conclusion ESR ptBP fianl Norway -...

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Conclusion of substance evaluation for transitional dossiers

Summary conclusion of evaluation of a substance according to transitional measures described in

Article 135(2), 136 (1) or 136(2) and 48 of the REACH Regulation.

Substance concerned:

1. Chemical name: 4-tert-butylphenol

2. EC No: 202-679-0

3. CAS No: 98-54-4

Member State reviewing the transitional dossier: Norway

Under which legislation was the information requested (Regulation 793/93 or Directive

67/548/EEC): Regulation 793/93

The specific decision, reference or regulation number, which relates to this testing request:

Commission Regulation (EC) No 506/2007/ and Com. Reg. (EC) No 466/2008

Date of submission by Member State: September 2013

Registration number (if available): http://apps.echa.europa.eu/registered/data/dossiers/DISS-

9d8bb7ca-18a5-44ef-e044-00144f67d249/DISS-9d8bb7ca-18a5-44ef-e044-

00144f67d249_DISS-9d8bb7ca-18a5-44ef-e044-00144f67d249.html

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CONCLUSION OF TRANSITIONAL SUBSTANCE EVALUATION

Tick

relevant

box(es)

Need for harmonised classification and labelling

Need for identification as SVHC (authorisation)

Need for a restrictions proposal

Need for other Community-wide measures

Such as: substance evaluation process/dossier evaluation

x

Need for action at national level or voluntary action by

industry

Such as: update of registrations

x

No follow-up action at EU level required

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SHORT JUSTIFICATION FOR CONCLUSION

1)

Commission Regulation No 466/2008 required local exposure information on the release from

two processing sites (5 and 6) into wastewater treatment plants and aquatic compartment

(freshwater and marine) from industry.

It is recognised that the exposure information in the EU risk assessment report is no longer

relevant since production and use volumes have changed significantly since REACH entered into

force. Several companies have submitted registrations dossier for 4-tert-butylphenol in 2010 and

2013.

2)

Commission Regulation No (EC) No 506/2007 requires an endocrine effects study with fish (

draft OECD ext. ELS test).

Background

In vitro data for ptBP and structurally related chemicals:

Para-tert-butylphenol (ptBP) has been identified as a potential endocrine disruptor based on the

chemicals ability to interact with and activate the estrogen receptor (ER) in vitro in several

organisms and bioassays. These in vitro studies include recombinant cell reporter systems (yeast

and bacterial estrogen screens) which express the human estrogen receptor , estrogen dependable

MCF7 cancer cells, receptor-binding assays with purified liver homogenates containing ERs and

induction of the estrogenic biomarker vitellogenin (VTG) in primary liver cells from fish.

Estrogen receptor-binding studies

The results from receptor-binding studies show that ptBP, and a range of alkylphenols and other

industrial chemicals, are able to bind to the human, rat and fish ERs. The studies with human

ERs report that ptBP binds to the ER with 500 000 times lower affinity than the natural ligand

17β-estradiol (E2) (Olsen et al., 2005). The binding affinity of ptBP to the human ER were 20

times lower than the more hydrophobic alkylphenol 4-tert-octylphenol (ptOP) and 500 times

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lower than Bisphenol A (BPA). The binding affinity of ptBP to the human ERs resemble that of

the rat ER, where binding affinity of ptBP were 400 000 times lower than E2, 15 times lower

than ptOP and 30 times lower than BPA (Blair et al., 2000). Interestingly, ptBP displayed similar

binding affinity as the structurally related alkylphenol 4-tert-pentylphenol, ptPP.

Studies with rainbow trout liver homogenates demonstrate that ptBP binds to the ER with about

13 000-25 000 times lower binding affinity than E2, and fairly similar binding affinity as ptPP,

ptOP and BPA (Olsen et al., 2005; Tollefsen and Nilsen, 2008).

The available in vitro receptor-binding studies clearly suggest that ptBP binds to the human, rat

and fish ER with binding affinities that are comparable to well-characterised endocrine

disruptors such as ptPP, ptOP and BPA.

Activation of the estrogen receptor

ptBP has been demonstrated to activate the human and fish ERs. Studies with the yeast estrogen

screen, which is stably transfected with the human ER, report that ptBP activate the human ER at

approximately 1.4 million times lower potency than E2, 10 times lower potency than ptPP, 1000

times lower potency than ptOP and 1500 lower potency than BPA (Routledge and Sumpter,

1997; Sohoni and Sumpter, 1998). Other studies using the estrogen dependent MCF7 cancer cell

line, which also express the human ER, confirm that ptBP has a relative low estrogenic potency

(0.3-5 million times lower than E2), similar potency as ptPP, about 10-100 times lower potency

than ptOP and BPA (Olsen et al., 2005; Soto et al., 1995).

Interestingly, induction of the estrogenic biomarker VTG in rainbow trout liver cells

(hepatocytes) show that ptBP exhibit a higher relative potency than that reported in bioassays

with the human ERs, with a potency 30 000-200 000 times lower than E2, similar potency as

ptPP and within one order of magnitude lower potency than ptOP and BPA (Olsen et al., 2005;

Tollefsen et al., 2008). An interspecies comparison confirms that ptBP display a higher relative

ER binding affinity and estrogenic potency in fish than human-derived from in vitro bioassays

(Olsen et al., 2005). Structure activity relationship (SAR) studies with a range of alkylphenols

with different chain lengths, number of alkylated substituents and substituent position show that

ptBP are among the most estrogenic alkylphenols in rainbow trout when tested in vitro

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(Tollefsen et al., 2008).

In vivo data and read across to structurally related chemicals

No fish in vivo data has to date been provided for ptBP in open literature, so read-across to

closely related alkylphenols was conducted. A full life-cycle (2 generation) study with Japanese

medaka (Oryzias latipes) exposed to ptPP demonstrated that low µg/L concentrations of ptPP led

to abnormal sexual differentiation (LOEC=224 µg/L) and VTG induction (LOEC=51 µg/L) in

the F1 generation (Seki et al., 2003). Reports of in vivo endocrine modulating and disrupting

effects of ptPP also in common carp (Cyprinus carpio) and fathead minnow (Pimephales

promelas) at low µg/L concentrations strengthened the concern that moderately sized para-

substituted alkylphenols such as ptPP and ptBP are likely to cause endocrine disruption in fish

(Gimeno et al., 1996; Gimeno et al., 1997; Hagino et al., 2001; Panter et al., 2006; Panter et al.,

2002). Studies with other well-characterised estrogenic compounds such as BPA and ptOP (see

RAR for BPA and ptOP) have previously led to proposal for low NOECs for reproductive effects

in fish at 16 and 12 µg/L, respectively. ptOP is currently identified as an SVHC and included in

the candidate list due to endocrine disrupting properties ( see .

The requirement for a long term study in fish

The in vitro estrogenic properties of ptBP, which were found to be fairly similar to ptPP, ptOP

and BPA in fish, and read across to in vivo data introduced the requirement for a regulatory-

initiated investigation of potential endocrine disrupting effects in in vivo. A protocol for

performing a Partial Life Cycle Test with the Fathead Minnow was therefore developed. The test

was conducted as a two tiered approach based on an initial test optimisation and range finding

test (pilot study) followed by a full study design (final study).

Pilot study: A Partial Life Cycle Test with the Fathead Minnow (Pimephales promelas)

A 128-day non GLP pilot study with ptBP to determine test concentrations for the full study and

evaluate the suitability of endocrine endpoints to be used in a partial life cycle test with fathead

minnow has been performed with ptBP at nominal concentrations of 1, 30, 100 and 500 µg/L.

Traditional endpoints of fish early life-stage studies, including effects of the test substance on

time to hatch, hatching success, stage specific survival and growth were monitored. Endocrine

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mediated endpoints were evaluated including gonadosomatic index (GSI), sex ratio, observation

of secondary sex characteristics, measurement of VTG and histopathology of gonads and

gonadal ducts. The protocol was based upon the experimental design presented in ANNEX E,

Partial Life Cycle Test (or Extended Early Life-Stage Test) of the OECD “Detailed Review

Paper on Fish Screening Assays for the Detection of Endocrine Active Substances (OECD,

2004). The study also incorporated procedures in the OECD Guideline for Testing of Chemicals,

210: Fish Early- Life Stage Toxicity Test (OECD, 1992) and ASTM Standard E1241-98

Standard Guide for Conducting Early Life Stage Toxicity Tests with Fish (ASTM, 1998).

The main findings of the pilot study were as follows (nominal concentrations in brackets):

1. Water concentrations: measured water concentrations were (2, 25, 82, 413 µg/l), thus

deviated more than 20% from the nominal concentrations (1, 30, 100, 500 µg/l). Suggestions to

use the measured, rather than nominal have been proposed and both have consequently been

presented for clarity.

2. Hatching success: No effects were observed in the hatching success in any group, but

a significant delay in hatching for the 82 µg/l (nominal: 100 µg/l) and 413 µg/l (nominal: 500

µg/l) group was observed according to the Jonkheere-Terpstra trend test (p<0.05). Although the

biological significance of these findings was questioned, a need for improved sampling design

was proposed to properly assess this effect.

3. Survival of Larvae and Juvenile fish: No significant differences in survival of fish at

any fish stage observed.

4. Sex ratio: A significant reduction in male fish and fish displaying male gonads was

observed at the 413 µg/l (nominal: 500 µg/l) treatment group according to the Jonkheere-

Terpstra trend test (p<0.05). The findings were based on gross internal sex and on external

sex determination.

5. Growth: No significant changes in length and weight of females were observed. A

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treatment-related effect on fish length and weight were observed for males at the

concentration of 413 µg/l (nominal: 500 µg/l) according to the Jonkheere-Terpstra trend test

(p<0.05). No significant differences were identified in males of any treatment group when

compared to the control according to the Dunnett’s test (p<0.05)

6. Gonadosomatic index (GSI): No significant changes in GSI of either males or

females were observed.

7. Vitellogenin (VTG): No significant changes in plasma VTG in males were observed,

apparently due to high inter-replicate variations. An apparent treatment-related increase in

female plasma concentrations of VTG in the 413 µg/l (nominal: 500 µg/l) group was suggested,

although this was not identified to be significant according to either the Jonkheere-Terpstra trend

test (p<0.05) nor the Dunnett’s test (p<0.05). Large intra and inter-replicate variation was clearly

evident in both males and female groups, leading to concern that an apparent trend in reduction

of VTG in females at the 2 µg/L (nominal: 1 µg/L) and 25 µg/L (nominal: 30 µg/L) may have

been treatment related. No explanation for a non-endocrine mechanism causing this low-

concentration effect could be provided, and thus leading to this observation remained unclear.

8. Onset of male sex characteristics: A treatment related effect on fish displaying at

least one male secondary sex characteristic was observed in the 413 µg/l (nominal: 500 µg/l)

group. It was not possible to discriminate whether the observed effect were due to a

delay in maturation or lack of ability to develop male secondary sexual characteristics, however.

9. Pigmentation on dorsal fin or nose/lip: Pigmentation on the dorsal fin or nose/lip of

fish in the treatment groups was not significantly different from the control. However, the fish in

the 413 µg/l (nominal: 500µg/l) treatment group displayed an apparent, although non-significant,

treatment-related effect.

10. Presence of fatpad and fatpad Score: A treatment-related reduction in the proportion of

male fish with a fatpad and in fatpad scores was identified in the 413 µg/l (nominal: 500 µg/l)

treatment group according to the Jonkheere-Terpstra trend test (p<0.05). The male fish in the 82

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µg/l (nominal: 100µg/l) treatment also displayed an apparent, although non-significant,

treatment-related effect.

11. Presence of Tubercles, Tubercle Count and Tubercle Score: Presence of tubercles

(counts and score) of fish in the treatment groups were not significantly different from

the control. However, the fish in the 413 µg/l (nominal: 500µg/l) treatment displayed an

apparent, although not significant, treatment-related effect.

12. Histopathology: All of the males (12 out of 12) evaluated in the 413 µg/L (nominal: 500

µg/L) treatment group exhibited feminization of gonadal ducts (minimal to moderate). Presence

of testicular oocytes (minimal to mild) was observed in 5 out of 12 samples evaluated at the

same treatment group. The presence of intravascular fluid in female ovaries, which was

considered indicative of increased VTG production, was observed at 82 µg/l (nominal: 100 µg/l)

and 413 µg/l (nominal: 500µg/L). The effect occurring at 82 µg/l was not considered statistically

significant.

Summary assessment of pilot study:

It is concluded that the induction of VTG in females, changes in male sex ratio, feminization of

male gonads and presence of testicular oocytes (intersex) are clear indicators of endocrine

disruption. Observations such as delayed onset of male sex charateristics, pigmentation of fin or

nose/lip, reduction in fatpads and/or fatpad scores, and reduction in tubercles, tubercle count and

score, and presence of intravascular fluid in female gonads were all considered to provide

supportive evidence for an ED mode of action. Delayed hatching, presence of intravascular fluid

in female gonads and the presence of fatpads and fadpad score in male fish were identified as

being the most sensitive endpoints determined and suggest a NOEC of 25 µg/l (nominal: 30 µg/l)

and a LOEC of 82 µg/l (nominal: 100 µg/l). A negative trend in VTG production in females was

indicated at even lower concentrations, although an endocrine mechanism to explain the

observations could not be provided. It was concluded that the limited test design of the PILOT

study could not secure sufficient statistical power to conclude on all of the endpoints tested nor

comply fully with test criteria proposed for a full fish test (E1241-1998; OECD, 1992, 2004),

thus required a full test adopting to a revised and improved test design.

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Full study: A Partial Life Cycle Test with the Fathead Minnow (Pimephales promelas)

A GLP study was performed with ptBP at 10, 30, 100 and 300 µg/L for 128 days to determine if

exposure of fathead minnows to ptBP during their early development would result in changes

typically associated with exposure of fish to estrogenic chemicals. The study was conducted

according to the procedure “Para-Tertiary Butyl Phenol (PTBP): A Partial Life Cycle Test with

the Fathead Minnow (Pimephales promelas)”(Krueger et al, 2008). The exposure period included

a five-day hatching period followed by up to 123 days of post-hatch development of larvae and

juvenile fish. Survival, body weights and lengths, and observations of abnormal behavior as well

as endocrine-mediated endpoints including time to hatch, hatching success, observations of

secondary sex characteristics, measurement of plasma VTG, measurement of GSI and

histopathology of gonads were recorded and results are summarised below. A study summary is

available in the disseminated data of the registration dossier:

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d8bb7ca-18a5-44ef-e044-

00144f67d249/AGGR-3f307790-b12d-4db2-b14a-f7e5e7601fc9_DISS-9d8bb7ca-18a5-44ef-

e044-00144f67d249.html#GEN_RESULTS_HD.

The main findings of the full study were as follows:

1. Water concentrations: The mean measured concentrations in the 10, 30, 100 and 300 µg/L

treatment groups were 96, 90, 83 and 85% of nominal concentrations, respectively. Although

some single measurements in the 100 and 300 µg/L groups were slightly lower than 80% of

nominal, measured concentrations in these groups remained within ±20% of the initial measured

concentrations.

2. Hatching Success and Time to Hatch: No effects were observed on hatching success at any

of the concentrations tested over the five-day hatching period. A significant delay in the mean

time to 50% hatch was observed at the highest concentration (300 µg/L) according to both the

Jonkheere-Terpstra trend test (p ≤ 0.05) and the Dunnett’s test (p ≤ 0.05).

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3. Survival of Larvae and Juvenile Fish: A significant reduction in the survival of fish at the

300 µg/L concentration was observed at day 33. The overall high survival rates (>90%) for all

groups were proposed to be an indicator of good health and findings proposed to be of low

biological relevance. There were no apparent effects on fish survival from day 33 to test

termination in any treatment group.

4. Sex Ratio: No significant changes in sex ratio were identified at the concentrations tested.

5. Growth: Treatment-related effects on growth (weight and length) in both males and females

were observed in the 30, 100 and 300 µg/L treatment groups according to both the Jonkheere-

Terpstra trend test (p ≤ 0.05) and the Dunnett’s test (p ≤ 0.05). No significant change in the

condition index of the fish was observed in either males or females. The lack of consistency

between the growth parameters (e.g. weight and length) and condition index was proposed

caused by a general treatment-related delay in fish development at concentrations higher than

10µg/L.

6. Gonadosomatic Index (GSI): There were no statistically significant differences in the GSI of

females or males between the negative control and any of the treatment groups.

7. Vitellogenin (VTG): A treatment-related increase in female plasma VTG concentrations was

identified in the 300 µg/L treatment group according to both the Jonkheere-Terpstra trend test (p

≤ 0.05) and the Dunnett’s test (p ≤ 0.05). No statistically significant differences were observed in

male plasma VTG concentrations.

8. Male Secondary Sex Characteristics: A treatment-related effect on fish displaying at least

one male secondary sex characteristic was observed in the 30, 100 and 300 µg/L treatment

groups according to the Jonkheere-Terpstra trend test (p ≤ 0.05). Only the 300 µg/L treatment

group was significantly different from the control according to the Dunnett’s test (p ≤ 0.05).

9. Pigmentation on dorsal fin or nose/lip: A treatment-related decrease in the proportion of

males with a pigmented spot on the dorsal fin or nose/lip was observed in the

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30, 100 and 300 µg/L treatment groups according to the Jonkheere-Terpstra trend test (p ≤ 0.05).

Only the 30 µg/L treatment group was significantly different from the control when assessing

pigmentation on the dorsal fin, whereas the 300 µg/L treatment group was significant different

from control when assessing pigmentation on the nose/lip according to a Dunnett’s test (p ≤

0.05).

10. Presence of fatpad and fatpad Score: A treatment-related decrease in the proportion of

males with a fatpad was observed in the 30, 100 and 300 µg/L treatment groups according to the

Jonkheere-Terpstra trend test (p ≤ 0.05). No significant differences was observed between the

control and any treatment group according to a Dunnett’s test (p ≤ 0.05), however.

11. Presence of Tubercles, Tubercle Count and Tubercle Score: A treatment-related decrease

in the proportion of males with tubercles, tubercules count and tubercle score were observed in

the 30, 100 and 300 µg/L treatment groups. No significant difference was observed between the

control and any treatment group according to the Dunnett’s test (p ≤ 0.05), however.

12. Frequency distribution of male secondary sex characteristics: A treatment-related change

in the frequency distribution of the various combinations of secondary sex characteristics was

observed in the 30, 100 and 300 µg/L treatment groups according to the Fisher’s Exact test.

13. Histopathology: Almost all of the males evaluated in the 300 µg/L treatment group (42 of

45) exhibited feminization of gonadal ducts (minimal to mild) according to a Fisher’s Exact test.

Presence of testicular oocytes (intersex) in one out of 45 male samples was also recorded.

Summary assessment of full study:

It is concluded that the induction of VTG in females, complete feminization of male gonads are

clear indicators of endocrine disruption. Observations such as delayed onset of male sex

characteristics, pigmentation of fin or nose/lip, reduction in fatpads and/or fatpad scores, and

reduction in tubercles, tubercle count and score, were all considered to provide supportive

evidence for an ED mode of action. It was noted by the contract laboratory that these endpoints

showed treatment-related effects that potentially could be related to small delays in development,

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where the overall effect on the fish population level was uncertain. Taking all available

information into account, the most sensitive endpoints were reduced growth, reduction in

secondary male sex characteristics, and the delay in the time to hatch. Overall statistical LOEC

and NOEC values were 30 µg/L and 10 µg/L, respectively. Clearly defined estrogenic effects

were clearly present in the 300 µg/L treatment group as evidenced by feminization of gonadal

ducts of male fish and elevated levels of plasma VTG in females.

Overall conclusion

As identification of an endocrine disruptor should be based on a weight-of-evidence (WoE)

approach providing causal relationship between an endocrine mode of Action (MoA) and

adverse effects (Kortenkamp et al., 2011; Munn and Goumenou, 2013), demonstration of an

estrogenic MoA and in vivo effects at the OECD conceptual framework (CF) for ED testing level

4 or 5 (OECD, 2012) is considered essential. A combination of available in vitro and in vivo data

from literature on ptBP and compounds with structural or mechanistic (e.g. estrogenic

compounds) similarities and data from the pilot and full fish studies have been used to support a

WoE approach. The present data clearly demonstrates that ptBP bind and activate human, rat and

fish ERs and in this respect display an endocrine MoA. The data from the two fish studies with

ptBP shares a resemblance with previously reported studies with ptPP in various fish species by

causing adverse effects such as changing male sex ratios (pilot study: 413 µg/L (nominal: 500

µg/L)), feminization of male gonads (Pilot study: 413 µg/L (nominal: 500 µg/L), Full study: 300

µg/L) and causing variable levels of intersex (pilot study: 413 µg/L (nominal: 500 µg/L), Full

study: 300 µg/L). A range of endpoints such as delayed onset of male sex characteristics,

pigmentation of fin or nose/lip, reduction in fatpads and/or fatpad scores, and reduction in

tubercles, tubercle count and score, were considered to provide supportive evidence for an ED

MoA in male fish, although the role of other factors such as treatment-related delay of fish

development may not be completely disregarded. Clear estrogenic effects consistent with

identifying ptBP as an endocrine disruptor was observed at 300 µg/L in the full study, leading to

an NOEC for endocrine disruption of 100 µg/L and a LOEC of 300 µg/L. Based on the available

fish studies and endpoints of ptBP reported herein, an overall NOEC of 10 µg/L and a LOEC of

30 µg/L on basis of data from the full study is justified.

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It is considered that the current information is sufficient to classify/identify ptBP as an endocrine

disruptor, although low-concentration effects observed in the fish studies such as changes in

secondary male characteristics and delay in fish development may warrant additional studies to

determine if they are mediated by an endocrine MoA.

SUMMARY OF INFORMATION REVIEWED

Include a brief overview of the new information reviewed in the transitional dossier.

Information Date study

was

conducted

Reason for

information request

Comments

A pilot study based on Annex E of OECD "Detailed Review Paper on Fish Screening Assays for the Detection of Endocrine Active Substances”

15.09.2006 Determine test concentrations and evaluate endocrine endpoints for the full study partial life cycle test.

Results from the pilot study will be used in designing a partial life cycle test with fathead minnow (Pimephales promelas)

A partial life cycle test with fathead minnow (Pimephales promelas)

10. 10.2008 Wildlife International, Ltd

Concern on endocrine disruption

Used to revise PNECaquatic, sediment and soil and update the risk assessment

SUPPORTING DOCUMENTS AVAILABLE

List documents available to support the conclusion of the substance evaluation e.g. risk

assessment addendum or update, Annex XV dossier.

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Title Author Date Comments

Risk assessment on p-tert butylphenol

Norway 2008

TIMETABLE FOR FOLLOW-UP ACTIONS (IF NECESSARY)

Indicate a preliminary timetable, if available, for any follow-up actions proposed.

A formal commitment to prepare an Annex XV dossier is made via the Registry of Intentions.

Follow-up action Date for completion Who to complete action?

Registrants to update their CSR to reflect the conclusion of this evaluation

-Norway concludes with an overall NOEC of 10 µg/L and a PNEC of 1 µg/L.

June 2014 Registrants

Propose ptBP for CoRAP

(substance evaluation)

References:

Blair, R.M., Fang, H., Branham, W.S., Hass, B.S., Dial, S.L., Moland, C.L., Tong, W., Shi, L.,

Perkins, R., Sheehan, D.M., 2000. The estrogen receptor relative binding affinities of 188

natural and xenochemicals: structural diversity of ligands. Toxicol Sci 54, 138-153.

E1241-1998, A.S., Standard Guide for Conducting Early Life-stage Toxicity Testswith Fish.

American Society for Testing and Materials.

European Union Risk Assessment Report, 4,4'-ISOPROPYLIDENEDIPHENOL (BISPHENOL-A); CAS No: 80-05-7; Complete risk assessment in one document, (February 2010) http://echa.europa.eu/web/guest/information-on-chemicals/information-from-existing-substances-regulation?search_criteria=Bisphenol A European Union Risk Assessment Report, P-TERT-BUTYLPHENOL CAS No: 98-54-4, RISK ASSESSMENT, Final report 2008

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http://echa.europa.eu/web/guest/information-on-chemicals/information-from-existing-substances-regulation?search_criteria=98-54-4 Environment Agency UK: Environmental Risk Evaluation Report: 4-tert-octylphenol. 2005. Gimeno, S., Gerritsen, A., Bowmer, T., Komen, H., 1996. Feminization of male carp. Nature

384, 221-222.

Gimeno, S., Komen, H., Venderbosch, P.W.M., Bowmer, T., 1997. Disruption of sexual

differentiation in genetic male common carp (Cyprinus carpio) exposed to an alkylphenol

during different life stages. Environ. Sci. Technol. 31, 2884-2890.

Hagino, S., Kagoshima, M., Ashida, S., 2001. Effects of ethinylestradiol, diethylstilbestrol, 4-t

pentylphenol, 17β-estradiol, methyltestosterone and flutamide on sex reversal in S-rR strain

medaka (Oryzias latipes). Environmental Sciences 8, 75-87.

Henry O. Krueger et al 2008: FINAL REPORT PARA-TERTIARY BUTYL PHENOL (PTBP): A Partial Life Cycle Test with the Fathead Minnow (Pimephales promelas) Kortenkamp, A., Martin, O., Faust, M., Evans, R., McKinlay, R., Orton, F., Rosivatz, E., 2011.

State of the art assessment of endocrine disrupters – final report.

Munn, S., Goumenou, M., 2013. Key scientific issues relevant to the identification and

characterisation of endocrine disrupting substances. Report of the Endocrine Disrupters Expert

Advisory Group (ED EAG), p. 34.

OECD, 1992. OECD Guidelines for Testing of Chemicals 210: Fish, Early-life Stage Toxicity

Test. , OECD Guideline for testing of chemicals. Organization for Economic Cooperation and

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active substances. Organization for Economic Cooperation and Development, Paris, France.

OECD, 2012. Draft Guidance Document on Standardised Test Guidelines for Evaluating

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for Economic Cooperation and Development, Paris, France., p. 44.

Olsen, C.M., Meussen-Elholm, E.T., Hongslo, J.K., Stenersen, J., Tollefsen, K.E., 2005.

Estrogenic effects of environmental chemicals: an interspecies comparison. Comp Biochem

Physiol C Toxicol Pharmacol 141, 267-274.

Panter, G.H., Hutchinson, T.H., Hurd, K.S., Bamforth, J., Stanley, R.D., Duffell, S., Hargreaves,

A., Gimeno, S., Tyler, C.R., 2006. Development of chronic tests for endocrine active

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chemicals. Part 1. An extended fish early-life stage test for oestrogenic active chemicals in the

fathead minnow (Pimephales promelas). Aquat Toxicol 77, 279-290.

Panter, G.H., Hutchinson, T.H., Lange, R., Lye, C.M., Sumpter, J.P., Zerulla, M., Tyler, C.R.,

2002. Utility of a juvenile fathead minnow screening assay for detecting (anti-)estrogenic

substances. Environ Toxicol Chem 21, 319-326.

Routledge, E.J., Sumpter, J.P., 1997. Structural features of alkylphenolic chemicals associated

with estrogenic activity. J. Biol. Chem. 272, 3280-3288.

Seki, M., Yokota, H., Matsubara, H., Maeda, M., Tadokoro, H., Kobayashi, K., 2003. Fish full

life-cycle testing for the weak estrogen 4-tert-pentylphenol on medaka (Oryzias latipes).

Environ. Toxicol. Chem. 22, 1487-1496.

Sohoni, P., Sumpter, J.P., 1998. Several environmental oestrogens are also anti-androgens. J

Endocrinol 158, 327-339.

Soto, A.M., Sonnenschein, C., Chung, K.L., Fernandez, M.F., Olea, N., Serrano, F.O., 1995. The

E-SCREEN assay as a tool to identify estrogens: An update on estrogenic environmental

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