DMDM Hydantoin (DMDMH) Product-type 13 (Metalworking Fluids) - Public/Library... · Directive...
Transcript of DMDM Hydantoin (DMDMH) Product-type 13 (Metalworking Fluids) - Public/Library... · Directive...
Directive 98/8/EC concerning the placing biocidal
products on the market
Inclusion of active substances in Annex I or IA to Directive 98/8/EC
Competent Authority Report This non-confidential version of the Evaluation Report for DMDMH has been produced by the
participant after evaluation of the RMS. The amendments made have not been validated by the
RMS. Therefore the confidential version is the only valid version of the report.
DMDM Hydantoin (DMDMH)
Product-type 13
(Metalworking Fluids)
Rapporteur Member State: Poland
Draft - June 2010
1. STATEMENT OF SUBJECT MATTER AND PURPOSE .................................................................................. 4
1.1 BACKGROUND OF THIS EVALUATION REPORT AND PURPOSE .................................................................................. 4
2. OVERALL SUMMARY AND CONCLUSIONS .............................................................................................. 5
2.1 PRESENTATION OF THE ACTIVE SUBSTANCE ......................................................................................................... 5
2.1.1 Identity, Physical‐Chemical Properties and Method of Analysis ..................................................... 5
2.1.1.1 Physical‐chemical properties ................................................................................................................. 5
2.1.1.2 Analytical Methods ................................................................................................................................ 6
2.1.2 Intended uses and Efficacy .............................................................................................................. 6
2.1.3 Classification and Labelling ............................................................................................................. 7
2.2 SUMMARY OF THE RISK ASSESSMENT ................................................................................................................. 8
2.2.1 Human Health Risk Assessment ...................................................................................................... 8
2.2.1.1 Hazard characterisation ........................................................................................................................ 8
2.2.1.1.1 DMDMH ........................................................................................................................................... 8
2.2.1.1.2 DMH ................................................................................................................................................. 9
2.2.1.1.3 Formaldehyde ................................................................................................................................ 10
2.2.1.1.4 Biocidal product ............................................................................................................................. 11
2.2.1.2 Professionals ....................................................................................................................................... 12
2.2.1.2.1 Risk assessment at the workplace .................................................................................................. 12
2.2.1.2.2 Risk assessment as a result of the use of the biocidal product ...................................................... 13
2.2.1.3 Non‐Professionals................................................................................................................................ 15
2.2.1.4 Indirect exposure as a result of use of the active substance in biocidal product ................................ 15
2.2.1.5 Combined exposure ............................................................................................................................ 15
2.2.2 Environmental Risk Assessment .................................................................................................... 16
2.2.2.1 Fate and Distribution in the Environment ........................................................................................... 16
2.2.2.1.1 Biodegradation ............................................................................................................................... 16
2.2.2.1.2 Abiotic Degradation ....................................................................................................................... 16
2.2.2.1.3 Distribution and Mobility ............................................................................................................... 17
2.2.2.1.4 Bioaccumulation ............................................................................................................................ 17
2.2.2.2 Effects Assessment .............................................................................................................................. 17
2.2.2.2.1 Aquatic Compartment .................................................................................................................... 17
2.2.2.2.2 Terrestrial Compartment ............................................................................................................... 18
2.2.2.3 PBT Assessment ................................................................................................................................... 18
2.2.2.4 Exposure Assessment .......................................................................................................................... 18
2.2.2.5 Risk Characterisation ........................................................................................................................... 20
2.2.2.5.1 Aquatic compartment including STP .............................................................................................. 20
2.2.2.5.2 Terrestrial Compartment ............................................................................................................... 21
2.2.3 Listing of Endpoints ....................................................................................................................... 21
3. PROPOSAL FOR THE DECISION ............................................................................................................ 22
3.1 BACKGROUND TO THE PROPOSED DECISION ...................................................................................................... 22
3.2 PROPOSED DECISION REGARDING THE INCLUSION IN ANNEX I ............................................................................... 22
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3.3 ELEMENTS TO BE TAKEN INTO ACCOUNT BY MEMBER STATES WHEN AUTHORIZING PRODUCTS .................................... 22
3.4 DEMAND FOR FURTHER INFORMATION ............................................................................................................. 23
3.5 UPDATING THIS ASSESSMENT REPORT .............................................................................................................. 23
APPENDIX I – LIST OF ENDPOINTS ................................................................................................................ 24
APPENDIX II ‐ LIST OF TERMS AND ABBREVIATIONS ..................................................................................... 52
APPENDIX III ‐ LIST OF ORGANISATIONS AND PUBLICATIONS ........................................................................ 59
DMDM Hydantoin (DMDMH) Product type 13 June 2010
1. STATEMENT OF SUBJECT MATTER AND PURPOSE
1.1 BACKGROUND OF THIS EVALUATION REPORT AND PURPOSE
This report has been established as a result of the evaluation of the biocidal active substance DMDMH in the frame of the Biocides Directive 98/8/EC. The aim of this report is to make available a detailed examination of the dossier of the existing active substance DMDMH and its biocidal product Dantogard (product type 13). The evaluation was performed in the context to the application for the inclusion of the biocidal active substance DMDMH into Annex I of the Directive 98/8/EC in frame of the review program of existing biocidal active substances according to the Commission Regulations (EC) No. 1896/2000 and No. 2032/2003 as amended by Commission Regulation (EC) No. 1048/2005, No. 1849/2006 and 1451/2007.
The evaluation was carried out on the basis of the provisions laid down in Article 6 of Commission Regulation (EC) No 1896/2000, Article 5 and Article 10 of Commission Regulation (EC) No. 2032/2003 and the provisions of Article 5(1) and Article 16(2) of Directive 98/8/EC. The evaluation followed the common principles laid down in Annex VI of Directive 98/8/EC and the Technical Notes for Guidance produced by the other contracts of the Commission and other applicable guidance documents.
The applicant for inclusion of DMDMH into the Annex I of Directive 98/8/EC is Lonza GmbH. DMDMH is manufactured in USA by Lonza Inc. The representative product is the product type 13 Dantogard produced by XXXXXX. The dossier was submitted within the deadline of the C priority list. The dossier was deemed as complete for the evaluation.
The information in this evaluation report is, at least partly, based on information, which are confidential and/or protected under the provisions of Directive 98/8/EC
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2. OVERALL SUMMARY AND CONCLUSIONS
2.1 PRESENTATION OF THE ACTIVE SUBSTANCE
2.1.1 Identity, Physical-Chemical Properties and Method of Analysis
Dimethylol Dimethyl Hydantoin (DMDMH, CAS 6440-58-0) is a formaldehyde releasing preservative agent (PT13) of Dantogard biocidal “dummy” product of Lonza GmbH company. It is manufactured through the reaction of Dimethyl Hydantoin (DMH) with formaldehyde. Dantogard is 70% aqueous solution of DMDMH as a worst case product and it is also active substance “as manufactured”. The minimum purity of solid DMDMH is 90% but active substance “as manufactured” is used for risk assessment. Detailed information on the composition of DMDMH (containing impurities) is submitted in a confidential attachment.
2.1.1.1 Physical-chemical properties
The pure Dimethylol Dimethyl Hydantoin (DMDMH) is a white non-uniform odourless powder with the melting point equal to 90°C. The active substance DMDMH decomposes before boiling at 200 °C. The bulk density of the active substance is equal to 0.4g/cm3. DMDMH is very slightly volatile (its vapour pressure was measured to be 0.000012Pa at 25°C). The active substance is very soluble in polar organic solvent and slightly soluble in non-polar organic solvent. The partition coefficient n-octanol/water is equal to -2.9. The DMDMH is not surface active substance - surface tension of 0.998 g/l solution was found to be 72.4 mN/m at 20°C. It is recognised to be not highly flammable and do not have the self-ignition temperature below the melting point. Based on the structure and experience in use it is concluded that DMDMH do not possess explosive nor oxidising properties. There are no known instances where the packaging with active substance has failed as a result of the contained product.
Due to specific properties of DMDMH (releaser of the active agent - HCHO)
properties of the second degradation product DMH are needed for complete risk assessment and are presented in the table, below.
Property Method Result
Molecular Weight 128.13
Melting point: A1 (DSC) 176°C
Boiling point: A2(DSC) 313°C
Vapour Pressure: A4 (vapour pressure balance) 0.00019 Pa at 20°C 0.00038 Pa at 25°C
Henry’s Law Constant: Calculated 1.74 x 10-7 Pa*m3*mol-1 at 20°C
Solubility in water: A6 (Flask method) 140 g/l at 20.0°C
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Property Method Result Partition coefficient n-octanol /water A8 (Shake flask method) Log Pow = – 0.475 at 22°C
pH = neutral Dissociation constant ACD/I-Lab Web Service 9.19
Solubility in organic solvents MT 181 A6 (Flask method)
Toluene: 0.136 g/l at 20°C
Methanol: 134 - 161 g/l at 20°C
Surface tension A5 (ring method) 71.6 mN/m (1.00 g/l solution)
at 21.0 ± 0.5°C
Oxidizing properties A17 Predicted negative based on structure
2.1.1.2 Analytical Methods
The identification of DMDMH and its impurities MMDMH and DMH can be performed using high performance liquid chromatography (HPLC) method with UV detector.
Since the active substance is hydrolytically unstable the substance which should be controlled in soil and water is DMH. Detection of DMH in soil can be carried out by using HPLC-MS system and was developed to analysis DMH with limit of quantification equal to 0.05 mg/kg.
HPLC-MS method is developed for residue in water with the use of two procedure types:
1. procedure A (500 times enrichment) with Limit of Quantification = 0.5μg/l and,
2. procedure B (2000 times enrichment) with Limit of Quantification = 0.1μg/l.
The active substance DMDMH and degradation product DMH are not considered to be volatile (i.e. vapour pressure ≥ 0.01 Pa) and the proposed use patterns do not indicate a high level of release to air so the method for controlling of their concentration in air is not considered to be needed.
DMDMH and DMH are not classified as toxic or highly toxic, therefore a method for determination in body fluids is not applicable. Additionally the active substance used in the biocidal product in metal working fluids will not have a contact with food and feedingstuffs.
2.1.2 Intended uses and Efficacy
Efficacy tests were performed with Dantogard in a metal working fluid against the following microorganisms:
Escherichia coli Pseudomonas aeruginosa Pseudomonas fluorescens Alcaligenes faecalis Staphylococcus aureus XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
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XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX DMDMH have to be consider as bactericidal product only because applicant did not presented studies concerning fungicidal or yeasticidal activity.
2.1.3 Classification and Labelling
Table 2-1 Proposal 1 for classification and labeling of DMDMH
Classification As documented in tests from the Biocidal Dossier
Classification Hazard Category 2, H315, H319
Hazard Category 4, H302, H311
GHS pictogram
Signal Word Warning
Hazard statements “Causes skin irritation”, H315
“Causes serious eye irritation”, H319
“Harmful if swallowed”, H302
“Harmful in contact with skin”, H311
Table 2-2 Proposal 2 for classification and labelling of DMDMH
Classification As documented in tests from the Biocidal Dossier
Classification Hazard Category 2, H315, H319, H351i
Hazard Category 4, H302, H311
GHS pictogram
Signal Word Warning
Hazard statements “Suspected of causing cancer by inhalation”, H351i
“Causes skin irritation”, H315
“Causes serious eye irritation”, H319
“Harmful if swallowed”, H302
“Harmful in contact with skin”, H311
Elements of classification and labelling marked in red are proposals with which
the applicant disagrees.
For the clarification please see Doc.IIA Chapter 1.5
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2.2 SUMMARY OF THE RISK ASSESSMENT
2.2.1 Human Health Risk Assessment
2.2.1.1 Hazard characterisation
The active substance, DMDMH hydrolyses to DMH and formaldehyde. Long-term toxicity is therefore due to exposure to the degradant DMH (Document I Appendix XIX Justification for long-term testing on DMH).
2.2.1.1.1 DMDMH
DMDMH is harmful by acute oral (LD50 = 1572mg/kg bw) and dermal (LD50 > 1052mg a.i./kg bw) routes.
On the basis of the in vivo eye irritation and 28-day and 90-day dermal studies it can be assumed that DMDMH in the higher concentration is at least irritating to eye. The in vitro eye irritation study (Bovine Corneal Opacity and Permeability Assay – BCOP) that was used could determine the severe irritant or corrosive properties of the substance. This in vitro study can not be used to determine the medium or light irritant properties. Under the condition of this study it could be concluded that DMDMH is not severe irritating or corrosive to the eye. In the light of acute and 28-day and 90-day dermal study there is a probability that DMDMH in the concentration of > 90% could be irritating to eye and skin.
DMDMH is not sensitising to skin. From an experimental perspective, it is not possible to directly address the in
vitro mutagenic potential of DMDMH since the compound hydrolyses to free formaldehyde and DMH in dilute solutions. Accordingly, at the low concentrations in the mutagenicity assays DMDMH is likely to exist as formaldehyde and DMH.
The Ames Test performed on the pure active substance gave a negative result. DMDMH (~50% aqueous solution) was positive in the Ames Test, Cytogenicity Study – Chinese Hamster Ovaries, mouse lymphoma assay and chromosome aberration studies both with and without metabolic activation. However, the positive results are attributed to free formaldehyde formed in the test medium and not to the parent compound itself. The basis for this conclusion is that formaldehyde produces positive results in the same assays (Formaldehyde Releasers Dossier Document IIIA). The other principal hydrolysis product, dimethylhydantoin (DMH), is not mutagenic in either of these assays.
A mouse micronucleus assay and an alkaline elution assay in the rat indicated that the active substance, DMDMH, did not induce mutagenic effects in two different tissues in vivo.
After repeated dose oral toxicity (90 days) study, statistically significant increase in the absolute and relative adrenal weight in high dose males was noted. The NOAEL was assigned as 110mg/kg bw.
Repeated dermal exposure (28 and 90-days) results in no systemic adverse effects but local effects were noted (epidermal inflammation, epidermal necrosis and
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ulceration). The lowest NOAEL local = 4.4mg a.i./kg bw/day. The lowest NOAEL systemic = 440mg a.i./kg bw. These studies have a lot of discrepancies and can not be used for the risk assessment (Reliability 3).
There are no indications of DMDMH neurotoxicity.
2.2.1.1.2 DMH
DMH is not harmful by acute oral exposure (LD50 > 10000mg/kg) or dermal exposure (LD50 > 20000mg/kg bw/day).
DMH is not irritating to skin or eye of rabbits. DMH is not a skin sensitiser (Buehler Test 0/10 responders). DMH was considered as the relevant metabolite available for absorption,
distribution, metabolism and excretion. Up to 97% of the radiolabelled DMH applied via the oral or i.v. routes was excreted in urine and faeces. Approximately 2.6% of the applied dose was not excreted within the observation period.
In the absence of a dermal absorption study a first tier of 100% absorption will be used as a default value.
In the subchronic oral study in rat (13 weeks), at the highest dose (1000mg DMH/kg/day) there was an equivocal decrease in body weight, liver weight and food consumption. The NOAEL was assigned as 1000mg DMH/kg bw/day.
In the sub-chronic dermal study in rat NOAEL was assigned as 390mg/kg bw/day.
In a 2 year chronic study in rat, an equivocal decrease in body weight and
survival was observed at the highest dose (1000mg DMH/kg bw/day). The NOAEL was assigned as 300mg DMH/kg bw/day.
In a 1 year chronic dog study, the highest dose (1000mg DMH/kg bw/day) resulted in small decreases in body weight, increase in adrenal weights and mild hypertrophy in adrenal cortex for males and small decreases in bodyweight for females. The NOAEL was assigned as 300mg DMH/kg bw/day.
Teratogenicity studies in the rat and rabbit on DMH dosed by oral gavage did not produce an overall indication of teratogenicity. The results of all the developmental toxicity studies conducted with DMH and EMH suggest that significant developmental toxicity was limited to the digit defects in the rabbit and not in the rat. The finding in question was only seen at a dose level that was toxic to the adult and the finding was only seen at low incidence.
Lowest NOAEL EMH ADULT 375mg/kg DMH ADULT 500mg/kg
Offspring 500mg/kg Exposure to DMH in the diet for two generations did not result in parental
toxicity or adverse effects on reproductive performance or reproductive tissues at dietary concentrations as high as 20000ppm. However, there were effects (decreased weight gain) in offspring during lactation. Small increases in parental food consumption and body weight and transient decreases in offspring body weight during lactation were observed at the 20000ppm dose level. The NOAEL from the study is for F0 = 1395mg/kg bw/day, with the NOAEL of 379mg/kg bw/day for F1 and F2.
DMH was not mutagenic or clastogenic with and without metabolic activation in a full series of in vitro mutagenicity tests (bacterial and mammalian cell lines).
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DMH did not produce any indication of carcinogenicity in the rat (104 weeks) or the mouse (78 weeks) at up to 1000mg/kg bw/day via oral feed.
There are no indications of DMH neurotoxicity.
2.2.1.1.3 Formaldehyde
Formaldehyde is harmful if swallowed (640mg/kg bw) and toxic in contact with the skin (270mg/kg bw) and by inhalation (about 100mg/kg bw).
Single and unoccluded administration of 1mL/kg bw formaldehyde in water was reported to cause erosion of rat skin during a one week observation period. Upon exposure to formaldehyde in the air, the highly water soluble gas dissolves in epithelial fluids cause local irritation of eyes, nose, throat and lung.
Formaldehyde is a known primary skin sensitiser inducing Type IV allergic contact dermatitis (WHO, 1989; ATSDR, 1999; OECD, 2002). These properties of formaldehyde are confirmed by a large number of tests in laboratory animals.
Oral repeated toxicity has been studied in rats with exposure through the drinking water for 28 days. Local effects in the forestomach and the glandular stomach and decreased plasma levels of albumin and total protein were seen.
Local effects on the epithelia of the respiratory tract were the main findings in rats, mice and cynomolgus monkeys after inhalation repeated exposure. The type of the lesions, squamous metaplasia and hyperplasia, was identical in these three species, indicating comparability of the mechanisms involved.
Positive results in Ames tests in S. typhimurium strains TA97, 98, 100, 102 and 104 suggest that formaldehyde may induce mutations by various mechanisms and independent of metabolic activation. TK and HPRT gene mutation analysis in mammalian cells confirmed this activity. A mechanistic study suggested that mutagenesis by formaldehyde in mammalian cells involves base pair substitutions as well as deletions. This is in accordance with induction of single strand breaks and DNA crosslinks and sister chromatid exchange, micronuclei formations and DNA crosslinks. In these studies, time-dependent repair of the lesions was also reported.
Systemic and local genotoxicity of formaldehyde was evaluated in rodents, monkeys and occupationally exposed humans. It is well established, that DPX can be repaired, but if it is present during DNA replication, clastogenic effects may result. A human cohort study on workers of a plywood factory chronically exposed to concentrations between 0.1 and 0.6µg/L revealed corresponding evidence for clastogenicity in the nasal epithelium in coincidence with histologic abnormalities. Pre- and post-exposure further analysis showed clastogenic (but not aneugenic) effects in students exposed during an embalming course. These effects were more obvious in buccal cells than in cells of the nasal epithelium and high peak exposures of 0.95 to 3.4µg/L were reported (Titenko-Holland et al. 1996). Overall, there is convincing evidence, that formaldehyde exposure can induce local genotoxic effects at the site of contact.
Currently, there is no convincing evidence for carcinogenicity of formaldehyde when administered via the oral route. An acceptable study with exposure of rats through the drinking noted local effects in the forestomach and the glandular stomach. A long-term oral NOAEL of 15mg/kg bw/d (0.026% in drinking water) can thus be derived from the 2-year study in rats. Reconsidering the NOAEL of 25mg/kg bw/d from the 28-days oral rat study and the effects observed at 125mg/kg bw/d, it seems reasonable to assume that the threshold dose for local lesions remains practically constant with time, while the nature of the lesions reflects the progressing
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pathology. Hence, it is proposed to use the long-term NOAEL of 15mg/kg bw/d as an overall value for subacute, subchronic and chronic oral exposure.
In a study over 60 weeks formaldehyde was applied to the back of hairless mice induced a slight hyperplasia of the epidermis and possibly some small skin ulcers at the higher dose level. No treatment-related tumours were detected in the skin or any other organ.
Experimental evidence in rats and mice demonstrates that long-term formaldehyde inhalation causes tumours in the upper respiratory tract from exposure concentrations of 7.2µg/L. The relevance of this effect for human health was recently confirmed by an independent assessment within the IPCS Human Framework for Analysing the Relevance of the Cancer Mode of Action for Humans.
Taking into account the dose-response after subacute, subchronic and chronic inhalation exposure, it can be further concluded that the threshold dose for local lesions remains practically constant with increasing time, while the nature of the lesions reflects the progressing pathology. Hence, an overall inhalation NOAEC of 1.2mg/m3 for local effects based on the 6-months studies in rats and monkeys is derived.
There is no concern for developmental and reproductive toxicity of formaldehyde.
2.2.1.1.4 Biocidal product
The product is specified in the risk assessment as having a 70% concentration of the active substance DMDMH as manufactured. In practice this 70% DMDMH solution will not be ‘stable’ once manufactured. As indicated in Document IIA DMDMH in aqueous solution will undergo an equilibrium reaction releasing free formaldehyde and DMH, the rate of generation of the degradation products being dependent upon thermodynamic forces driving the reaction to the equilibrium. During the product manufacturing process further amounts of DMH have to be added in order to lower the free formaldehyde below the 0.1% as specified.
Due to the equilibrium state of substances in the solution any commercial products will not be formally identified as being a 70% solution of DMDMH. The free formaldehyde concentration in any product is always at a level of < 0.1% in solution with the efficacy of the product based on the biocidal activity of the whole equilibrium solution.
The product specified in Document IIIB has been characterised as a ‘dummy product’ due to the above issue with stability but, for purposes of the evaluation and the Annex I inclusion for the active substance, use of a product containing 70% DMDMH does present a ‘worst case’ scenario with the appropriate highest possible concentrations of DMH and formaldehyde formed during the degradation being considered for human health and environmental risk assessment.
Trade name: Dantogard Ingredient of preparation: Function: Content:
DMDMH Biocide for metal working fluids 70%
Ingredient of preparation: Function: Content:
Water Solvent 30%
Ingredient of preparation: Function:
Formaldehyde Chemically equivalent by-product
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Trade name: Dantogard Content <0.1% Physical state: Liquid Nature of preparation: Aqueous solution Table 2-3 Identification of the product
Product type Field of use envisaged
Concentration of Dantogard
(%)
Likely conc. at which a.i will be used
Conc. of DMH
Conc. of formaldehyde
13 Water-based
metal working fluids
XXX XXX XXX XXX
2.2.1.2 Professionals
2.2.1.2.1 Risk assessment at the workplace
Risk assessment during manufacture and formulation The active substance is manufactured in the USA and the formulation of the
70% DMDMH solution (Dantogard) is formulated at a single site in Germany and is an intrinsic part of the manufacture and therefore is regarded as manufacture rather than formulation. Dantogard is the end product of a process which includes the reaction stage, and is carried out in an enclosed system.
The active substance, DMDMH is produced in a closed system. However, there is potential exposure to DMH dust while filling the reactor with the DMH powder.
Table 2-4 Summary of exposure estimates to professionals during manufacture of DMDMH (Dantogard)
Exposure DMH mg/kg/day Formaldehyde
Dermal negligible not applicable (close system)
Inhalation 0.0313 not applicable (close system)
Table 2-5 Risk characterisation for inhalation exposure during manufacture of DMDMH (Dantogard)
Task Exposure
(mg/kg bw/d)
AEL (mg/kg bw/d)
%AEL
(exposure/AEL x 100%)
MOE (NOEL/Exposure)
Filling DMH powder into the reactor system 0.0313 3.0 1.04 9854
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At the conclusion there is no concern for industrial workers during the Dantogard formulation process with respect to inhalation, dermal or oral exposure to DMH. There is no concern from inhalation dermal or oral exposure to formaldehyde.
2.2.1.2.2 Risk assessment as a result of the use of the biocidal product
Professional operators will undertake dilution of the Dantogard into the metal working fluid as well as all application and maintenance tasks relating to use of metal working fluid.
The most relevant routes are the dermal and inhalation routes as workers will be exposed during dilution of the product and during use of the metal working fluid.
Table 2-6 Summary of exposures from PT13 professional use
Exposure DMH mg/kg bw/day Formaldehyde
Diluting Dantogard into the metal working fluid with full PPE (47% DMH, 15min)
inhalation 1.16 × 10-2 3.9 × 10-3mg/m3
dermal 1.4 × 10-2 3.0 × 10-5mg/kg bw/day
Daily exposure from use in the metal working facility (0.17% DMH, 120min)
inhalation 1.34 × 10-5 1.3 × 10-3mg/m3
dermal 1.3 × 10-1 6.1 × 10-2mg/kg bw/day
Maintenance of the metal working fluid machinery (0.17% DMH, 240min)
inhalation 2.68 × 10-4 1.3 × 10-3mg/m3
dermal 2.6 × 10-1 1.2 × 10-1mg/kg bw/day
The AELlong–term are used for risk characterisation. There is no concern if
exposure is ≤ 100% of the AEL. An exposure level of 0.1ppm (AEC = 0.12mg/m3) is supposed to be a “safe
level” for human inhalation exposure to formaldehyde and is recommended to protect the whole population and is therefore used for risk characterisation to formaldehyde inhalation exposure.
Table 2-7 Risk characterisation to DMH
Task Exposure
(mg/kg bw/d) AEL
(mg/kg bw/d)
%AEL
(exposure/AEL x 100%)
MOE (NOEL/exposure)
Dermal exposure Diluting Dantogard into the metal working fluid with full PPE (47% DMH, 15min)
1.4 × 10-2 3.0 0.48 2.1 × 104
Daily exposure from use in the metal working facility (0.17% DMH, 120min)
1.3 × 10-1 3.0 4.3 2.3 × 103
Maintenance of the metal working fluid machinery (0.17% DMH, 240min)
2.6 × 10-1 3.0 8.5 1.1 × 103
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Inhalation exposure Diluting Dantogard into the metal working fluid with full PPE (47% DMH, 15min)
1.16 × 10-2 3.0 Effectively 0 2.6 × 104
Daily exposure from use in the metal working facility (0.17% DMH, 120min)
1.34 × 10-5 3.0 Effectively 0 2.2 × 107
Maintenance of the metal working fluid machinery (0.17% DMH, 240min)
2.68 × 10-4 3.0 Effectively 0 1.1 × 106
There is no concern for professionals from inhalation exposure to DMH whilst working with a metalworking machine and during dilution of the product into the metal working fluid. The very low vapour pressure of DMH means that the levels of active substance in the atmosphere will always be low. Additionally, the machines should have good extraction to remove any mist formed (effectively this is risk mitigation in place).There is no need to perform a tier 2 assessment as the %AELs are considered negligible. It is, however, still advisable to wear appropriate PPE to further minimise exposure. Also if the ventilation is deemed inadequate this should be reported to the Health and Safety Manager.) Table 2-8 Risk characterisation of dermal exposure to formaldehyde
Task Exposure
(mg/kg bw/d) AEL
(mg/kg bw/d)
%AEL
(exposure/AEL x 100%)
MOE (NOEL/exposure)
Dermal exposure Diluting Dantogard into the metal working fluid with full PPE (0.1%)
3.0 × 10-5 0.15 Effectively 0 5.0 × 105
Daily exposure from use in the metal working facility (120min) 6.1 × 10-2 0.15 40.6 2.5 × 102
Maintenance of the metal working fluid machinery (240min)
1.2 × 10-1 0.15 80.4 1.2 × 102
Table 2-9 Risk characterisation of inhalation exposure to formaldehyde
Task Exposure (mg/m3)
AEC (mg/m3)
%AEC (exposure/AEC x
100%)
MOE (NOEL/exposure)
Diluting Dantogard into the metal working fluid (0.1%) 3.9 × 10-3 0.12 3.25 3.1 × 102
Exposure from use in the metal working facility 1.3 × 10-3 0.12 1.05 9.5 × 102
There is no concern for the professional worker with respect to dermal
exposure to formaldehyde when using the machine or when diluting Dantogard into the tank as the %AEL ≤ 100% for all scenarios.
There is no risk to workers during dilution of Dantogard (70% solution) into metal working fluids. There is no concern for the professional workers in the metal working facility area as the formaldehyde concentration is predicted to be comfortably below the “safe level” for human inhalation exposure (0.12mg/m3).
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However, it is still recommended that care is always taken to ensure that the extraction systems are working correctly on metalworking machines and that if necessary any problem is reported to the Health and Safety Manager.
2.2.1.3 Non-Professionals
The Dantogard in PT13 is recommended to use only by the professional users.
2.2.1.4 Indirect exposure as a result of use of the active substance in biocidal
product
The TNsG give the secondary exposure scenario as adult dermal chronic, whilst doing home laundry of work clothes.
Formaldehyde is very volatile. It is not expected to be present on the work clothes by the time they reach home. For this reasons the dermal risk characterization was done.
Table 2-10 Risk characterisation for indirect exposure to DMH
Exposure Exposure
(mg/m3) AEL
%AEL
(exposure/AEL x 100%)
MOE (NOEL/exposure)
Chronic dermal Adult doing laundry of work clothes 1.4 × 10-2 3.0 0.46 2.1 × 104
For the purposes of risk assessment a worst case exposure has been considered
for workers exposed for 240min during maintenance tasks for both DMH and formaldehyde. As cleaners will not have this level of exposure it is not considered necessary to include the exposure scenarios for indirect exposure to cleaners via dermal and inhalation routes.
There will be no concern for indirect exposure to cleaners to DMH or formaldehyde.
2.2.1.5 Combined exposure
For determination of combined human exposure estimates a common-sense approach would be to determine exposure for the following scenario:
The professional worker performing the maintenance tasks (longest exposure) and washing clothes at the end of the day. Combined exposure to DMH is considered.
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Table 2-11 Combined exposure to DMH
Combined exposure Exposure
(mg/kg bw/d) AEL
%AEL
(exposure/AEL x 100%)
MOE (NOEL/exposure)
Inhalation and dermal routes 2.7 × 10-1 3.0 9.1 1.1 × 103
2.2.2 Environmental Risk Assessment
2.2.2.1 Fate and Distribution in the Environment
2.2.2.1.1 Biodegradation
DMDMH is readily biodegradable. However due to the rapid hydrolysis of DMDMH degradants: DMH and formaldehyde are considered to be the substances of interest.
DMH is readily biodegradable and is quite fast degraded in a water/sediment degradation study with t½ = 17.45 – 19.95 days, (t½ = 33.1-37.9 days after conversion to average EU outdoor temperature 12°C).
Formaldehyde is readily biodegradable failing 10-days window.
2.2.2.1.2 Abiotic Degradation
DMDMH is hydrolytically unstable at pH 7 and pH 9 at 25°C. It is hydrolytically stable at pH 4 at 25°C. In an aqueous environment it is expected to hydrolyse to DMH and formaldehyde. DMH is extremely stable to hydrolysis in pH 5, 7 and 9. Hydrolysis of formaldehyde can be excluded because of the absence of a hydrolysable group in the molecule.
Because DMDMH hydrolyses rapidly in aqueous solutions leaving DMH and formaldehyde, the photolysis of degradation products is considered to be less relevant for evaluation and use in risk assessment. DMH is considered to be stable in water at pH 7 at 25°C on the basis of conducted test. There are no tests on photolysis of formaldehyde in aqueous solutions available which would allow deriving a reaction rate for surface waters. In aqueous solutions formaldehyde hydrate is formed which has no chromophore that is capable of absorbing sunlight and thus should not decompose by direct photolysis. Hence photolysis in surface waters is expected to be of minor importance in abiotic degradation processes of DMDMH.
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2.2.2.1.3 Distribution and Mobility
The degradant DMH was considered relevant for soil adsorption studies due to the rapid hydrolysis of DMDMH. Based on the range of Koc values, DMH can be described as highly mobile to moderately mobile1 in all soil types used in study. The mean Koc value of 80.15 L/kg has been used for risk assessment. There is no study available on adsorption of formaldehyde in soils and sediments. The KOC was estimated using a QSAR model described in EU Technical Guidance Document on Risk Assessment (EC 2003). Based on a log KOW of 0.35 and the QSAR for non-hydrophobics, the KOC is calculated to be 15.9 L/kg. Hence formaldehyde can be described as highly mobile in soil.
2.2.2.1.4 Bioaccumulation
Because of rapid hydrolysis of DMDMH under environmental conditions, possibility of bioaccumulation of degradation products DMH and formaldehyde was investigated.
The log KOW (an indicator of the likelihood of a substance for dissolving in fatty tissue) for DMH was found to be -0.48 indicating low potential bioaccumulation in the food chain. An experimental bioaccumulation factor of <1.79 in fish also indicates it has a low bioaccumulation potential at least in the aquatic compartment.
Formaldehyde does not bioaccumulate taking into consideration log KOW (0.35) and estimated according to TGD bioconcentration factor (BCFfish = 0.4).
2.2.2.2 Effects Assessment
2.2.2.2.1 Aquatic Compartment
At a test concentration of 82.3 mg/l DMDMH did not show any acute toxic effects to fish. DMDMH is acutely harmful to Daphnia with LC50 of 29.1 mg/l and algae with ErC50 = 11 mg/l.
The degradants are considered more relevant for ecotoxicological studies. DMH is not acutely toxic to fish in concentration 972.2 mg/l. No acceptable acute test for Daphnia was provided. However chronic test is available with NOEC =70.9 mg/l. Chronic tests of DMH toxicity to fish and algae were also provided. NOEC of 14 mg/l in relation to toxic effects on the weight and growth of fish from an early life-stage study was selected for aquatic effect assessment.
Formaldehyde is acutely toxic to fish with 96h-LC50 of 5.7 mg/l. Formaldehyde is also acutely harmful for other aquatic species, obtained LC50 values are similar. LD50 for fish was used in risk assessment. No acceptable log-term toxicity study for formaldehyde was provided.
At a test concentration of 100 mg/l DMDMH did not show any effects to
microbial activity in STP. DMH is not harmful for microbial activity at concentration 1000 mg/l. Formaldehyde is harmful to STP microorganisms with LC50 = 20.4 mg/l
Sediment
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No test of DMDMH or product of hydrolysis toxicity to sediment dwelling organisms were provided. However taking into consideration behaviour of these substances in the environment no accumulation in sediment is expected.
2.2.2.2.2 Terrestrial Compartment
No tests of DMDMH toxicity to terrestrial organism were provided. However the degradation products are considered more relevant for risk assessment. DMH is not harmful to earthworms and microbial activity in soil in concentration 1000 mg/kg. The lowest NOEC = 160 mg/kg used was obtained from test on terrestrial plants. No tests of formaldehyde toxicity to terrestrial organism were provided. PNECsoil for formaldehyde was calculated using the equilibrium partitioning method from PNECwater
2.2.2.3 PBT Assessment
According to the TGD, ‘The Persistent, Bioaccumulative and Toxic (PBT) assessment is considered to be different from the local and regional assessments approaches, as it seeks to protect ecosystems where risks are more difficult to estimate’. Any substance which is found to be either a PBT or very Persistent very Bioaccumulative (vPvB) substance shall not be allowed on Annex I unless releases to the environment can be effectively prevented.
Provided tests of biodegrability shows that neither DMDMH nor product of hydrolysis are persistent according to TGD criteria of persistency. DMDMH and DMH are readily biodegradable. Formaldehyde is readily biodegradable failing 10-days window.
A substance is considered to have the potential to fulfill the criterion of
bioaccumulation when the log KOW exceeds 4.5. Values of n-octanol/water partition coefficient are lover that trigger value for DMDMH and product of hydrolysis. Additionally test of DMH bioaccumulation in fish was provided. Results of the test supported position that substance is not bioaccumulative.
There are no chronic toxicity test on DMDMH available. However product of
hydrolysis are more relevant for the effect assessment. The lowest NOEC for DMH is 14 mg/l. This means that the trigger of < 0.01 mg l-1 given in the TGD is not exceeded. There are no chronic toxicity test on formaldehyde available. However long-term exposure can be anticipated only for persistent and bioaccumulative substances. Since formaldehyde do not fulfill persistence and bioaccumulation criteria DMDMH and their degradation products are not PBT substances.
2.2.2.4 Exposure Assessment
The environmental exposure assessment for products of DMDMH hydrolysis has been done using all available information. This has been taken from submitted studies and the harmonized ESD for biocides.
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Information and guidance was also taken from part II of the Technical Guidance Document on risk assessment (TGD; EC, 2003).
The product is specified in the risk assessment as having a 70% concentration
of the active substance DMDMH as manufactured. In practice this 70% DMDMH solution will not be ‘stable’ once manufactured. As indicated in Document IIA section 1.2 DMDMH in aqueous solution will undergo an equilibrium reaction releasing free formaldehyde and DMH, the rate of generation of the degradation products being dependent upon thermodynamic forces driving the reaction to the equilibrium. During the product manufacturing process further amounts of DMH have to be added in order to lower the free formaldehyde below the 0.1% specified.
Due to the equilibrium state of substances in the solution any commercial
products will not be formally identified as being a 70% solution of DMDMH. The free formaldehyde concentration in any product is always at a level of <0.1% in solution with the efficacy of the product based on the biocidal activity of the whole equilibrium solution.
The product specified in Document IIIB has been characterised as a ‘dummy
product’ due to the above issue with stability but, for purposes of the evaluation and the Annex I inclusion for the active substance, use of a product containing 70% DMDMH does present a ‘worst case’ scenario with the appropriate highest possible concentrations of DMH and formaldehyde formed during the degradation being considered for environmental risk assessment.
All calculations within the exposure scenario apply to products of DMDMH hydrolysis: DMH and formaldehyde. 2-12 Identification of the product (PT 13)
Product type Field of use envisaged
Concentration of Dantogard
(%)
Likely conc. at which a.i will
be used
Conc. of DMH
Conc. of formaldehyde
13 Water-based metal working fluids
XXX XXXX XXX XXX
Predicted environmental concentrations resulted from the use of Dantogard
in PT 13 PEC in aquatic compartment
2-13 Local PECs for DMH and formaldehyde in STP
Substance Local PECs mg/l
DMH 0.171 Formaldehyde 0.208
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2-14 Local PECs for DMH and formaldehyde in surface water
Substance Local PECs mg/l
DMH 0.0171 Formaldehyde 0.0208
PEC in terrestrial compartment
2-15 Local PECs for DMH and formaldehyde in soil
Substance Local PECs DMH 0.027 Formaldehyde 3.25E-03
PEC in air
2-16 Local PECs for DMH and formaldehyde in air
Substance Local PECs DMH 4.17E-13 Formaldehyde 1.13E-08
2.2.2.5 Risk Characterisation
PEC/PNEC values have been determined for products of DMDMH hydrolysis:
DMH and formaldehyde.
2.2.2.5.1 Aquatic compartment including STP
Table 2-17 PEC/PNEC ratios (DMH) for the aquatic compartment
Compartment Local PECs PNEC PEC/PNEC ratio Use Surface water 0.0171 1. 4 0.0122 STP 0.171 100 0.00171
Table 2-18 PEC/PNEC ratios (Formaldehyde) for the aquatic compartment
Compartment Local PECs PNEC PEC/PNEC ratio Use Surface water 0.0208 0.0057 3.65 STP 0.208 0.2 1.04
Use of DMDMH as an active substance in Dantogard, according to the
proposed use pattern for products in PT 13, pose an unacceptable risk to STP micro-organisms and aquatic organisms. Risk is caused by formaldehyde released from DMDMH.
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2.2.2.5.2 Terrestrial Compartment
Table 2-19 PEC/PNEC ratios (DMH) for the terrestrial compartment
Scenario Local PECs mg/kgwwt
PNEC mg/kgwwt PEC/PNEC ratio
Use Soil 0.027 0.99 0.027
Table 2-20 PEC/PNEC ratios (Formaldehyde) for the terrestrial compartment
Scenario Local PECs mg/kgwwt
PNEC mg/kgwwt PEC/PNEC ratio
Use Soil 3.25E-03 0.0023 1.41
Use of DMDMH as an active substance in Dantogard, according to the
proposed use pattern for products in PT 13, poses an unacceptable risk to soil organisms. Risk is caused by formaldehyde released from DMDMH.
2.2.3 Listing of Endpoints
In order to facilitate the work of Member States in granting or reviewing
authorisations, and to apply adequately the provisions of Article 5(1) of Directive
98/8/EC and the common principles laid down in Annex VI of that Directive, the most
important endpoints, as identified during the evaluation process, are listed in
Appendix I.
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3. PROPOSAL FOR THE DECISION
3.1 BACKGROUND TO THE PROPOSED DECISION
The overall conclusion from the evaluation of 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDMH) for use in product type 13 (metalworking fluids) for the category of users industrial is that it is possible for the MS to issue authorisations on biocidal products containing DMDMH in accordance with the conditions laid down in article 5 (1) (b), (c), (d) of the directive 98/8EC.
The data on the active substance and biocidal product have demonstrated
sufficient efficacy in preservation of metalworking fluids by the control of microbial deterioration. For the proposed area and manner of use biocidal product does not cause unacceptable risk to human health and cause unacceptable risk to environment.
3.2 PROPOSED DECISION REGARDING THE INCLUSION IN ANNEX I
The 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione (DMDMH) shall be included in Annex I to Directive 98/8/EC as an active substance for use in product-types 13 (metalworking fluids).
The information outlined below will be included in the entry for Annex I inclusion:
Identity IUPAC Name: 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione CAS No: 6440-58-0 EINECS No: 229-222-8 Purity The active substance as manufactured, shall have a minimum purity of 90%
w/w Proposed product type 13 (metalworking fluids)
Justification for the Provisions regarding the Inclusion on to Annex I
-
3.3 ELEMENTS TO BE TAKEN INTO ACCOUNT BY MEMBER STATES WHEN AUTHORIZING PRODUCTS
Release of formaldehyde from the active substance and the concentration of formaldehyde should be taken into account during the biocidal product authorisation
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stage. During manufacture and formulation as the system should be completely enclosed and formaldehyde should be added to the reactor via pipes.
The release of biocides used as metalworking fluids has to be considered by the relevant national authorities when issuing permits for recovery plants (according to agreement at Technical Meeting IV09 - required when an environmental risk for metalworking fluids has been identified).
3.4 DEMAND FOR FURTHER INFORMATION
It is considered that the evaluation has shown that sufficient data have been provided to verify the outcome and conclusions, and permit the proposal for the inclusion of 1,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione in Annex I to Directive 98/8/EC.
In the situation when the biocidal product will be authorized with higher
concentration of DMDMH than 55% the new in vivo eye and skin irritation study should be provided.
3.5 UPDATING THIS ASSESSMENT REPORT
This assessment report may need to be updated periodically in order to take account of scientific developments and results from the examination of any of the information referred to in Articles 7, 10.4 and 14 of Directive 98/8/EC. Such adaptations will be examined and finalised in connection with any amendment of the conditions for the inclusion of DMDMH in Annex I to the Directive.
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APPENDIX I – LIST OF ENDPOINTS
Chapter 1: Identity, Physical and Chemical Properties, Details of Uses,
Further Information, and Proposed Classification and Labelling
Active substance (ISO Common Name) Dimethyloldimethylhydantoin (DMDMH)
Function (e.g. fungicide) Preservative – acts as a bactericide
Rapporteur Member State Poland
Identity (Annex IIA, point II.)
Chemical name (IUPAC) 1,3-bis(hydroxymethyl)-5,5-
dimethylimidazolidine-2,4-dione
Chemical name (CA) Dimethylol Dimethyl Hydantoin
CAS No 6440-58-0
EC No 229-222-8
Minimum purity of the active substance as
manufactured (g/kg or g/l)
900g/kg
Identity of relevant impurities and
additives (substances of concern) in the
active substance as manufactured (% w/w)
None
Molecular formula C7H12N2O4
Molecular mass 188
Structural formula
N N
O
O
CH2OHHOCH2
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Identity of Degradant
DMH has been considered as the substance of relevance long-term toxicity,
ecotoxicity and environmental fate studies (Document I Appendix XIV: Justification
for performance of long-term studies on DMH). Therefore this document also
contains information (where applicable) for DMH
Chemical name (IUPAC) 5,5 dimethylimidazolidine-2,4-dione
Chemical name (CA)
Dimethylhydantoin (DMH)
CAS No 77-71-4
EC No 201-051-3
Minimum purity of the active substance as
manufactured (g/kg or g/l)
Not applicable
Identity of relevant impurities and
additives (substances of concern) in the
active substance as manufactured (% w/w)
DMH: >90% w/w
Water : 9% (max)
Ammonia: 1% (max)
Molecular formula C5H8N2O2
Molecular mass 128.13
Structural formula
Physical and chemical properties (Annex IIA, point III., unless otherwise indicated)
Physical and chemical properties (where applicable) have also been stated for the
degradant DMH.
Melting point (state purity) DMDMDH: 90°C (purity 97.1%)
DMH: 176°C (purity: 99.82%)
Boiling point (state purity) DMDMH: decompose before boiling at 200 °C
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(purity 96.8%)
The calculated value of the boiling point is
equal to 412°C.
DMH: 313°C (purity: 99.82%)
Appearance (state purity) DMDMH: White non-uniform odourless powder
(purity 96.8%) DMH: not relevant
Specific gravity DMDMH: 0.4g/cm3 at 21°C
DMH: not relevant
Surface tension DMDMH: 72.4 mN/m (0.998 g/l solution) at 20.0 ± 0.5°C
DMH: 71.6 mN/m(1.00 g/l solution) at 21.0 ±
0.5°C
Vapour pressure (in Pa, state temperature) DMDMH: 0.000012 Pa at 25°C.
DMH: 0.00019 Pa at 20°C 0.00038 Pa at 25°C
Henry’s law constant DMDMH: not possible to determination due to
properties of the substance DMH: 1.74 x 10-7 Pa*m3*mol-1 at 20°C
Solubility in water (g/l or mg/l, state
temperature)
DMDMH: not possible to determination due to
properties of the substance DMH: 140 g/l at 20.0°C
Solubility in organic solvents (in g/l or
mg/l, state temperature) (Annex IIIA, point
III.1)
DMDMH:
Tolulene:
0.141 g/l @10 °C
0.214 g/l @20°C
0.279 g/l @30°C
Methanol
>252 g/l @ 10 °C
>250 g/l @20°C
>252 g/l @ 30°C DMH:
Toluene: 0.136 g/l at 20°C
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Methanol: 134 - 161 g/l at 20°C
Stability in organic solvents used in
biocidal products including relevant
breakdown products (IIIA, point III.2)
Not applicable
Partition coefficient (log POW) DMDMH: -2.9 at 20°C (pH=2.1) DMH: – 0.475 at 22°C (pH=neutral)
Storage stability (DT50) (state pH and
temperature) (point VII.7.6.2.1)
DMDMH hydrolyses in water with half-life ca
< 1 day at pH 7 and pH 9. DMDMH is
hydrolytically stable at pH4 with half life > 1
year..
Dissociation constant (not stated in Annex
IIA or IIIA; additional data requirement
from TNsG)
DMDMH: not possible to determination due to
properties of the substance
DMH: 9.19
UV/VIS absorption (max.) (if absorption >
290 nm state ε at wavelength)
DMDMH: Significant absorbance maxima at
wavelength equal to 206nm (molar absorption
coefficient 3.19 x 10 3)
Photostability (DT50) (aqueous, sunlight,
state pH)
(point VII.7.6.2.2)
As DMDMH hydrolyses in aqueous solutions,
leaving DMH, the photolysis of DMH is considered
to be more relevant to this endpoint. DMH is
photolytically stable DT50 =878 days (pH 7.0)
Quantum yield of direct
phototransformation in water at Σ > 290
nm (point VII.7.6.2.2)
As DMDMH hydrolyses in aqueous solutions,
leaving DMH, the photolysis of DMH is
considered to be more relevant to this endpoint.
There is no absorbance of DMH >290 nm.
Flammability DMDMH is not highly flammable
DMH: not relevant
Explosive properties DMDMH is not explosive based upon structure
and experience in use
DMH: not relevant
Summary of intended uses
Product type Field of use envisaged
(Hazard class)
Likely conc. at which a.s. will be
used
PT 13
Metalworking fluids
0.245%
Classification and proposed labelling (Annex IIA, point IX.)
with regard to physical/chemical data None
with regard to toxicological data
Elements of classification and labelling
marked in red are proposals with which
the applicant disagrees.
Proposal 1
“Causes skin irritation”, H315
“Causes serious eye irritation”, H319
“Harmful if swallowed”, H302
“Harmful in contact with skin”, H311
Proposal 2
“Causes skin irritation”, H315
“Causes serious eye irritation”, H319
“Harmful if swallowed”, H302
“Harmful in contact with skin”, H311
“Suspected of causing cancer by inhalation”,
H351i
with regard to fate and behaviour data None
with regard to ecotoxicological data None
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Chapter 2: Methods of Analysis
Analytical methods for the active substance
Technical active substance (principle of
method) (Annex IIA, point 4.1)
Method validation of the active ingredient
content by HPLC
Impurities in technical active substance
(principle of method) (Annex IIA, point
4.1)
Method validation of MMDMH and DMH
content by HPLC
Analytical methods for residues
Soil (principle of method and LOQ)
(Annex IIA, point 4.2)
Study on DMH:
The residues were determined by HPLC-MS.
The LOQ nominal was 0.05 mg/kg.
Air (principle of method and LOQ) (Annex
IIA, point 4.2)
Not applicable
Water (principle of method and LOQ)
(Annex IIA, point 4.2)
Study on DMH:
The residues were determined by HPLC-MS
with the use of:
1.procedure A (500 times enrichment) with
LOQ = 0.5μg/l and,
2. procedure B (2000 times enrichment) with
LOQ = 0.1μg/l.
Body fluids and tissues (principle of
method and LOQ) (Annex IIA, point 4.2)
Not applicable
Food/feed of plant origin (principle of
method and LOQ for methods for
monitoring purposes) (Annex IIIA, point
IV.1)
Not applicable
Food/feed of animal origin (principle of
method and LOQ for methods for
monitoring purposes) (Annex IIIA, point
IV.1)
Not applicable
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Chapter 3: Impact on Human Health
Absorption, distribution, metabolism and excretion in mammals (Annex IIA, point 6.2)
Rate and extent of oral absorption: Performed on the relevant degradation product
DMH
The majority of DMH is absorbed via the oral
and iv routes with elimination without
metabolism in the urine (up to 96%). A small
percentage (less than 1.37%) was eliminated in
faeces and can therefore be said not to have
been absorbed through the GI tract. Only 2.6%
of the oral dose was not recovered within the
test period and therefore, this percentage is
considered to be retained. The study identifies
hair and possibly fat as having the highest
residue levels but not at levels indicative of
bioaccumulation.
Formaldehyde:
100% uptake, rapid (based on 14C in exhaled
air, urine and carcass), low systemic
bioavailability (first-pass metabolism)
Rate and extent of dermal absorption: DMH
Study not performed. 100% default used in risk
assessment
Formaldehyde
100% uptake (based on 14C in excreta, organs
and carcass, and on in vitro data on human
skin), low systemic bioavailability (first-pass
metabolism)
Rate and extent of inhalative absorption Formaldehyde
100% uptake (based on 14C ) (rodents/primates
at rest: ~ 90 and 70% in nasal passages,
man/oronasal breathing: up to ~ 45% tracheo-
bronchially), systemic bioavailability below
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10% (first-pass metabolism)
Distribution: DMH
The majority of DMH was excreted in the urine
Formaldehyde 14C label widely distributed (introduction into
C1-pool)
Metabolism DMH
The majority of DMH is absorbed via the oral
and iv routes with elimination without
metabolism in the urine (up to 96%).
Formaldehyde
1) Reaction with GSH followed by enzymatic
conversion to formate and utilisation for C1-
transfer or oxidation to CO2
2) Direct enzymatic conversion to formate and
utilisation for C1-transfer or oxidation to CO2
3) Reaction with THF followed by conversion
to 5-methyl or 5-formyl THF and utilisation for
C1-transfer or transformation to 10-formyl
THF and release of formate or oxidation to CO2
4) Adduct formation with cysteine, urea,
proteins and nucleic acids
Pronounced first-pass metabolism at site of
entry
Rate and extent of excretion DMH
Elimination without metabolism in the urine
(up to 96%). A small percentage (less than
1.37%) was eliminated in faeces. Most of the
radioactivity recovered in the urine was
excreted within the first 12 hours. Urinary half
lives (obtained graphically from the data in the
reports by Σ-plots) were superimposable, with
values of 3.0 - 3.25h (males) and 2.4 - 2.8h
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(females).
Formaldehyde
Metabolic elimination, high, but variable rate
and extent of metabolite excretion (based on 14C) mainly with air and urine (initial plasma
t1/2 12h, terminal t1/2 50h, 10 - 40% 14C residues
after 3-4d)
Potential for accumulation: No evidence for accumulation for both
substances
Toxicologically significant metabolite None. DMDMH is rapidly hydrolyzed to DMH
which was considered relevant for ADME
studies.
Toxicity of metabolites of formaldehyde not
assessed separately
Urine: formate, hydroxymethylurea
Acute toxicity (Annex IIA, point 6.1)
Rat LD50 oral DMDMH: 1572mg a.i./kg bw
DMH: >10000mg/kg bw
Formaldehyde: 640mg/kg bw
Rat LD50 dermal DMDMH: >1052mg a.i./kg.bw
DMH: >20000mg/kg bw
Formaldehyde: 270mg/kg bw
Rat LC50 inhalation DMH, DMDMH Not available – not required
Formaldehyde: 0.6mg/Lx4h (~100mg/kg bw)
Skin irritation DMDMH: not irritating (53% aqueous
solution)
DMH: not irritating
Formaldehyde: Corrosive
Eye irritation DMDMH in vivo mildly irritating (53%
aqueous solution)
in vitro not corrosive
DMH not irritating
Formaldehyde: Corrosive
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Skin sensitization (test method used and
result)
DMDMH: Buehler and GPMT test not
sensitising
DMH: Buehler method not sensitising
Formaldehyde: Sensitising (M&K, LLNA,
human data)
Repeated dose toxicity (Annex IIA, point 6.3 - 6.5)
Species / target / critical effect The degradant DMH was considered relevant
for repeated dose toxicity
DMDMH
Rat/oral/90 days
High dose: a statistically significant increases
of mean absolute and relative adrenal weights
for males in both groups.
Mid and low dose: no treatment related
changes.
Rabbit/dermal/28 days
High dose: treatment related lesion at the skin
of the test sites (multifocal to diffuse epidermal
inflammation with focal to multifocal
epidermal necrosis and ulceration).
No systemic adverse effects at both doses
Rabbit/dermal/90 days
Progression of the acute and necrotizing
inflammatory process in the skin and
subsequent separation of the necrotic focus
which produced an ulcer.
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DMH
Rat/oral/90 days
High dose: males - equivocal decrease in body
weight, liver weight and food consumption;
females - equivocal increase in body weight,
liver weight and food consumption
Mid and low dose: no treatment related
changes.
Rat/oral/104 weeks
High dose: equivocal decrease in body weight
and survival.
Mid and low dose: no treatment related
changes
Dog/oral/1 year
High dose: small decreases in body weight,
increase in adrenal weights and mild
hypertrophy in adrenal cortex for males. Small
decreases in body weight for females
Mid and low dose: no treatment related
changes
Rat/dermal/90 days
No effects
Formaldehyde
Rat (oral): bw ↓; stomach: hyperkeratosis,
ulcerations, atrophy, hyperplasia; kidney:
papillary necrosis
Dog (oral): bw ↓
Mouse (dermal): skin: irritation, fissuring,
papules
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Rat/monkey (inhalation): nasal epithelium:
degeneration, necrosis, exfoliation, erosion,
squamous metaplasia, hyperplasia
Short-term, subchronic and toxicity
(Annex IIA, points 6.3 & 6.4)
Relevant oral NOAEL 300mg/kg bw/day, 1-year dog (DMH)
1000mg/kg bw/day, 90-day rat (DMH)
25mg/kg bw/day, 28-day rat (Formaldehyde)
Relevant dermal NOAEL 390mg/kg bw/day, 90-day rat (DMH)
Relevant inhalation NOAEL Not available – not required for DMH
1.2µg/L x 22h/day, 6-mo, rat, monkey
(Formaldehyde)
Chronic toxicity (Annex IIA, point 6.5)
Relevant chronic oral NOAEL 300mg/kg bw/day, 2-year combined chronic
toxicity/carcinogenicity study in rats (DMH)
15mg/kg bw/d, 24-mo rat (Formaldehyde)
Genotoxicity (Annex IIA, point 6.6)
In vitro tests performed on DMDMH and DMH
DMDMH: Ames test, chromosome aberration,
Cytogenicity Study – Chinese Hamster Ovaries
and mouse lymphoma assay gave a positive
result with 55% aqueous solution. Positive
results are attributed to free formaldehyde in
aqueous solution. Ames test with 100% pure
active substance gave a negative result.
DMH: Ames test, chromosome aberration and
mouse lymphoma assay were all negative.
In vivo performed on DMDMH
The in vivo micronucleus assay and alkaline
elution assay indicated no potential for
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mutagenicity.
Formaldehyde
Clastogenic locally in vivo (secondary to DNA-
protein crosslinks)
Carcinogenicity (Annex IIA, point 6.4)
Species / type of tumour The degradant DMH was considered relevant
for carcinogenicity
Performed on rat: The test substance did not
induce tumour formation or any other
carcinogenic effects.
Rat, Mouse (inhalative):
Nasal epithelium: squamous cell carcinoma
Lowest dose with tumours Formaldehyde:
Rat (24-mo): 7.2µg/L x 6h/d
Mouse (24-mo): 18µg/L x 6h/d
Reproductive toxicity (Annex IIA, point 6.8)
Species / Reproduction target / critical
effect
Performed on DMH, the substance of relevance
for long-term toxicity.
Rat/Oral/2-gen
No parental toxicity or adverse effects on
reproduction or reproductive tissues. Body
weight ↓ in F1 and F2 generations at high dose
level.
Results from a 2-generation reproductive toxicity study in rats showed that DMH is not selectively toxic to the fertility or the developing offspring. Exposure to DMH in the diet did not result in parental toxicity or adverse effects on reproductive performance or reproductive tissues at dietary concentrations as high as 20000ppm (~1395mg/kg bw/day). However, there were effects (decreased weight gain) in offspring during lactation. Small increases in parental food consumption and
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body weight and transient decreases in offspring body weight during lactation were observed at the 20000ppm dose level.
Lowest relevant reproductive NOAEL /
LOAEL
NOAEL parental = 1395mg/kg bw/day NOAEL offspring = 379mg/kg bw/day
Species/Developmental target / critical
effect
DMH, EMH:
In general, the administration of DMH or EMH
to pregnant rats or rabbits does not result in
profound toxicity to either species. High dose
levels are required to induce some toxic effects.
It is apparent that there was no significant
developmental toxicity to rat offspring.
Findings were limited, in this case to rib effects
which are most likely a consequence of toxicity
to the adult. The overall opinion must be that
DMH and EMH do not induce developmental
effects in the rat at non toxic dose levels and
the effects with DMH are not significant
enough to suggest it is a developmental
toxicant.
In the case of the rabbit, the findings are less
conclusive. At dose levels of EMH and DMH
that were toxic to the adult there was some
evidence of a specific developmental effect.
With DMH this was absence of a digit on the
forepaws. With EMH it was an increase in the
incidence of foetuses with unossified bones in
the forepaws. It is of note that these findings
were not seen in a second study (Hoar R.M.
(1986)) at a dose level of 1000mg/kg:
considered a limit dose (for developmental
toxicity studies). The effects seen were limited
in their incidence. It is also important to note
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that the effect with EMH was not considered to
be significant proof of developmental toxicity
by the author of the study (Beyer B.K. (1992)).
Most importantly, these findings are only seen
at dose levels that are toxic to the adult and are
therefore of limited significance.
In one developmental toxicity study in the
rabbit (Nemec M.D. (1992)), a further finding
seen at dose levels of 500 and 1000mg/kg was
considered to be an effect on foetal
development. The increase in incidence of
foetuses with 27 presacral vertebrae and 13 rib
pairs. At the time of the study this may have
been considered possible indicators of
developmental toxicity. However, subsequent
evidence (Drain M.R. and Wilby O.K. (1994))
do indicate that other factors influence these
findings and their toxicological significance is
highly questionable. It should be noted that
these findings were not seen in a second
developmental toxicity study in the rabbit. It is
the opinion of this study author that the true
NOAEL for developmental toxicity for the
study in question should be 500mg/kg and not
100mg/kg.
The results of all the developmental toxicity
studies conducted with DMH and EMH suggest
that significant developmental toxicity was
limited to the digit defects in the rabbit and not
in the rat. The finding in question was only
seen at a dose level that was toxic to the adult
and the finding was only seen at low incidence.
Formaldehyde:
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Rat, Mouse:
No teratogenic effects
Lowest relevant developmental NOAEL
EMH ADULT 375mg/kg
DMH ADULT 500mg/kg
Offspring 500mg/kg
It is considered, based on the weight of
evidence and the type of effects observed that
the lowest NOAEL applicable for the Risk
Assessment is 375mg/kg bw/day and that
further investigation is not warranted.
Neither DMH nor EMH should be considered
to be developmental toxins based on the results
of the available studies
Maternal:
Rat:1000mg/kg bw/day (DMH)
Rabbit: 1000mg/kg bw/day (DMH, EMH)
375mg/kg bw/day (EMH)
Developmental:
Rat:1000mg/kg bw/day (DMH)
Rabbit: 1000mg/kg bw/day (DMH, EMH)
375mg/kg bw/day (EMH, comparable
to DMH)
Formaldehyde:
Maternal:
Rat (inhalation): 24µg/L x 6h/day
Mouse: 148mg/kg bw/day
Developmental:
Rat: 24µg/L x 6h/day
Mouse: 148mg/kg bw/day
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Neurotoxicity / Delayed neurotoxicity (Annex IIIA, point VI.1)
Species / target / critical effect Not considered necessary
Lowest relevant developmental NOAEL /
LOAEL.
N/A
Other toxicological studies (Annex IIIA, VI/XI)
Ocular and respiratory irritation, human Formaldehyde:
Eye irritation:
≥ 0.36µg/L x 4h with peaks of
0.72µg/L,
Nasal irritation:
≥ 0.6µg/L x 4h with peaks of 1.2µg/L;
NOAEC: 0.36µg/L
population NOAEC: 0.12µg/L
Medical data (Annex IIA, point 6.9)
Cohort study
Formaldehyde:
Evidence for association of occupational
inhalative exposure with increase in
standardised mortality ratio for upper
respiratory tract cancer (NPC); increase in
relative risk with peak exposure and average
intensity
Patch test DMDMH:
12 formaldehyde-allergic patients applied a
cream containing 1% DMDMH and 4
formaldehyde-allergic patients applied cream
containing 0.25% DMDMH.
It concludes that an increase in the use of
DMDMH in cosmetic products will also
inevitably increase the risk of cosmetic
dermatitis in consumers allergic to
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formaldehyde.
1808 animals applied 2% aq. solution pet –
0.3% positive.
34321 human applied 2% aq. solution – 0.5%
positive.
The frequency of sensitisation was
comparatively low.
Summary (Annex IIA, point 6.10)
DMDMH Value Study Safety factor
AEL acute 3.75mg/kg
bw/d
Teratogenicity
study in rabbit
for EMH
100
AEL medium-term 3.0mg/kg
bw/d
1-year chronic
study in dog
100
Drinking water limit N/A N/A N/A
AEL long-term 3.0mg/kg
bw/d
1-year chronic
study in dog
100
ADI (if residues in food or feed) Not allocated
ARfD (if residues in food or feed) Not allocated
Formaldehyde
Value Study Safety factor
AELacute
AELmedium-term
AELlong-term
0.15mg/kg
bw/d
Rat, overall
(28-d, 90-d, 2-
yr)
100
AECacute, inhalative
AECmedium-term, inhalative
AEClong-term, inhalative
0.12µg/L Human, eye
irritation
3
Human,
overall
1
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ocular/respirat
ory irritation
Rat, Monkey,
6-mo
10
Drinking water limit Not allocated
ADI (if residues in food or feed) Not allocated
ARfD (if residues in food or feed) Not allocated
Acceptable exposure scenarios (including method of calculation)
Professional users PT13
Scenario 1: Professionals diluting product into
metal working fluids sump. 70% active
substance in product equivalent to 47.7% DMH
and 0.1% formaldehyde.
Model: TNsG exposure model for pouring and
pumping liquids into systems (Mixing and
Loading; Model 7) used for dermal and
inhalation exposure.
Exposure: Once a day, 15 minutes exposure.
Exposure to formaldehyde and DMH
considered.
Scenario 2: Professional users undertaking
metal working and maintenance tasks. 0.245%
active substance in product equivalent to 0.17%
DMH and 0.08% formaldehyde.
Model 1: Inhalation exposure, TNsG part 2
p.189 MWF.
Model 2: BEAT calculation for PT13 with
input value recommended by HEEG (TM III
08).
Exposure: Once a month maintenance for
240min, daily exposure during metal working
for 120min. Exposure to formaldehyde and
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DMH considered.
Non-professional users Non-professional use is not envisaged
Indirect exposure as a result of use Scenario: Deposits of metal working fluid on
clothes whilst doing laundry.
Model: CONSEXPO
Exposure: Dermal exposure to DMH ~ 1
minute.
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Chapter 4: Fate and Behaviour in the Environment
Route and rate of degradation in water (Annex IIA, point 7.6, IIIA, point XII.2.1, 2.2)
Hydrolysis of active substance and relevant
metabolites (DT50) (state pH and
temperature)
DMDMH: DT50 pH4 = > 1 year, pH 7= < 1
day, pH 9 = < 1 day at 25°C
DMDMH: DT50 pH 7.5 at 35°C dirty water
and tap water = < 1 hour
Hydrolyses to DMH and formaldehyde
DMH and formaldehyde stable in water
Photolytic / photo-oxidative degradation of
active substance and resulting relevant
metabolites
DMH: no photolytic degradation
Formaldehyde: no photolytic degradation
Readily biodegradable (yes/no) DMDMH: Yes, readily biodegradable
DMH: Yes, readily biodegradable
Formaldehyde: Yes, readily biodegradable
(failing 10-days window)
Biodegradation in seawater Not applicable
Non-extractable residues
Distribution in water / sediment systems
(active substance)
DMDMH undergoes rapid hydrolyses to DMH.
Distribution of the degradant considered below.
Distribution in water / sediment systems
(metabolites)
Performed on DMH the substance of relevance
for environmental fate studies
DMH was steadily degraded with whole
systems and aqueous phase DT50 values of
17.45 to 19.95 days (33.1-37.9 days after
conversion to average EU outdoor temperature
12°C). The unextractable radioactivity (bound
residue) increased from 0.5% to a maximum of
9.8% of the initial radioactivity after 84 days
incubation then decreased to 7.7% at the end
of the test. The predominant degradation
product was CO2 which accounted for 55 to
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65% of the applied radioactivity at the end of
the incubation phase
Route and rate of degradation in soil (Annex IIIA, point VII.4, XII.1.1, XII.1.4; Annex VI,
para. 85)
Mineralization (aerobic) Not performed
Laboratory studies (range or median, with
number of measurements, with regression
coefficient)
Not performed
Field studies (state location, range or
median with number of measurements)
Not performed
Anaerobic degradation Not performed
Soil photolysis Not performed
Non-extractable residues Not performed
Relevant metabolites - name and/or code,
% of applied a.i. (range and maximum)
Not performed
Soil accumulation and plateau
concentration
Not performed
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Adsorption/desorption (Annex IIA, point XII.7.7; Annex IIIA, point XII.1.2)
Ka , Kd
Kaoc , Kdoc
pH dependence (yes / no) (if yes type of
dependence)
Performed on DMH
DMH: Kd = 0.593 Koc = 80.15 (mean
values)
No
Formaldehyde (calculation)
Koc = 15.9
Fate and behaviour in air (Annex IIIA, point VII.3, VII.5)
Direct photolysis in air DMDMH will convert readily to DMH and
formaldehyde in the environment and therefore
the latter two molecules were considered.
Indirect phtolysis:
The half-life of photolysis of DMH is 3.495
days with an overall OH rate constant of
3.0608E-12 cm3/molecule-sec (half-life
calculated using EPIWIN v 3.12).
The half-life of photolysis of formaldehyde is
1.7 days with an overall OH rate constant of
3.0608E-12 cm3/molecule-sec (half-life
calculated using EPIWIN v 3.12).
Quantum yield of direct photolysis No data available
Photo-oxidative degradation in air Latitude: ............. Season: .................
DT50 ..............
Volatilization DMDMH is not volatile (vapour pressure
=0.00000012hPa at 25°C)
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Monitoring data, if available (Annex VI, para. 44)
Soil (indicate location and type of study) No data
Surface water (indicate location and type
of study)
No data
Ground water (indicate location and type
of study)
No data
Air (indicate location and type of study) No data
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Chapter 5: Effects on Non-target Species
Studies performed with DMDMH, DMH and formaldehyde
Toxicity data for aquatic species (most sensitive species of each group) DMDMH
(Annex IIA, point 8.2, Annex IIIA, point 10.2)
Species Time-
scale
Endpoint Toxicity
Fish
Brachydanio rerio 96 h LC50 >82.3 mg/l
Invertebrates
Daphnia magna 48h EC50 29.1 mg/l
Algae
Desmodesmus
subspicatus
72 h NOEC 5.1 mg/l
Microorganisms Activated sludge
3h EC50 > 100 mg/l
Toxicity data for aquatic species (most sensitive species of each group) DMH
(Annex IIA, point 8.2, Annex IIIA, point 10.2)
Species Time-
scale
Endpoint Toxicity
Fish
Oncorhynchus mykiss 96h LC50 >972.2 mg/l
Invertebrates
Daphnia magna 48h EC50 6200 mg/l
Algae
Pseudokirchneriella
subcapitata
96h NOEC >1000 mg/l
Microorganisms
Activated sludge,
domestic
3h EC50 > 1000 mg/l
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Toxicity data for aquatic species (most sensitive species of each group)
formaldehyde
(Annex IIA, point 8.2, Annex IIIA, point 10.2)
Species Time-
scale
Endpoint Toxicity
Fish
Morone saxatilis 96h LC50 5.7 mg/l
Invertebrates
Daphnia pulex 48h EC50 5.8 mg/l
Algae
Pseudokirchneriella
subcapitata
96h EC50 5.7 mg/l
Microorganisms
Activated sludge,
domestic
3h EC50 20.4 mg/l
Effects on earthworms or other soil non-target organisms
Acute toxicity to earthworms
(Annex IIIA, point XIII.3.2)
Performed on DMH
14-day LC50 > 1000 mg/kg
Reproductive toxicity to
…………………………
(Annex IIIA, point XIII.3.2)
N/A
Effects on soil micro-organisms (Annex IIA, point 7.4)
Nitrogen mineralization Performed on DMH
EC50 (28 days) > 1000 mg/kg
NOEC (28 days) = 1000 mg/kg
Carbon mineralization N/A
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Effects on terrestrial vertebrates
Acute toxicity to mammals
(Annex IIIA, point XIII.3.3)
N/A
Acute toxicity to birds
(Annex IIIA, point XIII.1.1)
N/A
Dietary toxicity to birds
(Annex IIIA, point XIII.1.2)
N/A
Reproductive toxicity to birds
(Annex IIIA, point XIII.1.3)
N/A
Effects on honeybees (Annex IIIA, point XIII.3.1)
Acute oral toxicity N/A
Acute contact toxicity N/A
Effects on other beneficial arthropods (Annex IIIA, point XIII.3.1)
Acute oral toxicity N/A
Acute contact toxicity N/A
Acute toxicity to
…………………………………..
N/A
Bioconcentration (Annex IIA, point 7.5)
Bioconcentration factor (BCF) Performed on the relevant degradant DMH.
DMH: BCF <1.79
Formaldehyde (calculation) BCF =0.396
Depuration time (DT50) N/A
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(DT90)
Level of metabolites (%) in organisms
accounting for > 10 % of residues
None
Chapter 6: Other End Points
Acute Toxicity to Plants - DMH (Annex IIIA, XIII.3.2)
Species Endpoint Toxicity Soybean
Emergence (EC50) >1000 mg/kg
Cucumber
Emergence (EC50) 990 mg/kg
Oat
Emergence (EC50) >1000 mg/kg
Soybean)
Growth (EC50) >1000 mg/kg
Cucumber
Growth (EC50) >1000 mg/kg
Oat
Growth (EC50) >1000 mg/kg
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APPENDIX II - LIST OF TERMS AND ABBREVIATIONS
Stand. term / Abbreviation
Explanation
A ampere
ACh acetylcholine
AChE acetylcholinesterase
ADI acceptable daily intake
ADME administration distribution metabolism and excretion
ADP adenosine diphosphate
AE acid equivalent
AEL Systemic (= Internal) Acceptable Exposure Level
AECinhalative Inhalative (= External) Acceptable Exposure Concentration
AF assessment factor
AFID alkali flame-ionisation detector or detection
A/G albumin/globulin ratio
ai active ingredient
ALD50 approximate median lethal dose, 50%
ALT alanine aminotransferase (SGPT)
Ann. Annex
AMD automatic multiple development
ANOVA analysis of variance
AP alkaline phosphatase
approx approximate
ARC anticipated residue contribution
ARfD acute reference dose
as active substance
AST aspartate aminotransferase (SGOT)
ASV air saturation value
ATP adenosine triphosphate
BAF bioaccumulation factor
BCF bioconcentration factor
bfa body fluid assay
Stand. term / Abbreviation
Explanation
BOD biological oxygen demand
bp boiling point
BPD Biocidal Products Directive
BSAF biota-sediment accumulation factor
BSE bovine spongiform encephalopathy
BSP bromosulfophthalein
Bt Bacillus thuringiensis
Bti Bacillus thuringiensis israelensis
Btk Bacillus thuringiensis kurstaki
Btt Bacillus thuringiensis tenebrionis
BUN blood urea nitrogen
bw body weight
c centi- (x 10 –2 )
°C degrees Celsius (centigrade)
CA controlled atmosphere
CAD computer aided design
CADDY computer aided dossier and data supply (an electronic dossier interchange and archiving format)
cd candela
CDA controlled drop(let) application
cDNA complementary DANN
CEC cation exchange capacity
cf confer, compare to
CFU colony forming units
ChE cholinesterase
CI confidence interval
CL confidence limits
cm centimetre
CNS central nervous system
COD chemical oxygen demand
CPK creatinine phosphatase
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Stand. term / Abbreviation
Explanation
cv coefficient of variation
Cv ceiling value
d day(s)
DES diethylstilboestrol
DIS draft international standard (ISO)
DMSO dimethylsulfoxide
DNA deoxyribonucleic acid
dna designated national authority
DO dissolved oxygen
DOC dissolved organic carbon
dpi days post inoculation
DRP detailed review paper (OECD)
DT50(lab) period required for 50 percent dissipation (under laboratory conditions) (define method of estimation)
DT90(field) period required for 90 percent dissipation (under field conditions) (define method of estimation)
dw dry weight
DWQG drinking water quality guidelines
ε decadic molar extinction coefficient
EC50 median effective concentration
ECD electron capture detector
ED50 median effective dose
EDI estimated daily intake
EINECS European inventory of existing commercial substances
ELINCS European list of notified chemical substances
ELISA enzyme linked immunosorbent assay
e-mail electronic mail
EMDI estimated maximum daily intake
EN European norm
EPMA electron probe micro-analysis
ERL extraneous residue limit
ESPE46/51 evaluation system for pesticides
Stand. term / Abbreviation
Explanation
EUSES European Union system for the evaluation of substances
F field
F0 parental generation
F1 filial generation, first
F2 filial generation, second
FBS full base set
FELS fish early-life stage
FIA fluorescence immuno-assay
FID flame ionisation detector
Fmol fractional equivalent of the metabolite´s molecular weight compared to the active substance
FOB functional observation battery
foc organic carbon factor (compartment dependent)
fp freezing point
FPD flame photometric detector
FPLC fast protein liquid chromatography
g gram(s)
GAP good agricultural practice
GC gas chromatography
GC-EC gas chromatography with electron capture detector
GC-FID gas chromatography with flame ionisation detector
GC-MS gas chromatography-mass spectrometry
GC-MSD gas chromatography with mass-selective detection
GEP good experimental practice
GFP good field practice
GGT gamma glutamyl transferase
GI gastro-intestinal
GIT gastro-intestinal tract
GL guideline level
GLC gas liquid chromatography
GLP good laboratory practice
GM geometric mean
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Stand. term / Abbreviation
Explanation
GMO genetically modified organism
GMM genetically modified micro-organism
GPC gel-permeation chromatography
GPS global positioning system
GSH glutathione
GV granulosevirus
h hour(s)
H Henry’s Law constant (calculated as a unitless value)
ha hectare(s)
Hb haemoglobin
HC5 concentration which will be harmless to at least 95 % of the species present with a given level of confidence (usually 95 %)
HCG human chorionic gonadotropin
Hct haematocrit
HDT highest dose tested
hL hectolitre
HEED high energy electron diffraction
HID helium ionisation detector
HPAEC high performance anion exchange chromatography
HPLC high pressure liquid chromatography or high performance liquid chromatography
HPLC-MS high pressure liquid chromatography - mass spectrometry
HPPLC high pressure planar liquid chromatography
HPTLC high performance thin layer chromatography
HRGC high resolution gas chromatography
HS Shannon-Weaver index
Ht haematocrit
HUSS human and use safety standard
I indoor
I50 inhibitory dose, 50%
IC50 median immobilisation
Stand. term / Abbreviation
Explanation
concentration or median inhibitory concentration 1
ICM integrated crop management
ID ionisation detector
IEDI international estimated daily intake
IGR insect growth regulator
im intramuscular
inh inhalation
INT 2-p-iodophenyl-3-p-nitrophenyl-5-phenyltetrazoliumchloride testing method
ip intraperitoneal
IPM integrated pest management
IR infrared
ISBN international standard book number
ISSN international standard serial number
IUCLID International Uniform Chemical Information Database
iv intravenous
IVF in vitro fertilisation
k (in combination)
kilo
k rate constant for biodegradation
K Kelvin
Ka acid dissociation constant
Kb base dissociation constant
Kads adsorption constant
Kdes apparent desorption coefficient
kg kilogram
KH Henry´s Law constant (in atmosphere per cubic metre per mole)
Koc organic carbon adsorption coefficient
Kom organic matter adsorption coefficient
Kow octanol-water partition coefficient
Kp solid-water partition coefficient
kPa kilopascal(s)
l, L litre
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Stand. term / Abbreviation
Explanation
LAN local area network
LASER light amplification by stimulated emission of radiation
LBC loosely bound capacity
LC liquid chromatography
LC-MS liquid chromatography- mass spectrometry
LC50 lethal concentration, median
LCA life cycle analysis
LC-MS-MS liquid chromatography with tandem mass spectrometry
LD50 lethal dose, median; dosis letalis media
LDH lactate dehydrogenase
ln natural logarithm
LOAEC lowest observable adverse effect concentration
LOAEL lowest observable adverse effect level
LOD limit of detection
LOEC lowest observable effect concentration
LOEL lowest observable effect level
log logarithm to the base 10
LOQ limit of quantification (determination)
LPLC low pressure liquid chromatography
LSC liquid scintillation counting or counter
LSD least squared denominator multiple range test
LSS liquid scintillation spectrometry
LT lethal threshold
m metre
M molar
µm micrometre (micron)
MAC maximum allowable concentration
MAK maximum allowable concentration
MC moisture content
MCH mean corpuscular haemoglobin
Stand. term / Abbreviation
Explanation
MCHC mean corpuscular haemoglobin concentration
MCV mean corpuscular volume
MDL method detection limit
MFO mixed function oxidase
µg microgram
mg milligram
MHC moisture holding capacity
MIC minimum inhibitory concentration
min minute(s)
MKC minimum killing concentration
mL millilitre
MLT median lethal time
MLD minimum lethal dose
mm millimetre
MMAD mass median aerodynamic diameter
mo month(s)
MOE margin of exposure
mol mole(s)
MOS margin of safety
mp melting point
MRE maximum residue expected
MRL maximum residue level or limit
mRNA messenger ribonucleic acid
MS mass spectrometry
MSDS material safety data sheet
MTD maximum tolerated dose
MT material test
MW molecular weight
n.a. not applicable
n- normal (defining isomeric configuration)
n number of observations
NAEL no adverse effect level
nd not detected
NEDI national estimated daily intake
NEL no effect level
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Stand. term / Abbreviation
Explanation
NERL no effect residue level
ng nanogram
nm nanometre
NMR nuclear magnetic resonance
no, n° number
NOAEC no observed adverse effect concentration
NOAEL no observed adverse effect level
NOEC no observed effect concentration
NOED no observed effect dose
NOEL no observed effect level
NOIS notice of intent to suspend
NPD nitrogen-phosphorus detector or detection
NPV nuclear polyhedrosis virus
NR not reported
NTE neurotoxic target esterase
OC organic carbon content
OCR optical character recognition
ODP ozone-depleting potential
ODS ozone-depleting substances
OEL occupational exposure limit
OH hydroxide
OJ Official Journal
OM organic matter content
Pa pascal
PAD pulsed amperometric detection
2-PAM 2-pralidoxime
pc paper chromatography
PC personal computer
PCV haematocrit (packed corpuscular volume)
PEC predicted environmental concentration
PECA predicted environmental concentration in air
PECS predicted environmental concentration in soil
PECSW predicted environmental
Stand. term / Abbreviation
Explanation
concentration in surface water
PECGW predicted environmental concentration in ground water
PED plasma-emissions-detector
pH pH-value
PHED pesticide handler’s exposure data
PIC prior informed consent
pic phage inhibitory capacity
PIXE proton induced X-ray emission
pKa negative logarithm (to the base 10) of the acid dissociation constant
pKb negative logarithm (to the base 10) of the base dissociation constant
PNEC predicted no effect concentration (compartment to be added as subscript)
po by mouth
POP persistent organic pollutants
ppb parts per billion (10 -9 )
PPE personal protective equipment
ppm parts per million (10 -6 )
PPP plant protection product
ppq parts per quadrillion (10 -24 )
ppt parts per trillion (10 -12 )
PSP phenolsulfophthalein
PrT prothrombin time
PRL practical residue limit
PT product type
PT(CEN) project team CEN
PTDI provisional tolerable daily intake
PTT partial thromboplastin time
QA quality assurance
QAU quality assurance unit
(Q)SAR quantitative structure-activity relationship
r correlation coefficient
r 2 coefficient of determination
RA risk assessment
RBC red blood cell
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Stand. term / Abbreviation
Explanation
REI restricted entry interval
RENI Registry Nomenclature Information System
Rf retardation factor
RfD reference dose
RH relative humidity
RL50 median residual lifetime
RNA ribonucleic acid
RP reversed phase
rpm revolutions per minute
rRNA ribosomal ribonucleic acid
RRT relative retention time
RSD relative standard deviation
s second
S solubility
SAC strong adsorption capacity
SAP serum alkaline phosphatase
SAR structure/activity relationship
SBLC shallow bed liquid chromatography
sc subcutaneous
sce sister chromatid exchange
SCAS semi-continous activated sludge
SCTER smallest chronic toxicity exposure ratio (TER)
SD standard deviation
se standard error
SEM standard error of the mean
SEP standard evaluation procedure
SF safety factor
SFC supercritical fluid chromatography
SFE supercritical fluid extraction
SIMS secondary ion mass spectroscopy
S/L short term to long term ratio
SMEs small and medium sized enterprises
SOP standard operating procedures
sp species (only after a generic name)
SPE solid phase extraction
Stand. term / Abbreviation
Explanation
SPF specific pathogen free
spp subspecies
SSD sulphur specific detector
SSMS spark source mass spectrometry
STEL short term exposure limit
STER smallest toxicity exposure ratio (TER)
STMR supervised trials median residue
STP sewage treatment plant
t tonne(s) (metric ton)
t½ half-life (define method of estimation)
T3 tri-iodothyroxine
T4 thyroxine
T25 tumorigenic dose that causes tumours in 25 % of the test animals
TADI temporary acceptable daily intake
TBC tightly bound capacity
TCD thermal conductivity detector
TG technical guideline, technical group
TGD Technical guidance document
TID thermionic detector, alkali flame detector
TDR time domain reflectrometry
TER toxicity exposure ratio
TERI toxicity exposure ratio for initial exposure
TERST toxicity exposure ratio following repeated exposure
TERLT toxicity exposure ratio following chronic exposure
tert tertiary (in a chemical name)
TEP typical end-use product
TGGE temperature gradient gel electrophoresis
TIFF tag image file format
TLC thin layer chromatography
Tlm median tolerance limit
TLV threshold limit value
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Stand. term / Abbreviation
Explanation
TMDI theoretical maximum daily intake
TMRC theoretical maximum residue contribution
TMRL temporary maximum residue limit
TNsG technical notes for guidance
TOC total organic carbon
Tremcard transport emergency card
tRNA transfer ribonucleic acid
TSH thyroid stimulating hormone (thyrotropin)
TTC 2,3,5-triphenylterazoliumchloride testing method
TWA time weighted average
UDS unscheduled DNA synthesis
UF uncertainty factor (safety factor)
ULV ultra low volume
UR unit risk
UV ultraviolet
UVC unknown or variable composition,
Stand. term / Abbreviation
Explanation
complex reaction products
UVCB undefined or variable composition, complex reaction products in biological material
v/v volume ratio (volume per volume)
vis visible
WBC white blood cell
wk week
wt weight
w/v weight per volume
ww wet weight
w/w weight per weight
XRFA X-ray fluorescence analysis
yr year
< less than
≤ less than or equal to
> greater than
≥ greater than or equal to
APPENDIX III - LIST OF ORGANISATIONS AND PUBLICATIONS
Abbreviation Explanation
ASTM American Society for Testing and Materials
BA Biological Abstracts (Philadelphia)
BART Beneficial Arthropod Registration Testing Group
BBA German Federal Agency of Agriculture and Forestry
CA(S) Chemical Abstracts (System)
CAB Centre for Agriculture and Biosciences International
CAC Codex Alimentarius Commission
CAS Chemical Abstracts Service
CCFAC Codex Committee on Food Additives and Contaminants
CCGP Codex Committee on General Principles
CCPR Codex Committee on Pesticide Residues
CCRVDF Codex Committee on Residues of Veterinary Drugs in Food
CE Council of Europe
CEC Commission of the European Communities
CEFIC European Chemical Industry Council
CEN European Committee for Normalisation
CEPE European Committee for Paints and Inks
CIPAC Collaborative International Pesticides Analytical Council Ltd
CMA Chemicals Manufacturers Association
COREPER Comite des Representants Permanents
COST European Co-operation in the field of Scientific and Technical Research
DG Directorate General
DIN German Institute for
Abbreviation Explanation Standardisation
EC European Commission
ECB European Chemicals Bureau
ECCO European Commission Co-ordination
ECDIN Environmental Chemicals Data and Information Network of the European Communities
ECDIS European Environmental Chemicals Data and Information System
ECE Economic Commission for Europe
ECETOC European Chemical Industry Ecology and Toxicology Centre
EDEXIM European Database on Export and Import of Dangerous Chemicals
EEC European Economic Community
EHC Environmental Health Criteria
EINECS European Inventory of Existing Commercial Chemical Substances
ELINCS European List of New Chemical Substances
EMIC Environmental Mutagens Information Centre
EPA Environmental Protection Agency
EPAS European Producers of Antimicrobial Substances
EPFP European Producers of Formulated Preservatives
EPO European Patent Office
EPPO European and Mediterranean Plant Protection Organization
ESCORT European Standard Characteristics of Beneficials Regulatory Testing
EU European Union
EUPHIDS European Pesticide Hazard Information and Decision Support System
EUROPOEM European Predictive Operator Exposure Model
EWMP European Wood Preservation
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Abbreviation Explanation Manufacturers
FAO Food and Agriculture Organization of the UN
FOCUS Forum for the Co-ordination of Pesticide Fate Models and their Use
FRAC Fungicide Resistance Action Committee
GATT General Agreement on Tariffs and Trade
GAW Global Atmosphere Watch
GIFAP Groupement International des Associations Nationales de Fabricants de Produits Agrochimiques (now known as GCPF)
GCOS Global Climate Observing System
GCPF Global Crop Protection Federation (formerly known as GIFAP)
GEDD Global Environmental Data Directory
GEMS Global Environmental Monitoring System
GRIN Germplasm Resources Information Network
IARC International Agency for Research on Cancer
IATS International Academy of Toxicological Science
ICBP International Council for Bird Preservation
ICCA International Council of Chemical Associations
ICES International Council for the Exploration of the Seas
ILO International Labour Organization
IMO International Maritime Organisation
IOBC International Organization for Biological Control of Noxious Animals and Plants
IPCS International Programme on Chemical Safety
IRAC Insecticide Resistance Action Committee
ISCO International Soil Conservation Organization
Abbreviation Explanation
ISO International Organization for Standardisation
IUPAC International Union of Pure and Applied Chemistry
JECFA FAO/WHO
Joint Expert Committee on Food Additives
JFCMP Joint FAO/WHO Food and Animal Feed Contamination Monitoring Programme
JMP Joint Meeting on Pesticides (WHO/FAO)
JMPR Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues (Joint Meeting on Pesticide Residues)
MITI Ministry of International Trade and Industry, Japan
NATO North Atlantic Treaty Organization
NAFTA North American Free Trade Agreement
NCI National Cancer Institute (USA)
NCTR National Center for Toxicological Research (USA)
NGO non-governmental organisation
NTP National Toxicology Program (USA)
OECD Organization for Economic Co-operation and Development
OLIS On-line Information Service of OECD
OPPTS Office of Prevention, Pesticides and Toxic Substances (US EPA)
OSPAR Oslo Paris Convention (Convention for the Protection of the Marine Environment of the North-East Atlantic)
PAN Pesticide Action Network
RIVM Netherlands National Institute of Public Health and Environmental Protection
RNN Re-registration Notification Network
RTECS Registry of Toxic Effects of Chemical Substances (USA)
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Abbreviation Explanation
SETAC Society of Environmental Toxicology and Chemistry
SI Système International d'Unitès
SITC Standard International Trade Classification
TOXLINE Toxicology Information On-line
UBA German Environmental Protection Agency
Abbreviation Explanation
UN United Nations
UNEP United Nations Environment Programme
WFP World Food Programme
WHO World Health Organization
WPRS West Palearctic Regional Section
WTO World Trade Organization