2end of treatment andafter 14 days of recovery

Smith et al. (1988)



0 mg/m3

1530

m f

0.8 1.30.5 1.12.2 2.01.1 1.0 after 2 weeks of exposure,values unusually high insome control animals

Hazleton Lab.(1983)

Abbreviations used: m = male; f = female; metHb = methaemoglobin.

employees also reacted positively to 2-amino-4-chloro-phenol, which was shown to be a strong sensitizer.Therefore, 2-amino-4-chlorophenol may act as theprimary allergen, and the effects observed with 4-nitro-phenol may be due to cross-sensitization.

In 27 patients primarily sensitized to 1-chloro-2,4-dinitrobenzene, no cross-sensitization due to 4-nitro-phenol (1–2% in petrolatum) was observed. In addition,15 patients with a chloramphenicol allergy failed to reactto 4-nitrophenol (Eriksen, 1978).

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

10.1 Aquatic environment

Experimental test results for the most sensitive

species are summarized in Table 5. Additional data onthe toxicity of 2- and 4-nitrophenol to aquatic organisms


20

Table 5: Aquatic toxicity of nitrophenols.

Most sensitive species(test method/end-point) Substance

Effective concentration(mg/litre) Reference

Bacteria

Pseudomonas putida

(cell multiplication inhibition test)2-NP4-NP

16-h MICa: 0.916-h MIC: 4.0

Bringmann & Kuehn (1977)

Protozoa

Entosiphon sulcatum

(cell multiplication inhibition test)2-NP4-NP

72-h MIC: 0.4072-h MIC: 0.83

Bringmann (1978); Bringmann etal. (1980)

Algae

Scenedesmus subspicatus

Chlorella vulgaris

(cell multiplication inhibition test)

2-NP2-NP4-NP

96-h EC50: 0.396-h EC50: 1.536-h EC50: 6.97

Broecker et al. (1984); Kramer etal. (1986)

Invertebrates

Moina macrocopa (acute)(immobilization)Daphnia magna (long-term)(immobilization/reproduction)Barentsia matsushimana (marine)(growth of germinated spores)

2-NP4-NP 2-NP4-NP 4-NP4-NP

3-h LC50: 1.93-h LC50: 1.321-day LOEC: 1.021-day NOEC: 1.349-day EC50: 0.2149-day ECm

b: 0.03

Yoshioka et al. (1985)

Koerdel et al. (1984)

Kuehn et al. (1988)Scholz (1986)

Fish

Cyprinus carpio (static)Oncorhynchus mykiss (static)Oncorhynchus mykiss (flow-through)

2-NP4-NP4-NP

96-h LC50: 36.696-h LC50: 3.896-h LC50: 7.93

Lang et al. (1996)Howe et al. (1994)

Abbreviations used: 2-NP = 2-nitrophenol; 4-NP = 4-nitrophenol.a MIC = minimum inhibitory concentration. b ECm = minimal effective concentration.

are cited in BUA (1992). Among all tested organisms, theprotozoan Entosiphon sulcatum and the green algaScenedesmus subspicatus proved to be most sensitive inchronic cell multiplication inhibition tests with fresh-water species. Daphnia magna exhibited a 21-daylowest-observed-effect concentration (LOEC) of 1.0 mg2-nitrophenol/litre in the Daphnia reproduction test(Koerdel et al., 1984). The entoproct Barentsiamatsushimana was the most sensitive marine inverte-brate species tested, exhibiting a 49-day EC50 value of0.21 mg 4-nitrophenol/litre and a minimal effectiveconcentration (ECm) of 0.03 mg/litre (end-point: growthof germinated spores) (Scholz, 1986). Freshwater fishshowed less sensitivity. The lowest 96-h LC50 value of3.8 mg 4-nitrophenol/litre was determined for rainbowtrout (Oncorhynchus mykiss) (Howe et al., 1994). Themeasured no-observed-effect concentration (NOEC) forbehavioural changes in a 28-day flow-through test withzebra fish was 2 mg 2-nitrophenol/litre (Broecker et al.,1984). After prolonged exposure of zebra fish to 4-nitrophenol, minor morphological alterations of the liver,even at a concentration of 0.1 mg/litre, were observed.At 1 and 5 mg/litre, about 25% of the animals showedsymptoms of degenerative transformation of the livertissue (Braunbeck et al., 1989).

10.2 Terrestrial environment

The toxicity of 2- and 4-nitrophenol on higherplants according to OECD Guideline 208 was tested inindependent studies. After incubation of seeds withdifferent test substance concentrations, 14-day EC50

values for reduced fresh weight of grown shoots were inthe range of 52–420 mg 2-nitrophenol/kg soil (Broecker etal., 1984; Koerdel et al., 1984) and 35–260 mg 4-nitrophenol/kg soil (Ballhorn et al., 1984; Marquart et al.,1984). The 14-day EC10 value for 2-nitrophenol was 10mg/kg soil for both species. Overall, turnip (Brassicarapa) proved to be more sensitive than oat (Avenasativa).

In tests conducted according to OECD Guideline207, the adverse effects of 2- and 4-nitrophenol onearthworms were examined in several independentstudies. In the contact test, in which the animals areexposed on filter paper soaked with the test substance,Neuhauser et al. (1985) established a 48-h LC50 value of5.9 :g/cm² for the toxicity of 2-nitrophenol on Eiseniafetida. For 4-nitrophenol, the 48-h LC50 values were inthe range of 0.7–2.7 :g/cm², with Eisenia fetida andEudrilus eugeniae being the most sensitive speciestested (Roberts & Dorough, 1984; Neuhauser et al., 1985,1986). When exposed in an artificial soil mixture, 28-dayLC50 values for 2-nitrophenol were in the range of250–500 mg/kg soil (Eisenia fetida) (Broecker et al., 1984;

Mononitrophenols

21

Koerdel et al., 1984), and 14-day LC50 values for 4-nitrophenol were in the range of 38–67 mg/kg soil, againwith Eisenia fetida and Eudrilus eugeniae as the mostsensitive species tested (Ballhorn et al., 1984; Marquartet al., 1984; Neuhauser et al., 1985, 1986).

The environmental relevance, particularly of theearthworm contact test, seems questionable. Criticalresults from this test, as sole effect data on terrestrialorganisms, should not justify a classification of testedsubstances as highly toxic to earthworms or other soilorganisms. The available data on microorganisms andplants indicate only a moderate toxicity potential in theterrestrial environment.

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–responseassessment

In general, there is only limited information con-cerning the toxicological profiles of 2- and 4-nitrophenol.

In experimental animals given 4-nitrophenol orally,intravenously, or intraperitoneally, most of the applieddose was excreted via the urine within 24–48 h as glucur-onide and sulfate conjugates, while only very smallamounts were excreted via faeces or as unchanged 4-nitrophenol. In rabbits, after oral dosing, 4-nitrophenolundergoes reduction to 4-aminophenol as well asglucuronidation and sulfation. In vivo and in vitrostudies gave an indication for dermal uptake. For 2-nitrophenol, the information is very limited. However, acomparable metabolic transformation is assumed basedon the available data. Owing to their rapid metabolismand excretion, bioaccumulation of 2- and 4-nitrophenol inorganisms is not to be expected.

With oral LD50 values of 220–620 mg/kg bodyweight in rats and 380–470 mg/kg body weight in mice, 4-nitrophenol is harmful after oral uptake and was found tobe more toxic than 2-nitrophenol. A dose-dependentincrease in the formation of methaemoglobin was seen incats after oral exposure to 2-nitrophenol — but not afterexposure to 4-nitrophenol — and in rats after exposureby inhalation to 4-nitrophenol.

Most of the studies concerning skin- or eye-irritating effects in experimental animals are limited as aresult of insufficient documentation. However, from theavailable data, it can be concluded that 2-nitrophenol isslightly irritating to the skin but non-irritating to the eye,and the substance proved to have no sensitizing effects.

For 4-nitrophenol, irritating effects on skin and eye areassumed based on the studies performed according toOECD/FDA guidelines; in addition, signs of irritationwere reported after exposure by inhalation as well assubchronic dermal exposure. In a guinea-pig maximiza-tion test, 4-nitrophenol was considered to be sensitizing.Positive patch tests were recorded in humans exposed to4-nitrophenol. Although this may have been due tocross-sensitization, sensitization to 4-nitrophenol inhumans cannot be excluded.

Only a few limited studies concerning repeated oralexposure to 2- and 4-nitrophenol in experimental animalswere identified. With 2-nitrophenol, decreases in bodyweight gain accompanied by decreased food con-sumption and differences in organ weights without cleardose dependency were found. However, the haema-tological examination, clinical chemistry, andhistopathological examination of the major organs andtissues gave no indication for a substance-related toxiceffect compared with controls. In rats dosed with 4-nitrophenol, a focal fatty degeneration of the liver as wellas congestion in several organs were the majorhistopathological findings. Other reported effectsincluded haematological changes, nephrosis, testicularatrophy, and follicular atresia in the ovaries. Theexposure by inhalation to 2-nitrophenol vapour causedsquamous metaplasia of the epithelium of the upperrespiratory tract; with 4-nitrophenol dust (applied assodium salt), haematological changes, increased met-haemoglobin values, and differences in organ weightswere noted. For the effects given in these studies, it wasnot possible to identify a clear dose–response or reliableNO(A)EL values.

Insufficient data are available on 2-nitrophenol to

allow any conclusions to be made about its possiblemutagenicity. For 4-nitrophenol, more mutagenicitystudies are available, and the substance was shown tobe mutagenic in some but not all of the bacterial assays.In addition, positive results were obtained in in vitrotests for chromosomal aberrations in mammalian cells;however, apart from one well-documented study, theavailable assays were inadequately reported. In theabsence of any in vivo mutagenicity studies in mammals,it is not possible to conclude whether or not the muta-genic potential of 4-nitrophenol is expressed in vivo.

4-Nitrophenol was not carcinogenic in male orfemale mice after dermal application over 78 weeks. In alimited study with female mice, no skin tumours wereseen after dermal application of 2- or 4-nitrophenol over12 weeks. No carcinogenicity studies using the oral orinhalation routes were available for either of the isomers.

No reproductive effects were observed in ratsexposed to 4-nitrophenol in a two-generation study. Fordevelopmental toxicity, the available studies were inade-


22

quately performed (i.e., only one dose was applied, oranimals were dosed only on one day with a mixture). Inan oral study with rats, 2-nitrophenol induced develop-mental effects in the offspring only at doses that alsoproduced maternal toxicity. However, the fetuses werenot examined for internal malformations.

Data on humans relevant for the assessment ofpotential adverse effects are limited to some patch testsperformed with 4-nitrophenol.

11.1.2 Criteria for setting guidance values for2- and 4-nitrophenol

As given in section 8, the database for 2-nitrophe-nol is inadequate for calculating a tolerable daily intake(TDI) or a tolerable concentration (TC).

For 4-nitrophenol, the formation of methaemo-globin was shown to be the most critical end-point afterexposure by inhalation and is assumed to be relevant fororal exposure too. However, owing to the inaccuracy ofthe analytical method used in the 13-week study withoral application, a reliable NO(A)EL cannot be derived.Therefore, at present, no TDI for 4-nitrophenol can bedeveloped owing to inadequacy of the database.

Longer-term toxicity studies concerning inhalationexposure were not identified in the literature, and theNO(A)EL values derived for 4-nitrophenol from short-term studies gave considerable differences (2-weekexposure: NO(A)EL of about 30 mg/m3; 4-week exposure:NO(A)EL of about 5 mg/m3). The NO(A)EL of 5 mg/m3

was derived for local effects (cataracts), whereas theNO(A)EL for systemic effects (formation ofmethaemoglobin) may be lower. Therefore, a reliable TCfor exposure by inhalation cannot be calculated, as theformation of methaemoglobin is the critical end-point.

11.1.3 Sample risk characterization

As given in section 6.2, workers may be exposed to2- and 4-nitrophenol via inhalation and skin contactduring production and processing (mainly in the manu-facturing of pesticides). However, data on nitrophenolconcentrations at the workplace were not identified.

For the general population, an exposure to nitro-phenols via the environment cannot be excluded (seealso section 6.2). Assuming an ambient atmosphericconcentration of about 1 :g/m3, an inhalation uptake of100%, a daily respiratory volume of 22 m3 for adults, amean body weight of 64 kg for males and females, andthat 4 of 24 h are spent outdoors (IPCS, 1994), the uptakeby inhalation of nitrophenols is calculated to be 0.06:g/kg body weight per day. In addition, 4-nitrophenol

accumulates in fog. From the mean measured level of 20:g/litre, the uptake of the substance by inhalation(using the same assumptions as above) can becalculated to be about 8 ng during a 1-h exposure period(i.e., 0.12 ng/kg body weight), assuming a maximum watercontent of fog of 0.1 g/m3 (Pruppacher & Klett, 1978).The uptake via drinking-water for 2- and 4-nitrophenolcan be calculated to be about 0.02 :g/kg body weightper day, assuming a maximum concentration of 1 :g/litredrinking-water, a daily drinking-water consumption of 1.4litres, and a mean body weight of 64 kg for males andfemales.

From these data, it can be concluded that exposureof the general population to the nitrophenol isomers ismainly through ambient air and drinking-water.

11.2 Evaluation of environmental effects

Releases of 2- and 4-nitrophenol into the environ-ment are primarily emissions into air, water, and soil fromdiffuse sources, such as vehicle traffic and hydrolyticand photolytic degradation of the respective pesticides.

2-Nitrophenol emitted to the troposphere will staypredominantly in the gaseous phase and should berapidly removed by nitration. The major portion ofairborne 4-nitrophenol is expected to be particle boundand can be washed out to surface waters and soil by wetand dry deposition. Because of their removal from airand their insignificant volatility, nitrophenols are notconsidered to contribute directly to the depletion of thestratospheric ozone layer or to global warming. Mea-sured bioconcentration factors indicate a low potentialfor bioaccumulation.

Nitrophenols exhibit moderate to high toxicity toaquatic organisms, with lowest effect concentrationsreported from chronic studies on algae, Daphnia, andaquatic invertebrates. The lowest effect concentrationsfound in chronic studies with freshwater organisms(Scenedesmus subspicatus, 96-h EC50: 0.39 mg 2-nitro-phenol/litre; Entosiphon sulcatum, 72-h MIC: 0.83 mg 4-nitrophenol/litre) were 40–50 times higher than maximumlevels determined in a densely populated and highlyindustrialized Asian river basin (0.0072 mg2-nitrophenol/litre and 0.019 mg 4-nitrophenol/litre).From these data, the safety margin between the LOECand maximum surface water concentrations is insufficientto exclude any risk for sensitive aquatic organisms,particularly under surface water conditions not favour-ing both elimination pathways. Taking into account themissing chronic effect data for fish, an uncertainty/assessment factor of 100 has to be applied to derive apredicted no-effect concentration (PNEC) according tostandard procedures for environmental risk assessment.

Mononitrophenols

23

From acute tests (see section 10.1), however, fishobviously seem to be the least sensitive aquatic speciestested. Thus, an assessment factor of 10 might beappropriate. Furthermore, the use pattern and the releasescenario outlined in section 4 lead to the conclusion thatnitrophenols emitted to surface waters will pose only aminor risk to aquatic organisms.

There were no data available on the occurrence ofnitrophenols in the terrestrial compartment. Therefore, anassessment of possible effects on organisms for thiscompartment could be conducted only with regard to thedegradation of pesticides. For the insecticidesmentioned in section 4 (parathion, parathion-methyl,carbofuran, phosalon, fluorodifen) and the herbicidesbifenox and nitrofen, predicted soil concentrations werecalculated from the maximum application rates (takenfrom Domsch, 1992) according to the EPPO (1993) guide-lines for environmental risk assessment of plant protec-tion products. Based on the relative molecular mass ofthe pesticides, the maximum concentration of nitrophe-nols in the top 5 cm of soil was calculated (worst case;one application). For pesticides that are applied at timeswhen the soil is plant covered to a high degree, it isassumed that only half of the amount applied reachesthe soil. Thus, the predicted environmentalconcentration (PEC) for the insecticides was reduced by50%. Dividing the PECsoil by the lowest LC50 value for aterrestrial species gives the toxicity exposure ratio (TER).The lowest LC50 value for earthworms (38 mg/kg bodyweight; see section 10.2) has to be corrected by a factorof 2 because of the higher organic matter content inartificial soil compared with natural agricultural soil. Thefollowing TERs were derived:

Insecticides HerbicidesParathion: 244 Bifenox: 131Parathion-methyl: 557 Nitrofen: 18Carbofuran: 47Phosalon: 36Fluorodifen: 69

According to the EPPO (1993) guidelines, the trig-ger value for concern is <10. Therefore, these pesticidesare expected to pose only a minor risk to earthworms,even under a worst-case scenario. Furthermore, theherbicide nitrofen and the insecticides phosalon andfluorodifen are no longer manufactured or marketed forcrop protection use.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

Previous evaluations of mononitrophenols byinternational bodies were not identified.

Information on international hazard classificationand labelling for mononitrophenols is included in theInternational Chemical Safety Card reproduced in thisdocument.

13. HUMAN HEALTH PROTECTION ANDEMERGENCY ACTION

Human health hazards, together with preventativeand protective measures and first aid recommendations,are presented on the enclosed International ChemicalSafety Card (ICSC 1342) reproduced in this document.

14. CURRENT REGULATIONS,GUIDELINES, AND STANDARDS

Information on national regulations, guidelines,and standards is available from the International Registerof Potentially Toxic Chemicals (IRPTC) legal file.

The reader should be aware that regulatory deci-sions about chemicals taken in a certain country can befully understood only in the framework of the legislationof that country. The regulations and guidelines of allcountries are subject to change and should always beverified with appropriate regulatory authorities beforeapplication.

Prepared in the context of cooperation between the InternationalProgramme on Chemical Safety and the European Commission

© IPCS 2000

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

MONONITROPHENOLS 1342November 1998

CAS No: 25154-55-6RTECS No:UN No: 1663

Nitrophenols (mixed isomers)NitrophenolsC6H5O3NMolecular mass: 139.1

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Combustible. Gives off irritating ortoxic fumes (or gases) in a fire.

NO open flames. Powder, water spray, foam, carbondioxide.

EXPLOSION Finely dispersed particles formexplosive mixtures in air.

Prevent deposition of dust; closedsystem, dust explosion-proofelectrical equipment and lighting.

In case of fire: keep drums, etc.,cool by spraying with water.

EXPOSURE PREVENT DISPERSION OF DUST!STRICT HYGIENE!

Inhalation Blue lips or finger nails. Blue skin.Confusion. Convulsions. Cough.Dizziness. Headache. Nausea.Sore throat. Unconsciousness.

Local exhaust or breathingprotection.

Fresh air, rest. Refer for medicalattention.

Skin MAY BE ABSORBED! Protective gloves. Protectiveclothing.

Remove contaminated clothes.Rinse and then wash skin withwater and soap. Refer for medicalattention.

Eyes Redness. Pain. Safety goggles, or eye protection incombination with breathingprotection.

First rinse with plenty of water forseveral minutes (remove contactlenses if easily possible), then taketo a doctor.

Ingestion Abdominal pain. Sore throat.Vomiting. (See Inhalation).

Do not eat, drink, or smoke duringwork.

Rinse mouth. Rest. Refer formedical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Sweep spilled substance into sealable containers.Carefully collect remainder, then remove to safeplace. Do NOT let this chemical enter theenvironment. (Extra personal protection: P2 filterrespirator for harmful particles).

UN Hazard Class: 6.1UN Pack Group: III

Do not transport with food andfeedstuffs.

EMERGENCY RESPONSE STORAGE

Separated from combustible and reducing substances, food and feedstuffs.Dry. Well closed.

Boiling point: 194-279Melting point: 44-116°CDensity: 1.5 g/cm3

Solubility in water, g/100 ml: 0.13-1.2

Vapour pressure, Pa at 20°C: 0.0032 - 7Relative vapour density (air = 1): 4.81Flash point: 169°C

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

©IPCS 2000

1342 MONONITROPHENOLS

IMPORTANT DATA

Physical State; AppearanceYELLOW CRYSTALS

Physical dangersDust explosion possible if in powder or granular form, mixedwith air.

Chemical dangersMay explode on heating. On combustion, forms nitrogen oxides.The substance decomposes on heating producing toxic fumesincluding nitrogen oxides. Reacts with strong oxidants.

Occupational exposure limitsTLV not established.

Routes of exposureThe substance can be absorbed into the body by inhalation ofits aerosol, through the skin and by ingestion.

Inhalation riskEvaporation at 20°C is negligible; a harmful concentration ofairborne particles can, however, be reached quickly.

Effects of short-term exposureThe substance irritates the eyes and the skin and therespiratory tract. The substance may cause effects on theblood, resulting in formation of methaemoglobin. The effectsmay be delayed. Medical observation is indicated.

Effects of long-term or repeated exposureRepeated or prolonged contact may cause skin sensitization.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

The substance is toxic to aquatic organisms. Avoid release to the environment in circumstances different to normal use.

NOTES

Depending on the degree of exposure, periodic medical examination is indicated.Specific treatment is necessary in case of poisoning with this substance; the appropriate means with instructions must be available.

ADDITIONAL INFORMATION


26

REFERENCES

Aelion CM, Swindoll CM, Pfaender FK (1987) Adaptation to andbiodegradation of xenobiotic compounds by microbialcommunities from a pristine aquifer. Applied environmental

microbiology, 53:2212–2217.

Amacher DE, Turner GN (1982) Mutagenic evaluation ofcarcinogens and non-carcinogens in the L5178Y/TK assayutilizing postmitochondrial fractions (S9) from normal rat liver.Mutation research, 97:49–65.

Andrae U, Bieniek D, Freitag D, Goeggelmann W, Huber W,Klein W, Kotzias D, Lahaniatis E, Mansour M, Parlar H, PolitzkiG, Rohleder H, Rott B, Scheunert I, Spieser H, Viswanathan R(1981) Feasibility of test guidelines and evidence of the base-

set testing according to the chemicals legislation. Muenchen,Gesellschaft für Strahlen- und Umweltfoschung mbH (inGerman).

Angerhofer RA (1985) Final phase: Effect of dermal applications

of paranitrophenol on the reproductive functions of rats.

Aberdeen Proving Ground, MD, US Army EnvironmentalHygiene Agency (Study No. 75-51-0047-85).

ATSDR (1992) Toxicological profile for nitrophenols: 2- and 4-

nitrophenol. Atlanta, GA, US Department of Health and HumanServices, Public Health Service, Agency for Toxic Substancesand Disease Registry (Report No. TP-91/23).

Ballhorn D, Freitag D, Geyer H, Quast I, Rott B, Scheunert I,Spieser H, Viswanathan R (1984) Assessment of the feasibility

and evidence of the test methods of levels I and II of the

chemicals act. Berlin, Umweltbundesamt (in German).

BASF AG (1969) Results of the toxicological testing of Rongal-

Stabilisator A. Ludwigshafen (unpublished report) (in German).

BASF AG (1970) Results of the toxicological testing of o-nitro-

phenol. Ludwigshafen (unpublished report) (in German).

Battersby NS, Wilson V (1989) Survey of the anaerobicbiodegradation potential of organic chemicals in digestingsludge. Applied environmental microbiology, 55:433–439.

Baumgartner A, Liebscher H-J (1990) Allgemeine Hydrologie.

Quantitative Hydrologie. Berlin, Gebrueder Borntraeger Verlag,pp. 93–96.

Booth G (1991) Nitro compounds, aromatic. In: Ullmann’s

encyclopedia of industrial chemistry. Vol. A17. Weinheim, VCHVerlagsGmbH, pp. 411–455.

Booth GM, Bradshaw WS, Carter MW (1983) Screening of

priority chemicals for potential reproductive hazard. Orem, UT,MESA Corp. (Report No. PB83-213017).

Boutwell RK, Bosch DK (1959) The tumor-promoting action ofphenol and related compounds for mouse skin. Cancer research,19:413–424.

Boyd SA (1982) Adsorption of substituted phenols by soil. Soil

science, 134:337–343.

Boyd SA, Shelton DR, Berry D, Tiedje JM (1983) Anaerobicbiodegradation of phenolic compounds in digested sludge.Applied environmental microbiology, 46:50–54.

Braunbeck T, Storch V, Nagel R (1989) Sex-specific reaction ofliver ultrastructure in zebra fish (Brachydanio rerio) afterprolonged sublethal exposure to 4-nitrophenol. Aquatic

toxicology, 14:185–202.

Bringmann G (1978) Determination of the toxicity of waterpollutants on protozoa. I. Bacteriovorous flagellates. Zeitschrift

fuer Wasser und Abwasser Forschung, 11:210–215 (in German).

Bringmann G, Kuehn R (1977) Results of the damaging effectsof water pollutants on Daphnia magna. Zeitschrift fuer Wasser

und Abwasser Forschung, 10:161–165 (in German).

Bringmann G, Kuehn R, Winter A (1980) Determination of thebiological effect of water pollutants in protozoa. III. Saprozoicflagellates. Zeitschrift fuer Wasser und Abwasser Forschung,13:170–173 (in German).

Broecker B, Fischer R, Gerber HG, Goerlitz G, Markert M,Wellens H (1984) Assessment of the feasibility and evidence of

the test method of level 1 and 2 of the chemical act. Berlin,Umweltbundesamt (in German).

BUA (1992) BUA-Stoffbericht 2- und 4-Nitrophenol.

Beratergremium fuer Umweltrelevante Altstoffe. Weinheim, VCHVerlagsGmbH (Report No. 75; February 1992).

Budavari S, O’Neil MJ, Smith A, Heckelmann PE, Kinneary JE,eds. (1996) The Merck Index. An encyclopedia of chemicals,

drugs and biologicals, 12th ed. Whitehouse Station, NJ, Merck &Co. Inc.

Buselmaier W, Roehrborn G, Propping P (1972) Mutagenitaets-Untersuchungen mit Pestiziden im Host-mediated assay und mitdem Dominanten Letaltest an der Maus. Biologisches

Zentralblatt, 91:311–325.

Capel PD, Leuenberger C, Giger W (1991) Hydrophobic organicchemicals in urban fog. Atmospheric environment,25A:1335–1346.

Chiu CW, Lee LH, Wang CY, Bryan GT (1978) Mutagenicity ofsome commercially available nitro compounds for Salmonella

typhimurium. Mutation research, 58:11–22.

CITI (1992) Biodegradation and bioaccumulation. Data of

existing chemicals based on the CSCL Japan. Tokyo, JapanChemical Industry Ecology-Toxicology & Information Center,Chemicals Inspection & Testing Institute.

Dellarco VL, Prival MJ (1989) Mutagenicity of nitro compoundsin Salmonella typhimurium in the presence of flavinmononucleotide in a preincubation assay. Environmental

molecular mutagenesis, 13:116–127.

Domsch KH (1992) Pesticides in soil. Weinheim, VCH-Verlag (inGerman).

Eastman Kodak Co. (1980) Toxicology Laboratory Report No.125877V; US Environmental Protection Agency Report No. 86-890000202. Rochester, NY [cited in Cantilli R (1991) Drinking

water health advisory for p-nitrophenol. Washington, DC, USEnvironmental Protection Agency (Report No. PB92-135490)].

Mononitrophenols

27

Ensenbach U, Nagel R (1991) Toxicokinetics of xenobiotics in zebrafish

— comparison between tap and river water. Comparative biochemistry

and physiology, 100C:49–53.

EPPO (1993) Decision-making scheme for the environmental risk

assessment of plant protection products. Paris, European and

Mediterranean Plant Protection Organization.

Eriksen K (1978) Cross allergy between paranitro compounds with

special reference to DNCB and chloramphenicol. Contact dermatitis,

4:29–32.

Fahrig R (1974) Comparative mutagenicity studies with pesticides. IARC

scientific publications, 10:161–181.

Figge K, Klahn J, Koch J (1985) Chemicals in ecosystems. Inventory,

evaluation and application of distribution models. Society for Water, Soil

and Air Hygiene, 61:1–234 (in German).

Foureman P, Mason JM, Valencia R, Zimmering S (1994) Chemical

mutagenesis testing in Drosophila. IX. Results of 50 coded compounds

tested for the National Toxicology Program. Environmental molecular

mutagenesis, 23:51–63.

Freitag D, Geyer H, Kraus A, Viswanathan R, Kotzias D, Attar A, Klein

W, Korte F (1982) Ecotoxicological profile analysis. VII. Screening

chemicals for their environmental behavior by comparative evaluation.

Ecotoxicology and environmental safety, 6:60–81.

Geissler A, Schoeler HF (1993) Atmospheric deposition of pesticides

and nitrophenols in the Rhine/Sieg-area (Germany). Vom Wasser,

80:357–370.

Geissler A, Schoeler HF (1994) Gas chromatographic determination of

phenol, methylphenols, chlorophenols, nitrophenols and nitroquinones in

water at 0.1 :g l–1. Water research, 28:2047–2053.

Gerike P, Fischer WK (1979) A correlation study of biodegradability

determination with various chemicals in various tests. Ecotoxicology

and environmental safety, 3:159–173.

Gessner T, Hamada N (1970) Identification of p-nitrophenol glucoside

as a urinary metabolite. Journal of pharmaceutical sciences,

59:1528–1529.

Geyer H, Viswanathan R, Freitag D, Korte F (1981) Relationship

between water solubility of organic chemicals and their bioaccumulation

by the alga Chlorella. Chemosphere, 14:1307–1313.

Gile JD, Gillett JW (1981) Transport and fate of organophosphate

insecticides in a laboratory model ecosystem. Journal of agricultural

and food chemistry, 29:616–621.

Hansch C, Leo A (1979) Substituent constants for correlation analysis in

chemistry and biology. New York, NY, John Wiley & Sons.

Harrison I, Leader RU, Higgo JJW, Tjell JC (1994) Determination of

organic pollutants in small samples of groundwaters by liquid–liquid

extraction and capillary gas chromatography. Journal of chroma-

tography, 688:181–188.

Haworth S, Lawlor T, Mortelmans K, Speck W, Zeiger E (1983)

Salmonella mutagenicity test results for 250 chemicals. Environmental

mutagenesis, 5 (Suppl. 1):3–142.

Hazleton Lab. (1983) Subacute dust inhalation toxicity study in rats. p-

Nitrophenol. Final report. Sponsored by Monsanto Co., St. Louis, MO

(HLA Study No. 82-242).

Hazleton Lab. (1984) Subacute inhalation toxicity study in rats. o-

Nitrophenol. Final report. Sponsored by Monsanto Co., St. Louis, MO

(HLA Study No. 82-254).

Hazleton Lab. (1989) Subchronic toxicity study in rats with para-

nitrophenol . Sponsored by Monsanto Co., St. Louis, MO (HLA Study

No. 241-221).

Herterich R, Herrmann R (1990) Comparing the distribution of nitrated

phenols in the atmosphere of two German hill sites. Environmental

technology letters, 11:961–972.

Hoechst AG (1977a) Acute oral toxicity of p-nitrophenol in female SPF-

Wistar rats. Frankfurt/Main, Hoechst AG (unpublished report) (in

German).

Hoechst AG (1977b) Acute dermal toxicity of p-nitrophenol in female

SPF-Wistar rats. Frankfurt/Main, Hoechst AG (unpublished report) (in

German).

Hoechst AG (1977c) Skin and eye irritating effects of p-nitrophenol in

rabbits. Frankfurt/Main, Hoechst AG (unpublished report) (in German).

Hoechst AG (1980) A mutagenicity screening of 408 / 80 A in bacteria

(Ames test). Frankfurt/Main, Hoechst AG (unpublished report).

Hoover DG, Borgonovi GE, Jones SH, Alexander M (1986) Anomalies in

mineralization of low concentrations of organic compounds in lake water

and sewage. Applied environmental microbiology, 51:226–232.

Howe GE, Marking LL, Bills TD, Rach JJ, Mayer FLJ (1994) Effects of

water temperature and pH on toxicity of terbufos, trichlorfon, 4-

nitrophenol and 2,4-dinitrophenol to the amphipod Gammarus

pseudolimnaeus and rainbow trout (Oncorhynchus mykiss). Environmental

toxicology and chemistry, 13:51–66.

HSDB (1998) Hazardous substances data bank. Bethesda, MD, National

Library of Medicine.

Huang Q, Wang L, Han S (1995) The genotoxicity of substituted

nitrobenzenes and the quantitative structure–activity relationship

studies. Chemosphere, 30:915–923.

Huang Q-G, Kong L-R, Liu Y-B, Wang L-S (1996) Relationships between

molecular structure and chromosomal aberrations in in vitro human

lymphocytes induced by substituted nitrobenzenes. Bulletin of

environmental contamination and toxicology, 57:349–353.

Huq AS, Ho NFH, Husari N, Flynn GL, Jetzer WE, Condie LJ Jr (1986)

Permeation of water contaminative phenols through hairless mouse

skin. Archives of environmental contamination and toxicology,

15:557–566.

Hustert K, Mansour M, Parlar H, Korte F (1981) The EPA test — A

method for the determination of the photochemical degradation of

organic compounds in aquatic systems. Chemosphere, 10(9):995–998

(in German).

International Research and Developmental Corporation (1983) Range-

finding teratology study in rats. Sponsored by Monsanto Co., St. Louis,

MO (IR-83-100).

IPCS (1994) Assessing human health risks of chemicals: derivation of

guidance values for health-based exposure limits. Geneva, World Health

Organization, International Programme on Chemical Safety

(Environmental Health Criteria 170).

IPCS (1998) International Chemical Safety Card — Mononitrophenols.

Geneva, World Health Organization, International Programme on

Chemical Safety (ICSC 1342).

Japan Environment Agency (1979) Chemicals in the environment.

Monitoring of the general environment in Japan 1978. Tokyo.




28



Jetzer WE, Huq AS, Ho NFH, Flynn GL, Duraiswamy N, Condie L Jr

(1986) Permeation of mouse skin and silicone rubber membranes by

phenols: relationship to in vitro partitioning. Journal of pharmaceutical

sciences, 75:1098–1103.

Kavlock RJ (1990) Structure–activity relationships in the developmental

toxicity of substituted phenols: In vivo effects. Teratology, 41:43–59.

Kawai A, Goto S, Matsumoto Y, Matsushita H (1987) Mutagenicity of

aliphatic and aromatic nitro compounds. Japanese journal of industrial

health, 29:34–54.

Kayser G, Koch M, Ruck W (1994) Simultaneous quantitative

measurement of biodegradation and toxicity of environmental

chemicals. Vom Wasser, 82:219–232.

Koerdel W, Schoene K, Bruckert J, Pfeiffer U, Schreiber G, Rittmann

D, Hochrainer D, Otto F, Spielberg T, Fingerhut R, Kuhnen-Clausen D,

Koenig J (1981) Assessment of the feasibility of test guidelines as well

as the evidence of the base set of the law on chemicals. Hanover,

Fraunhofer Institute for Toxicology and Aerosol Research (in German).

Koerdel W, Kuhnen-Clausen D, Fabig W, Otto F (1984) Evaluation of

test guidelines for environmental chemicals. Schmallenberg, Fraunhofer

Institute for Environmental Chemistry and Ecotoxicology (in German).

Koop DR (1986) Hydroxylation of p-nitrophenol by rabbit ethanol-

inducible cytochrome P-450 isozyme 3a. Molecular pharmacology,

29:399–404.

Koop DR, Laethem CL (1992) Inhibition of rabbit microsomal

cytochrome P-450 2E1-dependent p-nitrophenol hydroxylation by

substituted benzene derivatives. Drug metabolism and disposition,

20:775–777.

Kramer CR, Truemper l, Berger L (1986) Quantitative structure–activity

relations for the autotrophic growth inhibition of synchrone Chlorella

vulgaris suspensions by monosubstituted nitrobenzenes. Biochemie und

Physiologie der Pflanzen, 181:411–420 (in German).

Kubinski H, Gutzke GE, Kubinski ZO (1981) DNA-cell-binding (DCB)

assay for suspected carcinogens and mutagens. Mutation research,

89:95–136.

Kuehn R, Pattard M, Pernak K-D, Winter A (1988) Damaging effects of

environmental chemicals in the Daphnia reproductive toxicity test as a

basis for the evaluation of environmental hazards in aquatic systems.

Berlin, Institute for Water, Soil and Air Hygiene (in German).

Landrum PF, Crosby DG (1981) Comparison of the disposition of

several nitrogen-containing compounds in the sea-urchin and other

marine invertebrates. Xenobiotica, 11:351–361.

Lang P-Z, Ma X-F, Lu G-H, Wang YI, Bian Y (1996) QSAR for the acute

toxicity of nitroaromatics to the carp (Cyprinus carpio). Chemosphere,

32:1547–1552.

Leone JA, Seinfeld JH (1985) Comparative analysis of chemical

reaction mechanism for photochemical smog. Atmospheric environment,

19:437–464.

Leone JA, Flagan RC, Grosjean D, Seinfeld JH (1985) An outdoor smog

chamber and modeling study of toluene–NOx photooxidation.

International journal of chemical kinetics, 17:177–216.

León-González ME, Perez-Arribas LV, Santos-Delgado MJ, Polo-Diez LM

(1992) Simultaneous flow-injection determination of o- and p-nitrophenol

using a photodiode-array detector. Analytica Chimica Acta, 258:269–273.

Leuenberger C, Czuczwa J, Tremp J, Giger W (1988) Nitrated phenols in

rain: atmospheric occurrence of phytotoxic pollutants. Chemosphere,

17(3):511–516.

Levsen K, Behnert S, Priess B, Svoboda M, Winkeler H-D, Zietlow J

(1990) Organic compounds in precipitation. Chemosphere,

21:1037–1061.

Levsen K, Behnert S, Mussmann P, Raabe M, Priess B (1993) Organic

compounds in cloud and rain water. International journal of environmental

analytical chemistry, 52:87–97.

Løkke H (1984) Sorption of selected organic pollutants in Danish soils.

Ecotoxicology and environmental safety, 8:395–409.

Luettke J, Levsen K (1994) Partitioning of phenol and nitrophenols in

gas and liquid phase of clouds. In: Borrell PM, Borrell P, Cvitas T, Seiler

W, eds. Transport and transformation of pollutants in the troposphere.

Proceedings of EUROTRAC Symposium ’94 Garmisch-Patenkirchen,

11–15 April 1994. Garmisch-Patenkirchen, SPB Academic Publishing bv

/ EUROTRAC International Scientific Secretariat (ISS); Fraunhofer

Institute for Atmospheric Environmental Research, pp.1075–1078.

Luettke J, Scheer V, Levsen K, Wuensch G, Cape JN, Hargreaves KJ,

Storeton-West RL, Acker K, Wieprecht W, Jones B (1997) Occurrence

and formation of nitrated phenols in and out of cloud. Atmospheric

environment, 31:2637–2648.

Machida M, Morita Y, Hayashi M, Awazu S (1982) Pharmacokinetic

evidence for the occurrence of extrahepatic conjugative metabolism of

p-nitrophenol in rats. Biochemical pharmacology, 31:787–791.

Mansour M (1996) Abiotic degradation of pesticides and other organic

chemicals in aquatic systems. Pesticide outlook, 7:9–10.

Marquart HW, Sewekow B, Hamburger B, Harzdorf C, Hellbusch HD

(1984) Assessment of the feasibility and evidence of the test methods of

levels I and II of the chemicals act. Part II. Leverkusen, Bayer-AG, pp.

1–128 (in German).

Massey IJ, Aitken MD, Ball LM, Heck PE (1994) Mutagenicity screening

of reaction products from the enzyme-catalyzed oxidation of phenolic

pollutants. Environmental toxicology and chemistry, 13:1743–1752.

McCann J, Choi E, Yamasaki E, Ames BN (1975) Detection of

carcinogens as mutagens in the Salmonella/microsome test: assay of

300 chemicals. Proceedings of the National Academy of Sciences of the

United States of America, 72:5135–5139.

McCoy GD, Koop DR (1988) Biochemical and immunochemical

evidence for the induction of an ethanol-inducible cytochrome P-450

isoenzyme in male Syrian golden hamsters. Biochemical pharmacology,

37:1563–1568.

Means JL, Anderson SJ (1981) Comparison of five different methods

for measuring biodegradability in aqueous environment. Water, air, and

soil pollution, 16:301–315.

Meerman JH, Nijland C, Mulder GJ (1987) Sex differences in sulfation

and glucuronidation of phenol, 4-nitrophenol and N-hydroxy-2-

acetylaminofluorene in the rat in vivo. Biochemical pharmacology,

36:2605–2608.

Mussmann P, Levsen K, Radeck W (1994) Gas-chromatographic

determination of phenols in aqueous samples after solid phase

extraction. Fresenius journal of analytical chemistry, 348:654–659.

Nakamura S, Oda Y, Shimada T, Oki I, Sugimoto K (1987) SOS-inducing

activity of chemical carcinogens and mutagens in Salmonella

typhimurium TA1535/pSK1002: examination with 151 chemicals. Mutation

research, 192:239–246.

Mononitrophenols

29

Naniwa S (1979) Industrial contact dermatitis due to nitro and amino

derivatives. 1st report: mass-examination of a factory. Journal of

dermatology, 6:59–63.

Nasseredine-Sebaei SM, Crider AM, Carroll RT, Hinko CN (1993)

Determination of m-nitrophenol and nipecotic acid in mouse tissues by

high-performance liquid chromatography after administration of the

anticonvulsant m-nitrophenyl-3-piperidinecarboxylate hydrochloride.

Journal of pharmaceutical sciences, 82:39–43.

Neuhauser EF, Loehr RC, Malecki MR, Milligan DL, Durkin PR (1985)

The toxicity of selected organic chemicals to the earthworm Eisenia

fetida. Journal of environmental quality, 14:383–388.

Neuhauser EF, Durkin PR, Malecki MR, Anatra M (1986) Comparative

toxicity of ten organic chemicals to four earthworm species.

Comparative biochemistry and physiology, C 83:197–200.

Nick K, Schoeler HF (1992) Gas-chromatographic determination of

nitrophenols after derivatization with diazomethane. Fresenius journal of

analytical chemistry, 343:304–307.

Nojima K, Kawaguchi A, Ohya T, Kanno S, Hirobe M (1983) Studies on

photochemical reaction of air pollutants. X. Identification of nitrophenols

in suspended particulates. Chemical and pharmaceutical bulletin,

31:1047–1051.

NTP (1993) Toxicology and carcinogenesis studies of p-nitrophenol (CAS

No. 100-02-7) in Swiss Webster mice (dermal studies). Research Triangle

Park, NC, US Department of Health and Human Services, National

Toxicology Program (NTP Report No. TR-417).

Nyholm N, Lindgaard-Jœrgensen P, Hansen N (1984) Biodegradation of

4-nitrophenol in standardized aquatic degradation tests. Ecotoxicology

and environmental safety, 8:451–470.

Oberly TJ, Bewsey BJ, Probst GS (1984) An evaluation of the L5178Y

TK+/– mouse lymphoma forward mutation assay using 42 chemicals.

Mutation research, 125:291–306.

Ohkura K, Iwamoto K, Terada H (1990) Transcellular permeation of

nitrophenols through newborn rat skin epidermal cells in monolayer

culture. Chemical and pharmaceutical bulletin, 38:2788–2791.

Ou L-T (1985) Methyl parathion degradation and metabolism in soil:

Influence of high soil-water contents. Soil biology and biochemistry,

17:241–243.

Pagga U, Haltrich WG, Guenthner W (1982) Investigations of the effect

of 4-nitrophenol on activated sludge. Vom Wasser, 59:51–65 (in

German).

Paterson B, Cowie CE, Jackson PE (1996) Determination of phenols in

environmental waters using liquid chromatography with electrochemical

detection. Journal of chromatography, A 731:95–102.

Pitter P (1976) Determination of biological degradability of organic

substances. Water research, 10:231–235.

Pocurull E, Marce RM, Borrull F (1996) Determination of phenolic

compounds in natural waters by liquid chromatography with ultraviolet

and electrochemical detection after on-line trace enrichment. Journal of

chromatography, 738:1–9.

Poirier MC, De Cicco BT, Lieberman MW (1975) Nonspecific inhibition

of DNA repair synthesis by tumor promoters in human diploid

fibroblasts damaged with N-acetoxy-2-acetylaminofluorene. Cancer

research, 35:1392–1397.

Probst GS, McMahon RE, Hill LE, Thompson CZ, Epp JK, Neal SB

(1981) Chemically-induced unscheduled DNA synthesis in primary rat

hepatocyte cultures: a comparison with bacterial mutagenicity using 218

compounds. Environmental mutagenesis, 3:11–32.

Pruett SB, Chambers JE (1988) Effects of paraoxon, p-nitrophenol,

phenyl saligenin cyclic phosphate, and phenol on the rat interleukin 2

system. Toxicology letters, 40:11–20.

Pruppacher HR, Klett JD (1978) Microphysics of clouds and

precipitation. Dordrecht/Boston/London, D. Reidel Publishing Co.

Puig D, Barcelo D (1996) Determination of phenolic compounds in water

and waste water. Trends in analytical chemistry, 15:362–375.

Rashid KA, Mumma RO (1986) Screening pesticides for their ability to

damage bacterial DNA. Journal of environmental science and health,

21:319–334.

Reinke LA, Moyer MJ (1985) p-Nitrophenol hydroxylation. A microsomal

oxidation which is highly inducible by ethanol. Drug metabolism and

disposition, 13:548–552.

Richartz H, Reischl A, Trautner F, Hutzinger O (1990) Nitrated phenols

in fog. Atmospheric environment, 24:3067–3072.

Rippen G, Flothmann D, Witt W (1984) Improvement of the OECD test

guideline A 80/9 and comparative evaluation of other relevant methods

for the measurement of volatility. Frankfurt a. M., Batelle-Institut e.V.

(Report No. 106 02 024/06) (in German).

Roberts BL, Dorough HW (1984) Relative toxicities of chemicals to the

earthworm Eisenia fetida. Environmental toxicology and chemistry,

3:67–78.

Robinson D, Smith JN, Williams RT (1951) Studies in detoxication. 39.

Nitro compounds. (a) The metabolism of o-, m-, and p-nitrophenols in

the rabbit. (b) The glucuronides of the mononitrophenols and

observations on the anomalous optical rotations of triacetyl $-o-

nitrophenylglucuronide and its methyl ester. Biochemical journal ,

50:221–227.

Rott B, Viswanathan R, Freitag D, Korte F (1982) Comparative

investigation on the feasibility of different tests for the evaluation of

the degradation of environmental chemicals. Chemosphere, 11:531–538

(in German).

Ruana J, Urbe I, Borrull F (1993) Determination of phenols at the ng/l

level in drinking and river waters by liquid chromatography with UV and

electrochemical detection. Journal of chromatography, A 655:217–226.

Rubin HE, Subba-Rao RV, Alexander M (1982) Rates of mineralization

of trace concentrations of aromatic compounds in lake water and

sewage samples. Applied environmental microbiology, 43:1133–1138.

Rush GF, Newton JF, Hook JB (1983) Sex differences in the excretion

of glucuronide conjugates: The role of intrarenal glucuronidation. Journal

of pharmacology and experimental therapeutics, 227:658–662.

Sax NI, Lewis RJ (1987) Hawley’s condensed chemical dictionary, 11th

ed. New York, NY, Van Nostrand Reinhold Co.

Scheer V, Luettke J, George C, Levsen K, Frenzel A, Behnke W,

Zetzsch C (1996) Atmospheric nitration of phenol in clouds by N2O5 and

ClNO2. In: Borrell PM, Borrell P, Kelly K, Cvitas T, Seiler W, eds.

Transport and transformation of pollutants in the troposphere.

Proceedings of EUROTRAC Symposium ‘96. Garmisch-Patenkirchen,

25–29 March 1996. Southhampton, Computational Mechanics

Publications.

Scheubel JB (1984) Assessment of the feasibility and evidence of the

test method of level 1 and 2 of the chemical act. Marl, Chemische Werke

Huels AG (Report No. 106 04 011/5 CWH) (in German).

Scheunert I (1984) Examination and optimization of the “GSF-Cold-Finger-

Method” and comparative calculations of the volatility. Gesellschaft fuer

Strahlen- und Umweltforschung (Report No. 10602024/08) (in German).


30

Schoene K, Steinhanses J (1984) Comparative measurements of the

volatility in open systems. Schmallenberg, Fraunhofer Institute for

Toxicology and Aerosol Research (Report No. 10602024/7 Part II) (in

German).

Scholz N (1986) Development of test guidelines on marine species for

ecotoxicological studies according to the chemicals act -

Bryozota/Camptozoa. Berlin, Umweltbundesamt (Report No.

10603042/02) (in German).

Schwarzenbach RP, Stierli R, Folsom BR, Zeyer J (1988) Compound

properties relevant for assessing the environmental partitioning of

nitrophenols. Environmental science and technology, 22:83–92.

Sewekow B (1983) Feasibility of test guidelines and evidence of the

base-set testing according to the chemicals legislation. Muenchen,

Gesellschaft fuer Strahlen- und Umweltforschung (in German).

Shimizu M, Yano E (1986) Mutagenicity of mono-nitrobenzene

derivatives in the Ames test and rec assay. Mutation research,

170:11–22.

Smith LW, Hall GT, Kennedy GL (1988) Acute and repeated dose

inhalation toxicity of para-nitrophenol sodium salt in rats. Drug chemistry

and toxicology, 11:319–327.

Snodgrass HL Jr (1983) Phase I, dermal penetration and distribution of14C-labeled paranitrophenol (PNP). Aberdeen Proving Ground, MD, US

Army Environmental Hygiene Agency (Study No. 75-51-0047-84).

Spain JC, van Veld PA, Monti CA, Pritchard PH, Cripe CR (1984)

Comparison of p-nitrophenol biodegradation in field and laboratory test

systems. Applied environmental microbiology, 48:944–950.

Storer RD, McKelvey TW, Kraynak AR, Elia MC, Barnum JE, Harmon

LS, Nichols WW, DeLuca JG (1996) Revalidation of the in vitro alkaline

elution/rat hepatocyte assay for DNA damage: improved criteria for

assessment of cytotoxicity and genotoxicity and results for 81

compounds. Mutation research, 368:59–101.

Subba-Rao RV, Rubin HE, Alexander M (1982) Kinetics and extent of

mineralization of organic chemicals at trace levels in freshwater and

sewage. Applied environmental microbiology, 43:1139–1150.

Suzuki J, Koyama T, Suzuki S (1983) Mutagenicities of mono-

nitrobenzene derivatives in the presence of norharman. Mutation

research, 120:105–110.

Tabak HH, Quave SA, Mashni CI, Barth EF (1981) Biodegradability

studies with organic priority pollutant compounds. Journal of the Water

Pollution Control Federation, 52:1503–1518.

Tan GH, Chong CL (1993) Trace monitoring of water-borne phenolics in

the Klang River basin. Environmental monitoring and assessment,

24:267–277.

Thompson MJ, Ballinger LN, Cross SE, Roberts MS (1996) High-

performance liquid chromatographic determination of phenol, 4-

nitrophenol, beta-naphthol and a number of their glucuronide and sulfate

conjugates in organ perfusate. Journal of chromatography, B

677:117–122.

Tremaine LM, Diamond GL, Quebbemann AJ (1984) In vivo

quantification of renal glucuronide and sulfate conjugation of 1-naphthol

and p-nitrophenol in the rat. Biochemical pharmacology, 33:419–427.

Tremp J, Mattrel P, Fingler S, Giger W (1993) Phenols and nitrophenols

as tropospheric pollutants: Emissions from automobile exhausts and

phase transfer in the atmosphere. Water, air, and soil pollution,

68:113–123.

TRI (1998) Toxics release inventory. Washington, DC, US

Environmental Protection Agency, Office of Toxic Substances

(17 December 1998).

Tseng S, Lin M (1994) Treatment of organic wastewater by anaerobic

biological fluidized bed reactor. Water science and technology,

29:157–166.

Urano K, Kato Z (1986) Evaluation of biodegradation ranks of priority

organic compounds. Journal of hazardous materials, 13:147–159.

Van Veld PA, Spain JC (1983) Degradation of selected xenobiotic

compounds in three types of aquatic test systems. Chemosphere,

12:1291–1305.

Vasilenko NM, Volodchenko VA, Baturina TS, Kolodub FA (1976)

Toxicological peculiarities of mononitrophenols with regard for their

isomeric form. Farmakologiya i Toksikologiya, 39:718–721.

Vernot EH, MacEwen JD, Haun CC, Kinkead ER (1977) Acute toxicity

and skin corrosion data for some organic and inorganic compounds and

aqueous solutions. Toxicology and applied pharmacology, 42:417–423.

Verschueren K, ed. (1983) Handbook of environmental data on organic

chemicals, 2nd ed. New York, NY, Van Nostrand Reinhold Co.

Vozñáková Z, Podehradská J, Kohlicková M (1996) Determination of

nitrophenols in soil. Chemosphere, 33:285–291.

Wagner R, Braeutigam H-J (1981) Development and testing of a

method for studying the degradation of organic compounds under

anaerobic conditions (report no. 03 7221). In: Biehl HM, Fuehr F, Seibert

K, eds. Methods for the ecotoxicological evaluation of chemicals, Part 1,

Aquatic systems. Juelich, Forschungszentrum, pp. 20–41 (in German).

Weast RC (1979) CRC handbook of chemistry and physics, 69th ed.

Boca Raton, FL, CRC Press, Inc.

Wiggins BA, Jones SH, Alexander M (1987) Explanations for the

acclimation period preceding the mineralization of organic chemicals in

aquatic environments. Applied environmental microbiology, 43:791–796.

Yamada K, Murakami H, Yasumura K, Shirahata S, Shinohara K, Omura

H (1987) Production of DNA-breaking substance after treatment of

monophenols with sodium nitrite and then with dimethyl sulfoxide.

Agricultural and biological chemistry, 51:247–248.

Yoshida K, Shigeoka T, Yamauchi F (1983) Non-steady-state

equilibrium model for the preliminary prediction of the fate of chemicals

in the environment. Ecotoxicology and environmental safety, 7:179–190.

Yoshioka Y, Ose Y, Sato T (1985) Testing for the toxicity of chemicals

with Tetrahymena pyriformis. The science of the total environment,

43:149–157.

Zetzsch C, Rinke M, Scharpring H, Schueler P, Urbanik E, Wahner A,

Wiedelmann A, Witte F (1984) Upper limits of the persistence of

chemicals in the atmosphere from their reactivity against OH radicals.

University of Bochum, Bochum, pp. 1–20 (BMFT Report No. PTU

037253).

Zimmering S, Mason JM, Valencia R, Woodruff RC (1985) Chemical

mutagenesis testing in Drosophila. II. Results of 20 coded compounds

tested for the National Toxicology Program. Environmental mutagenesis,

7:87–100.

Mononitrophenols

31

OH

NO2

APPENDIX 1 — 3-NITROPHENOL

Identity and physical/chemical properties

3-Nitrophenol (CAS No. 554-84-7; 3-hydroxy-1-nitrobenzene, m-nitrophenol) has the empirical formula C6H5NO3.Its structural formula is shown below:

Physicochemical properties of 3-nitrophenol are given inTable A-1.

Table A-1: Physicochemical properties of 3-nitrophenol.

Parameter Value

Molecular mass (g/mol) 139.11

Melting point (°C) 96–97 (1)(2)

Boiling point (°C) 194 (1)

Vapour pressure (kPa; 20 °C) 0.10 (3)

Water solubility (g/litre; 25 °C) 13.5 (1)

n-Octanol/water partition coefficient(log Kow)

2.00 (4)

Dissociation constant (pKa) (18 °C) 8.34 (2)

Conversion factors 1 mg/m3 = 0.173 ppmv1 ppmv = 5.78 mg/m3

References: (1) Verschueren (1983); (2) Budavari et al. (1996);(3) HSDB (1998); (4) Hansch & Leo (1979)

Environmental transport, distribution, andtransformation

Data on the abiotic degradation of 3-nitrophenol were notavailable.

Three studies on biotic degradation, summarized inTable A-2, indicate the isomer to be inherently biodegradablein water under aerobic conditions.

In tests on biotic degradation under anaerobic conditionsusing sewage sludge and sludge from the primary anaerobicstage of a municipal sewage treatment plant, respectively, initial3-nitrophenol concentrations in the range of 96.5–579 mg/litrewere not degraded at all within 7–60 days (Wagner &Braeutigam, 1981; Battersby & Wilson, 1989). Boyd et al.(1983), however, found complete anaerobic removal of 50mg/litre within 1 week of incubation. In this test, mineralizationwas demonstrated only if the incubation period was extended to10 weeks. Anaerobic degradation, even of high initialnitrophenol concentrations, was found by Tseng & Lin (1994),who observed 90% removal of 3-nitrophenol (350–650 mg/litre)in a biological fluidized bed reactor with three different kinds of

wastewater. From the available results, a slow mineralization of3-nitrophenol under anaerobic conditions by adaptedmicroorganisms can be expected.

A soil sorption coefficient (Koc) of 52.83, determined byBoyd (1982), and the n-octanol/water partition coefficient (logKow) of 2.0, reported by Hansch & Leo (1979), indicate a low tomoderate potential for soil sorption as well as forbioaccumulation.

Environmental levels

3-Nitrophenol was not detected in 27 samples of air(detection limit 8 ng/m3) in Japan in 1994 (Japan EnvironmentAgency, 1995). It was not detected in 177 samples of Japanesesurface waters (detection limits 0.04–10 :g/litre) or in 177sediment samples (detection limits 0.002–0.8 :g/kg) in 1978,1979, and 1994 (Japan Environment Agency, 1979, 1980,1995). 3-Nitrophenol was not detected in 129 fish samples(detection limits 0.005–0.2 :g/kg) in Japan in 1979 and 1994(Japan Environment Agency, 1980, 1995).

Comparative kinetics and metabolism inlaboratory animals and humans

Studies providing quantitative information on theabsorption, metabolism, or elimination of 3-nitrophenol inhumans were not identified. In addition, there is only verylimited information available for experimental animals. Inrabbits given a single dose of 150–200 mg/kg body weight viagavage, most of the applied dose (o80%) was excreted via theurine within 24 h. About 68–86% was conjugated withglucuronic acid and sulfonic acid, whereas about 7–13% wasreduced to aminophenols (Robinson et al., 1951). Skinpermeation was shown in several in vitro experiments (Huq etal., 1986; Jetzer et al., 1986; Ohkura et al., 1990). Although theinformation is limited, bioaccumulation of 3-nitrophenol inorganisms is not to be expected owing to the isomer’s rapidmetabolism and excretion.

Effects on laboratory mammals and in vitro testsystems

The oral LD50 of 3-nitrophenol is quoted to be $930mg/kg body weight for rats (Vasilenko et al., 1976; Vernot et al.,1977) and $1070 mg/kg body weight for mice (Vasilenko et al.,1976; Vernot et al., 1977).

The available in vitro and in vivo genotoxicity studies on3-nitrophenol are summarized in Table A-3. 3-Nitrophenol wasshown to be mutagenic in a rec-assay and gave inconsistentresults in Salmonella/microsome assays. One study showed it tobe non-mutagenic in the Salmonella typhimurium TA98 andTA100 strains, whereas another study showed mutagenicity inboth of these strains in both the presence and absence ofmetabolic activation. In view of the conflicting results fromSalmonella/microsome assays and the absence of any data onclastogenicity, no conclusions can be made regarding themutagenicity of 3-nitrophenol.

For 3-nitrophenol, there are no studies availableconcerning irritating or sensitizing effects, repeated exposure,reproductive and developmental toxicity, or effects on humans.

Effects on aquatic species

In tests performed on the toxicity of 3-nitrophenol tovarious aquatic organisms (see Table A-4), 3-nitrophenolexhibited a moderate to high toxicity.


32

Table A-2: Biotic degradation of 3-nitrophenol under aerobic conditions.

TestConcentration(mg/litre)

Additionalcarbon source

Test duration(days)

Removal(%) Reference

Tests on ready biodegradability

MITI I 100 no 14 0 Gerike & Fischer (1979);Urano & Kato (1986)

Tests on inherent biodegradability

Batch test, aerated 200 CODa no 5 95 Pitter (1976)

Respirometric test 300 yes 10 44 Kayser et al. (1994)

a COD = chemical oxygen demand.

Table A-3: Genotoxicity of 3-nitrophenol in vitro and in vivo.

Resultsa

Species (test system) End-pointConcentrationrange


Withmetabolicactivation Remarks References

In vitro studies


Recombination assay

0.01–5mg/plate

+ 0 positive at $0.5mg/plate

Shimizu &Yano (1986)

Salmonella

typhimurium TA1535,TA1537, TA1538

Reversemutations

0.01–5mg/plate

! ! Shimizu &Yano (1986)

Salmonella

typhimurium TA98,TA100

Reversemutations

0.1–5 mg/plate + + Study in Japanese(data taken fromtables)

Kawai et al.(1987)

Salmonella

typhimurium TA98,TA100

Reversemutations

0.01–5mg/plate

! ! Suzuki et al. (1983)also tested bothstrains in the pres-ence of norharman,which also gavenegative results

Suzuki et al.(1983); Shimizu& Yano (1986)

In vivo studies

Drosophila

melanogaster

SLRL assay via feed (5000ppm) or injec-tion (1200ppm)

Foureman et al.(1994)

a !, negative; +, positive; 0, not tested.

Table A-4: Aquatic toxicity of 3-nitrophenol.

Species(test method/end-point)

Effective concentration(mg/litre) Reference

Bacteria

Pseudomonas putida (cell multiplication inhibitiontest)

16-h MICa: 7.0 Bringmann & Kuehn (1977)

Protozoa

Entosiphon sulcatum (cell multiplication inhibitiontest)

72-h MIC: 0.97 Bringmann (1978); Bringmann et al.(1980)

Algae

Scenedesmus subspicatus

Chlorella vulgaris (cell multiplication inhibition test)6-h EC50: 6.21 Kramer et al. (1986)

Invertebrates

Moina macrocopa (acute) (immobilization) 3-h LC50: 1.7 Yoshioka et al. (1985)

Fish

Cyprinus carpio (static) 96-h LC50: 17.5 Lang et al. (1996)

a MIC = minimum inhibitory concentration.

Mononitrophenols

33

APPENDIX 2 — SOURCE DOCUMENTS

BUA (1992): BUA-Stoffbericht 2- und 4-Nitrophenol. Beratergremium fuerUmweltrelevante Altstoffe. Weinheim, VCHVerlagsGmbH (Report No. 75; February 1992)

For the BUA review process, the company that is in chargeof writing the report (usually the largest producer in Germany)prepares a draft report using literature from an extensiveliterature search as well as internal company studies. This draft issubject to a peer review during several readings of a workinggroup consisting of representatives from government agencies,the scientific community, and industry.

The English translation of BUA Report No. 75 (BUA

Report 2- and 4-Nitrophenol. GDCh-Advisory Committee onExisting Chemicals of Environmental Relevance. Stuttgart,Hirzel Verlag [February 1992]) was released in 1993.

ATSDR (1992): Toxicological profile fornitrophenols: 2- and 4-nitrophenol. Atlanta, GA,US Department of Health and Human Services,Public Health Service, Agency for ToxicSubstances and Disease Registry (Report No.TP-91/23)

Copies of the ATSDR Toxicological profile for

nitrophenols: 2- and 4-nitrophenol (ATSDR, 1992) may beobtained from the:

Agency for Toxic Substances and Disease RegistryDivision of Toxicology1600 Clifton Road, E-29Atlanta, Georgia 30333USA

Initial drafts of the Toxicology profile for nitrophenols: 2-

and 4-nitrophenol were reviewed by scientists from the Agencyfor Toxic Substances and Disease Registry, the US Centers forDisease Control, the US National Toxicology Program, and otherfederal agencies. The document was also reviewed by an expertpanel of nongovernmental reviewers, consisting of the followingmembers:

Dr Martin Alexander, Cornell UniversityDr Gary Booth, Brigham Young UniversityDr Samuel Cohen, University of Nebraska Medical CenterDr Loren Koller, Oregon State UniversityDr Frederick Oehme, Kansas State University

APPENDIX 3 — CICAD PEER REVIEW

The draft CICAD on mononitrophenols was sent for reviewto institutions and organizations identified by IPCS after contactwith IPCS national Contact Points and Participating Institutions,as well as to identified experts. Comments were received from:

Federal Institute for Health Protection of Consumers &Veterinary Medicine, Berlin, Germany

Gesellschaft Deutscher Chemiker, Frankfurt, Germany

Institute of Occupational Medicine, Chinese Academy ofPreventive Medicine, Ministry of Health, Beijing, People’sRepublic of China

Institute of Terrestrial Ecology, Huntingdon, UnitedKingdom

Joint Food Safety and Standards Group, Department ofHealth, London, United Kingdom

National Institute of Health Sciences, Tokyo, Japan

National Institute of Public Health, Prague, CzechRepublic

United States Department of Health and Human Services(National Institute of Environmental Health Sciences,Research Triangle Park), USA

United States Environmental Protection Agency (NationalCenter for Environmental Assessment, Washington, DC;Region VIII), USA

World Health Organization/International Programme onChemical Safety, Montreal, Canada


34

APPENDIX 4 — CICAD FINAL REVIEWBOARD

Washington, DC, USA, 8–11 December 1998

Members

Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna,Sweden (Vice-Chairperson)

Mr R. Cary, Toxicology Unit, Health Directorate, Health andSafety Executive, Bootle, Merseyside, United Kingdom(Rapporteur)

Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom

Dr O. Faroon, Agency for Toxic Substances and DiseaseRegistry, Centers for Disease Control and Prevention, Atlanta,GA, USA

Dr G. Foureman, National Center for Environmental Assessment,US Environmental Protection Agency, Research Triangle Park,NC, USA

Dr H. Gibb, National Center for Environmental Assessment, USEnvironmental Protection Agency, Washington, DC, USA(Chairperson)

Dr R.F. Hertel, Federal Institute for Health Protection ofConsumers & Veterinary Medicine, Berlin, Germany

Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,Fraunhofer Institute for Toxicology and Aerosol Research,Hanover, Germany

Dr A. Nishikawa, Division of Pathology, National Institute ofHealth Sciences, Tokyo, Japan

Dr E.V. Ohanian, Office of Water/Office of Science andTechnology, Health and Ecological Criteria Division, USEnvironmental Protection Agency, Washington, DC, USA

Dr J. Sekizawa, Division of Chem-Bio Informatics, NationalInstitute of Health Sciences, Tokyo, Japan

Professor P. Yao, Institute of Occupational Medicine, ChineseAcademy of Preventive Medicine, Ministry of Health, Beijing,People’s Republic of China

Observers

Dr K. Austin, National Center for Environmental Assessment, USEnvironmental Protection Agency, Washington, DC, USA

Dr I. Daly (ICCA representative), Regulatory and TechnicalAssociates, Lebanon, NJ, USA

Ms K.L. Lang (CEFIC, European Chemical Industry Council,representative), Shell International, London, United Kingdom

Ms K. Roberts (ICCA representative), Chemical Self-fundedTechnical Advocacy and Research (CHEMSTAR), ChemicalManufacturers Association, Arlington, VA, USA

Dr W. Snellings (ICCA representative), Union CarbideCorporation, Danbury, CN, USA

Dr M. Sweeney, Document Development Branch, NationalInstitute for Occupational Safety and Health, Cincinnati, OH,USA

Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt undGesundheit GmbH, Institut für Toxikologie, Oberschleissheim,Germany

Secretariat

Dr M. Baril, Institut de Recherches en Santé et Sécurité duTravail du Québec (IRSST), Montreal, Quebec, Canada

Dr H. Galal-Gorchev, Chevy Chase, MD, USA

Ms M. Godden, Health and Safety Executive, Bootle,Merseyside, United Kingdom

Dr R.G. Liteplo, Environmental Health Directorate, HealthCanada, Ottawa, Ontario, Canada

Ms L. Regis, Programme for the Promotion of Chemical Safety,World Health Organization, Geneva, Switzerland

Mr A. Strawson, Health and Safety Executive, London, UnitedKingdom

Dr P. Toft, Programme for the Promotion of Chemical Safety,World Health Organization, Geneva, Switzerland

Mononitrophenols

35

RÉSUMÉ D’ORIENTATION

Ce CICAD relatif aux isomères en position 2-, 3- et4- du nitrophénol a été préparé par l’Institut Fraunhoferde recherche en toxicologie et sur les aérosols deHanovre (Allemagne). Il est basé sur des mises au pointrédigées par le Comité consultatif allemand sur lesproduits chimiques qui posent un problème écologique(BUA, 1992) et par l’US Agency for Toxic Substancesand Disease Registry (ATSDR, 1992) afin d’évaluer leseffets potentiels du 2- et du 4-nitrophénol surl’environnement et la santé humaine. Les données prisesen compte dans ces mises au point vont jusqu’en 1992.Une recherche bibliographique exhaustive a été effectuéeen 1998 sur plusieurs bases de données afin de releverles références intéressantes sur le 2- et le 4-nitrophénolpubliées après celles qui figurent dans les documents debase et d’obtenir toutes celles qui contiennent desdonnées utiles sur le 3-nitrophénol. On a trouvé très peude données sur cet isomère, ce qui rend impossible unevéritable évaluation. Les données concernant cetisomère sont donc récapitulées à l’appendice 1. Ontrouvera à l’appendice 2 des indications sur le moded’examen par des pairs ainsi que sur les sourcesdocumentaires utilisées. Les renseignements concernantl’examen du CICAD par des pairs font l’objet de l’appen-dice 3. Ce CICAD a été approuvé en tant qu’évaluationinternationale lors de la réunion du Comité d’évaluationfinale qui s’est tenue à Washington du 8 au 11 décembre1998. La liste des participants à cette réunion figure àl’appendice 4. La fiche d’information internationale sur lasécurité chimique (ICSC No 1342) relative au mélanged’isomères du nitrophénol, établie par le Programmeinternational sur la sécurité chimique (IPCS, 1998) estégalement reproduite dans ce document.

Les isomères du nitrophénol sont des solidessolubles dans l’eau qui sont légèrement acides dans cesolvant par suite de leur dissociation. Les isomères 2- et4- sont utilisés comme intermédiaires dans la synthèsed’un certain nombre d’insecticides organophosphorés etde composés à usage médical. Lorsqu’ils passent dansl’environnement, c’est principalement par suited’émissions dans l’eau, l’air et le sol provenant desources diffuses comme la circulation automobile ou ladécomposition par photolyse ou hydrolyse de certainsinsecticides. Le dépôt par voie sèche ou humide denitrophénols présents dans l’atmosphère constitue unapport supplémentaire dans l’hydrosphère et la géo-sphère. La formation photo-oxydative du 2- et du 4-nitrophénol dans l’atmosphère est encore débattue.

Les données disponibles montrent que le 2-nitro-phénol ne devrait se volatiliser que lentement dans

l’atmosphère et qu’il ne passe sans doute qu’en quantiténégligeable de l’eau à l’air selon ce processus. Onconstate un enrichissement en 2-nitrophénol de la phaseaqueuse des nuages; en revanche, dans la phasegazeuse, la proportion de 4-nitrophénol est plusimportante qu’on pourrait le penser en fonction desdonnées physico-chimiques, par suite d’une importantefixation du composé sur les particules. Compte tenu deleur solubilité dans l’eau et de leur concentration dans laphase gazeuse, on peut s’attendre à ce que lesnitrophénols présents dans l’atmosphère se déposentpar voie humide sur la surface du sol et de l’eau. Laprincipale voie de transformation du 2-nitrophénolprésent dans l’atmosphère est vraisemblablement sanitration rapide en 2,4-dinitrophénol, le 4-nitrophénolétant quant à lui en majeure partie fixé aux particulesaéroportées et donc disponible en petites quantitésseulement pour des réactions photochimiques. Lamajeure partie du 4-nitrophénol devrait d’ailleursdisparaître de l’atmosphère en se déposant soit par voiesèche, soit par voie humide. Il ne semble pas que lesnitrophénols contribuent directement à la dégradation dela couche d’ozone stratosphérique ni au réchauffementgénéral de la planète. Soumis à une photodécompositionen milieu aqueux, le 4-nitrophénol a une demi-vie quipeut aller de 2,8 à 13,7 jours selon les mesures. Lesnombreuses études consacrées à la biodégradation du 2-et du 4-nitrophénol montrent que ces deux isomères sontintrinsèquement biodégradables dans l’eau en aérobiose.La minéralisation des nitrophénols en anaérobiose exigeà l’évidence une importante adaptation des populationsmicrobiennes.

La valeur du coefficient de sorption par lesparticules du sol (Koc), qui se situe entre 44 et 530,indique que le potentiel de sorption est faible à modéré.Les nitrophénols qui passent dans le sol vont vraisem-blablement subir une biodégradation aérobie. Il nedevrait y avoir infiltration dans les eaux souterraines quelorsque les conditions ne sont pas favorables à une bio-dégradation. Pour le 2- et le 4-nitrophénol, la mesure dufacteur de bioconcentration donne des valeurs allant de11 à 76, ce qui indique un faible potentiel de bioconcen-tration.

On connaît plutôt mal le profil toxicologique du 2-et du 4-nitrophénol. Lorsqu’il est administré à desanimaux de laboratoire par voie orale, intraveineuse ouintrapéritonéale, le 4-nitrophénol est en majeure partieexcrété dans les urines en l’espace de 24 à 48 h sousforme de glucuronide ou de sulfo-conjugué, une faiblepartie seulement passant dans les matières fécale ourestant inchangée. On a montré que la proportion deglucuronide et de sulfo-conjugués variait selon lesespèces. Après administration par voie orale à des


36

lapins, le 4-nitrophénol est réduit en p-aminophénol etsubit aussi une transformation en glucuronide et sulfo-conjugués. Les données tirées des études in vivo et invitro donnent une indication sur la résorption du 4-nitrophénol par la voie transcutanée. En revanche, lesdonnées concernant le 2-nitrophénol sont très limitées.Quoi qu'il en soit, on peut considérer, en se basant surles données disponibles, que les deux isomères ont unmétabolisme comparable. Le 2- et le 4-nitrophénol nedevraient pas s’accumuler dans l’organisme en raison deleur métabolisation et de leur excrétion rapides.

Les études de toxicité aiguë montrent que le 4-nitrophénol a un effet nocif après ingestion et qu’il estplus toxique que le 2-nitrophénol. Chez des chats, on aconstaté une augmentation du taux de méthémoglobineliée à la dose après ingestion de 2-nitrophénol; la mêmeconstatation a été faite chez des rats après inhalation de4-nitrophénol. Une exposition répétée à du 4-nitrophénola montré que la formation de méthémoglobine est l’effetle plus déterminant d’une exposition par la voierespiratoire et cela vaut sans doute aussi pour la voieorale. Parmi les autres effets observés, on peut citer unmoindre gain de poids, une modification du poids desorganes, une dégénérescence graisseuse du foie et desanomalies hématologiques. Il n’a pas été possible dedégager une véritable relation dose-réponse ni dedéterminer de manière fiable la dose sans effet (nocif)observable (NO(A)EL) correspondant à ces effets.

Le 2-nitrophénol est légèrement irritant pour lapeau mais il n’irrite pas la muqueuse oculaire. Le test deBuehler montre que le composé n’a pas non plus d’effetsensibilisateur. En s’appuyant sur des études valableseffectuées sur l’animal, on peut conclure que le 4-nitrophénol a par contre une légère action irritante sur lapeau et les yeux. Un test de maximalisation sur le cobayea montré que le 4-nitrophénol avait également une légèreaction sensibilisatrice. Chez l’homme, on ne peut exclureune légère sensibilisation après un contact avec lecomposé, d’autant plus que la pose d’un timbre cutanéchez des ouvriers pouvant avoir été en contact avec du4-nitrophénol a permis de constater une tellesensibilisation.

Aucun des deux isomères n’a fait l’objetd’épreuves de génotoxicité suffisamment complètes.S’agissant du 2-nitrophénol, les données sont insuf-fisantes pour que l’on puisse tirer la moindre conclusionconcernant une mutagénicité éventuelle. Dans le cas du4-nitrophénol, les études de mutagénicité sont plusnombreuses, mais le compte rendu en est parfoisinsuffisant. On est fondé à penser que ce composé estsusceptible de provoquer des aberrations chromoso-miques in vitro . Faute d’études de mutagénicité in vivo

sur des mammifères, il n’est pas possible de savoir si lepouvoir mutagène de cet isomère peut s’exprimer in vivo.

Chez la souris l’application cutanée de 4-nitro-phénol pendant une durée de 78 semaines n’a pas donnéd’indices d’effets cancérogènes. Dans une autre étudesur la souris, qui présentait toutefois un certain nombred’insuffisances, on n’a pas non plus observé de tumeurscutanées après application cutanée de ces deux isomèrespendant 12 semaines. Aucune étude de cancérogénicitéutilisant la voie orale ou respiratoire n’était disponible.

Les données relatives au 4-nitrophénol ne révèlentaucun effet indésirable sur la reproduction ou ledéveloppement qui soit statistiquement significatif aprèsexposition de rats et de souris par voie orale ou cutanée.Après administration par voie orale de 2-nitrophénol àdes rats, on a constaté dans la progéniture des animauxdes effets indésirables sur le développement, maisseulement aux doses toxiques pour les mères. On n’atoutefois pas recherché la présence de malformationsinternes.

La base de données relative au 2-nitrophénol estextrêmement limitée et celle qui concerne le 4-nitrophénolest insuffisante pour qu’on puisse en tirer une valeurfiable de la NO(A)EL. Il est donc impossible de fixer pourl’instant une valeur pour la dose journalière tolérable(DJT) ou pour la concentration tolérable (CT) de cesdeux isomères.

D’après les résultats des études toxicologiquesvalables effectuées sur divers organismes aquatiques ,on peut considérer que ces deux nitrophénols sontmodérément à fortement toxiques pour la vie aquatique.La concentration sans effet la plus faible qui ait étéobtenue lors d’études de longue durée sur desorganismes d’eau douce (Scenedesmus subspicatus,EC50 à 96 h : 0,39 mg de 2-nitrophénol/litre; Entosiphonsulcatum, concentration minimale inhibitrice à 72 h ouCMI : 0,83 mg de 4-nitrophénol/l) était 40 à 50 fois plusforte que la valeur maximale obtenue dans un bassinfluvial d’Asie situé dans une zone très industrialisée etdensément peuplée (respectivement 0,0072 mg/l et 0,019mg/l). Par conséquent, malgré la biodégradation et ladécomposition photochimique, les nitrophénolsdéversés dans l’eau peuvent présenter un certain risquepour les organismes aquatiques sensibles, notammentdans des eaux superficielles où les conditions ne sontpas favorables à ces deux modes d’élimination.Cependant, compte tenu de leurs usages et de leurspossibilités de libération dans l’environnement, ces deuxnitrophénols ne présentent qu’un risque mineur pour lesorganismes aquatiques.

Mononitrophenols

37

Les données disponibles indiquent que la toxicitépotentielle de ces nitrophénols est modérée dans l’envi-ronnement terrestre. Le calcul du rapport d’expositiontoxique (TER) des nitrophénols provenant de la décom-position de certains pesticides montre que, dans cemilieu, le risque reste faible pour la faune et la flore,même dans la pire des hypothèses.


38

RESUMEN DE ORIENTACIÓN

Preparó el presente CICAD sobre los isómeros 2-,3- y 4-nitrofenol el Instituto Fraunhofer de Toxicología yde Investigación sobre los Aerosoles de Hannover,Alemania. Se basa en los exámenes compilados por elComité Consultivo Alemán sobre las SustanciasQuímicas Importantes para el Medio Ambiente (BUA,1992) y la Agencia para el Registro de SustanciasTóxicas y Enfermedades de los Estados Unidos(ATSDR, 1992) para evaluar los efectos potenciales del2- y el 4-nitrofenol en el medio ambiente y en el serhumano. En estos exámenes se incluyeron los datosidentificados hasta 1992. En 1998 se realizó unabúsqueda bibliográfica amplia de varias bases de datospara identificar todas las referencias importantesrelativas al 2- y el 4-nitrofenol publicadas conposterioridad a las que figuran en los documentosoriginales y para conocer todas las referencias con datospertinentes sobre el isómero 3-nitrofenol. La informaciónobtenida sobre el 3-nitrofenol fue muy escasa, lo queimpide una evaluación válida. En consecuencia, losdatos sobre este isómero se resumen en el apéndice 1. Lainformación relativa al carácter del examen colegiado y ala disponibilidad de los documentos originales figura enel apéndice 2. La información sobre el examen colegiadode este CICAD se presenta en el apéndice 3. Este CICADse aprobó como evaluación internacional en una reuniónde la Junta de Evaluación Final celebrada enWashington, DC, Estados Unidos, los días 8-11 dediciembre de 1998. La lista de participantes en estareunión figura en el apéndice 4. La Ficha internacional deseguridad química (ICSC 1342) para las mezclas deisómeros de nitrofenoles, preparada por el ProgramaInternacional de Seguridad de las Sustancias Químicas(IPCS, 1998), también se reproduce en el presentedocumento.

Los isómeros del nitrofenol son sólidos hidro-solubles con una acidez moderada en agua debido a ladisociación. El 2-nitrofenol y el 4-nitrofenol se utilizancomo intermediarios en la síntesis de diversosplaguicidas órganofosforados y algunos productosmédicos. La liberación en el medio ambiente se producefundamentalmente por emisiones en el aire, el agua y elsuelo a partir de fuentes difusas, como el tráfico devehículos y la degradación hidrolítica y fotolítica de losrespectivos plaguicidas. También se produce liberaciónen la hidrosfera y la geosfera a partir de la atmósferadebido a la deposición seca y húmeda de nitrofenolessuspendidos en el aire. La formación fotooxidativa de 2-y 4-nitrofenol en la atmósfera es todavía objeto deestudio.

Con los datos disponibles sólo cabe esperar unavolatilización lenta desde el agua hacia el aire para el 2-nitrofenol y no significativa para el 4-nitrofenol. El 2-nitrofenol se enriquece en la fase líquida de las nubes,mientras que es posible encontrar más 4-nitrofenol delprevisto a partir de los datos fisicoquímicos en la fasegaseosa de las nubes, debido a una amplia unión apartículas. Habida cuenta de la solubilidad en agua y lapresencia prevista en la fase de vapor, cabe esperar unadeposición húmeda de nitrofenoles del aire en las aguassuperficiales y en el suelo. La vía principal de trans-formación del 2-nitrofenol emitido a la troposfera debeser la nitración rápida a 2,4-dinitrofenol, mientras que sesupone que la mayor parte del 4-nitrofenol suspendidoen el aire se encuentra unido a partículas y, por con-siguiente, disponible solamente en menor cantidad parareacciones fotoquímicas. La mayor parte del 4-nitrofenoldel aire debe precipitar por deposición húmeda y seca.No se considera que los nitrofenoles contribuyandirectamente al agotamiento de la capa de ozonoestratosférico o al calentamiento mundial. La semividamedida para la descomposición fotoquímica del 4-nitrofenol en agua osciló entre 2,8 y 13,7 días. Numero-sos estudios sobre la biodegradación del 2- y el 4-nitrofenol indican que los isómeros son inherentementebiodegradables en agua en condiciones aerobias. Lamineralización de los nitrofenoles en condicionesanaerobias requiere evidentemente una amplia adap-tación de las comunidades microbianas.

Los coeficientes de sorción en el suelo (Koc)medidos del orden de 44-530 indican un potencial debajo a moderado para la sorción en el suelo. Losnitrofenoles liberados al suelo se deben biodescomponeren condiciones aerobias. Cabe prever filtración hacia elagua freática sólo en condiciones desfavorables para labiodegradación. Para el 2- y el 4-nitrofenol, los factoresde bioconcentración medidos de 11 a 76 ponen demanifiesto un potencial bajo de bioacumulación.

Se dispone sólo de información limitada relativa alos perfiles toxicológicos del 2- y el 4-nitrofenol. Losanimales experimentales a los que se administró 4-nitrofenol por vía oral, intravenosa o intraperitonealexcretaron la mayor parte de la dosis aplicada por víaurinaria en un plazo de 24-48 horas en forma de conju-gados de glucurónidos y sulfatos, mientras que por lasheces se excretaron solamente cantidades muypequeñas, o bien como 4-nitrofenol inalterado. Seobservó que los porcentajes de conjugados deglucurónidos y sulfatos eran dependientes de la especiey de la dosis. Tras la administración oral a conejos, el 4-nitrofenol sufre una reducción a p-aminofenol, así comouna glucuronización y sulfatación. Los datosdisponibles de estudios in vivo e in vitro dan una idea

Mononitrophenols

39

de la absorción cutánea del 4-nitrofenol. Los datos parael 2-nitrofenol son muy limitados. Sin embargo, teniendocuenta los datos disponibles, se supone que se produceuna transformación metabólica comparable. No cabeprever bioacumulación de 2- y 4-nitrofenol en losorganismos debido a la rapidez de su metabolismo yexcreción.

En estudios de toxicidad aguda, el 4-nitrofenol esperjudicial tras la absorción oral, y se observó que eramás tóxico que el 2-nitrofenol. Se detectó un aumento enla formación de metahemoglobina dependiente de ladosis en gatos tras la exposición oral al 2-nitrofenol y enratas tras la exposición por inhalación al 4-nitrofenol.Después de una exposición repetida al 4-nitrofenol, seobservó la formación de metahemoglobina como elefecto final más importante de la exposición porinhalación, y se considera que esto es aplicable tambiéna la exposición oral. Otros efectos observados fueron lareducción del aumento del peso corporal, diferencias enel peso de los órganos, degeneración adiposa focal delhígado y cambios hematológicos. Para esos efectos nofue posible determinar una relación clara dosis-respuestao concentraciones sin efectos (adversos) observados(NO(A)EL) fidedignas.

El 2-nitrofenol es ligeramente irritante para la piel,pero no para los ojos. En una prueba de Buehler no seobservó efecto sensibilizador. Tomando como base losestudios válidos con animales experimentales, se suponeque el 4-nitrofenol tiene efectos irritantes en la piel y losojos. En una prueba de maximización en cobayas, seobservó que el 4-nitrofenol era ligeramente sensibili-zante. En el ser humano no se puede excluir una posiblesensibilización tras el contacto con 4-nitrofenol,especialmente teniendo en cuenta que se ha observadosensibilización cutánea en pruebas de parche entrabajadores de fábricas que podían haber estadoexpuestos al 4-nitrofenol.

No se ha sometido a pruebas completas degenotoxicidad ninguno de los dos isómeros delnitrofenol. Los datos disponibles sobre el 2-nitrofenolson insuficientes para poder sacar conclusiones acercade su posible mutagenicidad. Hay más estudios demutagenicidad para el 4-nitrofenol, aunque algunos senotificaron de manera inadecuada. Hay pruebas queparecen indicar que el 4-nitrofenol puede produciraberraciones cromosómicas in vitro . En ausencia deestudios de mutagenicidad in vivo en mamíferos, no esposible llegar a la conclusión de si se expresa o no invivo el potencial mutagénico del 4-nitrofenol.

Tras la aplicación cutánea de 4-nitrofenol aratones durante 78 semanas no se observaron efectos

carcinogénicos. En otro estudio con ratones, que tienevarias limitaciones, no se detectaron tumores cutáneostras la aplicación en la piel de 2- ó 4-nitrofenol durante 12semanas. Para ninguno de los isómeros había estudiosde carcinogenicidad utilizando la vía oral o la inhalación.

Los datos disponibles para el 4-nitrofenol nopusieron de manifiesto efectos específicos o estadística-mente significativos de toxicidad reproductiva o deldesarrollo tras la administración cutánea u oral a ratas yratones. En un estudio de administración por vía oral aratas, el 2-nitrofenol indujo efectos en el desarrollo de lacamada sólo con dosis que también producían toxicidadmaterna. Sin embargo, en estos estudios no se examin-aron los fetos para investigar malformaciones internas.

La base de datos para el 2-nitrofenol esenormemente limitada y la relativa al 4-nitrofenol esinsuficiente para deducir valores fidedignos de la(NO(A)EL). Por consiguiente, es imposible determinar eneste momento la ingesta diaria tolerable o lasconcentraciones tolerables para el 2- ó el 4-nitrofenol.

De los resultados disponibles de pruebas válidassobre la toxicidad del 2-y el 4-nitrofenol para diversosorganismos acuáticos, los nitrofenoles se puedenclasificar como sustancias con una toxicidad entremoderada y alta en el compartimento acuático. Lasconcentraciones más bajas con efectos obtenidas enestudios crónicos con organismos de agua dulce(Scenedesmus subspicatus, CE50: 0,39 mg de 2-nitro-fenol/litro a las 96 h; Entosiphon sulcatum, concentra-ción inhibitoria mínima a las 72 horas: 83 mg de 4-nitrofenol/litro) fueron 40-50 veces superiores a losniveles máximos determinados en una cuenca fluvialasiática densamente poblada y muy industrializada(0,0072 mg de 2-nitrofenol/litro y 0,019 mg de 4-nitro-fenol/litro). Por consiguiente, a pesar de la descomposi-ción biótica y fotoquímica, los nitrofenoles emitidos alagua pueden representar algún peligro para los organis-mos acuáticos sensibles, particularmente en las condici-ones de las aguas superficiales que no favorecen ambasvías de eliminación. Habida cuenta de sus pautas de usoy sus características de liberación, probablemente losnitrofenoles plantean sólo un pequeño riesgo para losorganismos acuáticos.

Los datos disponibles indican solamente unatoxicidad potencial moderada de los nitrofenoles en elmedio ambiente terrestre. A partir de los cálculos de larazón exposición-toxicidad de los nitrofenoles a partir dela degradación de plaguicidas, sólo cabe esperar unpequeño riesgo para los organismos en este comparti-mento, incluso en el peor de los casos.

MONONITROPHENOLS - WHO | World Health Organization · purpose of the IOMC is to promote...

Documents

Transcript of MONONITROPHENOLS - WHO | World Health Organization · purpose of the IOMC is to promote...