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Long-term toxicity to fish

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Endpoint:
fish early-life stage toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
Cresols are isomers and, thus ideally fulfill the recommended criteria of structural similarity. In its chemical structure, a cresol molecule has a methyl group substituted onto the benzene ring of a phenol molecule, by different arrangement of the -CH3 groups are three structural isomers possible. (ortho-cresol, meta-cresol and para-cresol). Of particular importance to environmental effects are the values for partition coefficient (log Kow), vapour pressure, water solubility and dissociation constant. The values of the isomers are very close together, resulting in the same environmental fate and behaviour. Further, with regard to the bioderadation behavior, all 3 cresols are readily biodegradable. Concerning aquatic toxicity of the cresols on aquatic species, a large number of experimental results from tests with fish, invertebrates and algae are available, indicating a similar toxicity of all isomers, with p-cresol being slightly more toxic in acute tests: Based on the similarities in the results mentioned above the read-across approach is therefore scientifically justified.
Studies resulting in the most sensitive NOEC are used for read-across.
Chronic toxicity of p-cresol to fish was tested with Pimephales promelas in an Early-Life Stage Toxicity Test equivalent to OECD Guideline 210. The 32d NOEC is 1.35 mg/L.
Concerning long-term toxicity of p-cresol to aquatic invertebrates a semi-static test according to the preliminary guideline proposal of the German Umweltbundesamt from 1984 was conducted. After 21 days of exposure a NOEC of 1 mg/l was determined.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 210 (Fish, Early-Life Stage Toxicity Test)
Principles of method if other than guideline:
Early life stage test
GLP compliance:
no
Analytical monitoring:
not specified
Test organisms (species):
Pimephales promelas
Test type:
flow-through
Water media type:
freshwater
Limit test:
no
Total exposure duration:
32 d
Hardness:
soft water from lake Superior
Test temperature:
25 +/-0.2 °C
Details on test conditions:
- Fluorescent lights provided 16h light per day
- Fish were fed newly hatched brine shrimp ad libitum twice per day so that moderate accumulation occured.
Duration:
32 d
Dose descriptor:
NOEC
Effect conc.:
1.35 mg/L
Conc. based on:
test mat.
Duration:
32 d
Dose descriptor:
LOEC
Effect conc.:
2.57 mg/L
Conc. based on:
test mat.

NOEC for macromolecular content (nucleic acid, protein) was 2.57 mg/L (LOEC 4.20 mg/L). NOEC for growth was >4.2 mg/L

Validity criteria fulfilled:
not specified
Conclusions:
The chronic toxicity of p-cresol to fish was tested with Pimephales promelas in an Early-Life Stage Toxicity Test equivalent to OECD Guideline 210. The 32d NOEC is 1.35 mg/L.This toxicity study is classified as acceptable and satisfies the guideline requirements for the chronic fish study.
Executive summary:

The long-term study on toxicity towards fish by Barron and Adelman (1984) has been designed similar to OECD Guideline 210 . However, the documentation of the derived NOEC and LOEC values is insufficient to allow a score better than Klimisch 4. The derived 32 d-NOEC = 1.35 mg/L and 32 d-LOEC = 2.57 mg/L (Pimphales promelas) appear to be obtained by “personal communication” from Norberg and Mount. Unfortunately, the original article does not contain information on the raw data, which could have allowed for confirmation of the values. Neither thorough literature search nor contacting the authors directly yielded any useful results. As these values have been assessed multiple times over the past decade, including OECD SIDS and HPV reports, and since the 32d-NOEC = 1.35 mg/L is comparable to the 21 d-NOEC = 1 mg/L (Daphnia magna) of the long-term toxicity study towards aquatic invertebrates, the value appears reasonable.

In order to comply with the standard information requirements of Annex X of REACH at this tonnage level, the registrant proposes an OECD Guideline 210 (Fish, Early-Life Stage Toxicity Test) on the source substance, p-cresol, as best course of action. The study results from this test will be adequate for the purpose of classification and labelling and/or risk assessment. The consecutive read-across approach will depict a worst-case approach, hereby reducing unnecessary vertebrate animal testing and complying with Article 13(3).

Endpoint:
fish, juvenile growth test
Type of information:
experimental study planned (based on read-across)
Justification for type of information:
Cresols are isomers and, thus ideally fulfill the recommended criteria of structural similarity. In its chemical structure, a cresol molecule has a methyl group substituted onto the benzene ring of a phenol molecule, by different arrangement of the -CH3 groups are three structural isomers possible. (ortho-cresol, meta-cresol and para-cresol). Of particular importance to environmental effects are the values for partition coefficient (log Kow), vapour pressure, water solubility and dissociation constant. The values of the isomers are very close together, resulting in the same environmental fate and behaviour. Further, with regard to the bioderadation behavior, all 3 cresols are readily biodegradable. Concerning aquatic toxicity of the cresols on aquatic species, a large number of experimental results from tests with fish, invertebrates and algae are available, indicating a similar toxicity of all isomers, with p-cresol being slightly more toxic in acute tests: Based on the similarities in the results mentioned above the read-across approach is therefore scientifically justified.

TESTING PROPOSAL ON VERTEBRATE ANIMALS FOR o-CRESOL

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: o-Cresol [EC: 202-423-8; CAS: 95-48-7].
- Name of the substance for which the testing proposal will be used [if different from tested substance]: p-Cresol [EC: 203-398-6; CAS: 106-44-5].

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Available GLP studies: There are no GLP-compliant chronic fish studies available on the substance.
- Available non-GLP studies: Acute toxicity studies are available for daphnids, fish and algae. In addition, a daphnia reproduction study is available. A chronic fish study by Barron and Adelmann (1984) reports NOEC values, however after thorough investigation, reported values are insufficiently documented for evaluation and must be classified as Klimisch 4. Additionally, Falk-Petersen et al. (1985) report a study performed on gadus morrhua (Atlantic Cod). This study does not satisfy the requirements according to OECD Guidance and cannot be used to fulfill the information requirements for REACH.
- Historical human data: Not relevant for this endpoint.
- (Q)SAR: There are no QSAR models available for this higher tier ecotoxicological endpoint that are sufficiently validated and acceptable (according to OECD Q/SAR validation criteria).
- In vitro methods: The registrant is not aware of any validated alternative tests that use in vitro methodologies that could be used to meet the standard requirement of the REACH regulation for long-term toxicity towards fish.
- Weight of evidence: No data are available for use in a weight of evidence approach.
- Grouping and read-across: Grouping and read-across approaches have been evaluated and are not considered feasible in this case. p-Cresol is considered to be the most toxic regioisomer of cresols towards the aquatic environment with a 96h-LC50 = 4.4 mg/L (Salmo trutta) determined in an acute fish toxicity study, compared to 96h-LC50 = 6.2 mg/L (Salmo trutta) for o-cresol and 96h-LC50 = 7.6 mg/L (Salvelinus fontinalis) for m-cresol , respectively. This is continued within the acute toxicity studies on invertebrates, where the 48h-EC50 value for p-cresol is 7.7 mg/L (Daphnia magna), while it is 9.6 mg/L (Daphnia pulex) for o-cresol. For m-cresol a 24h-EC50 of 99.5 mg/L could be determined on Daphnia pulicaria. Hence, testing of p-cresol is considered as the worst-case approach regarding long-term aquatic toxicity testing towards fish.
- Substance-tailored exposure driven testing [if applicable] : Not applicable
- Approaches in addition to above [if applicable] : Not applicable
- Other reasons [if applicable] : Not applicable

Overall, the registrant has carefully considered all general adaptation procedures as listed in Annex XI of the Reach regulation, however the registrant has come to the conclusion that the lack of available data through studies and the level of extensiveness of the study proposed herein, the conduction of an OECD TG 210: Fish Early Life Stage (FELS) toxicity test is considered the best course of action in order to elucidate the long-term toxicity towards fish of p-cresol This study can be further used in read-across approaches for the other regioisomers, o- and m- cresol, as it will cover the worst-case approach. The data generated within this study may be used to cover data gaps of o- and m-cresol through a read-across approach.
CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
According to REACH Annex IX, 9.1.6. ‘Long-term toxicity testing on fish, (unless already provided as part of Annex VIII requirements)’ is a standard information requirement and cannot be generated otherwise. The Fish Early Life Stage (FELS) toxicity test (OECD TG 210) is regarded as the most suitable test guideline for addressing the information requirements.

Furthermore, section 9.1, column 2 states:
'Long-term toxicity testing shall be proposed by the registrant if the chemical safety assessment according to Annex I indicates the need to investigate further the effects on aquatic organisms. The choice of the appropriate test(s) depends on the results of the chemical safety assessment.'

The widespread dispersive uses of the registered substance leads to release to the aquatic environment. There is a need for further information on the long-term effects of the registered substance on aquatic organisms. Since long-term data are available for daphnia and algae, data for fish are required as the third pelagic level.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:

- Details on study design / methodology proposed [if relevant]: - An OECD 210 Guideline study has been proposed to assess the long-term toxicity towards fish. The substance shall be applied via the freshwater medium.
Qualifier:
according to guideline
Guideline:
OECD Guideline 210 (Fish, Early-Life Stage Toxicity Test)
Water media type:
freshwater

Description of key information

For o-cresol no reliable data on chronic fish toxicity are available. A read-across from p-cresol is applied. The chronic toxicity of p-cresol to fish was tested with Pimephales promelas in an Early-Life Stage Toxicity Test equivalent to OECD Guideline 210. The 31d NOEC is 1.35 mg/

Key value for chemical safety assessment

Fresh water fish

Fresh water fish
Dose descriptor:
NOEC
Effect concentration:
1.35 mg/L

Additional information

Concerning long-term toxicity to fish there are no reliable data available for o-cresol. The SIDS document on o-Cresol (OECD undated) has proposed to perform a fish early life stage test with Oncorrhynchus mykiss. This proposal was given at that time as PNECs were only "based on QSARs for long-term effects on fish" and as "a risk to the aquatic ecosystem has to be assumed". A read-across approach from p-cresol is applied to get a comprehensive data set for o-cresol, based on the following justification:

Justification for the read-across approach:

Data from substances who’s physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be used in a read-across approach in order to avoid unnecessary animal testing. It can be stated that the 3 cresols act as a prime example of substances that are suitable for read-across. Cresols are isomers and, thus ideally fulfill the recommended criteria of structural similarity. In its chemical structure, a cresol molecule has a methyl group substituted onto the aromatic ring of a phenol molecule, by different arrangement of the -CH3 groups are three structural isomers possible. (ortho-cresol, meta-cresol and para-cresol). Of particular importance to environmental effects are the values for partition coefficient (log Kow), vapour pressure, water solubility and dissociation constant. The values of the isomers are very close together, resulting in the same environmental fate and behaviour. Further, with regard to the bioderadation behavior, all 3 cresols are readily biodegradable. Concerning aquatic toxicity of the cresols on aquatic species, a large number of experimental results from tests with fish, invertebrates and algae are available, indicating a similar toxicity of all isomers, with p-cresol being slightly more toxic in acute tests: Based on the similarities in the results mentioned above the read-across approach is therefore scientifically justified.

The most reliable chronic toxicity value was obtained in an Early-Life Stage Toxicity Test with Pimephales promelas. The OECD SIDS report recommends using Oncorhynchus mykiss as test species, as salmonids showed the lowest effect values in acute fish studies. It is expected however that Oncorhynchus mykiss and Pimephales promelas will show similar effects in a FELS test. A review of the 20 relevant data for acute fish tests for o-cresol showed that LC50 values are in the range of 6.2 to 41 mg/L, among them 3 results with Oncorhynchus mykiss in the range of 7 to 13 mg/L and 5 results with Pimephales promelas, in the range of 12.6 to 18.2 mg/L. These results are in the same order of mangnitude and it is therefore not predictable which of the species would show the lowest effect values in chronic tests. Pimephales promelas is also one of the recommended species in OECD guideline 210.

The OECD SIDS document for o-cresol has presented QSAR data for 30- and 60 -day FELS test with Oncorrhynchus mykiss: 30d-NOEC=1.8 mg/L, 60d-NOEC=0.12 mg/L. It is generally accepted that QSARs for long-term tests should be for orientation only. In OECD 210, the typical duration of a FELS test with Oncorrhynchus mykiss is 60 days. For pimephales promelas the recommended test period is 28 days which is in good consistency with the test from Barron and Adelman (31 days). Also the outcome of this test (31d-NOEC=1.35 mg/L is in agreement with the QSAR prediction of 0.12 - 1.8 mg/L.

In a recent and thorough investigation of the study, however, the documentation of the derived NOEC and LOEC values had to be decieded to be insufficient to allow a score better than Klimisch 4. In order to comply with the standard information requirements of Annex X of REACH at this tonnage level, the registrant proposes an OECD Guideline 210 (Fish, Early-Life Stage Toxicity Test) on the source substance, p-cresol, as best course of action. The study results from this test will be adequate for the purpose of classification and labelling and/or risk assessment. The consecutive read-across approach will depict a worst-case approach, hereby reducing unnecessary vertebrate animal testing and complying with Article 13(3).