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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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