Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Study period:
2019 - 2021 (an updated dossier has to be submitted by 28 June 2021)
Justification for type of information:
The extended one generation study has been identified as standard requirement for reproductive toxicity according to Annex IX and X. Since 2-amylanthraquinone has been registered at a volume of >1000 tonnes/year and a data gap has been identified for reproductive toxicity, the EOGRTS is proposed.

Considerations that the general adaptation possibilities of Annex XI of the REACH Regulation were not adequate to generate the necessary information:

• Available GLP studies
No GLP studies are available on the test substance for the endpoint ‘reproductive toxicity’. A developmental toxicity / teratogenicity study according to OECD 414 has been conducted with 2-amylanthraquinone and rats. However, this study did not provide sufficient data on reproductive parameters.

• Available non-GLP studies
Non-GLP studies are not available for the endpoint ‘reproductive toxicity’.

• Historical human data
No human data are available for this substance.

• (Q)SAR
No validated (Q)SAR’s exist for the endpoint ‘reproductive toxicity’ in organic substances. There is no known mode of action for 2-amylanthraquinone causing reprotoxic effects.

• In-vitro methods
With regards to in vitro studies for reproductive toxicity, the regulatory acceptance of these studies and approaches to replace the animal testing for reproductive toxicity has not been achieved as they do not provide equivalent information and thus, cannot be used alone for classification and labelling and/or risk assessment.

• Weight of evidence
No data are available to complete the IUCLID requirements as a weight of evidence approach.

• Grouping and read-across
The registrant has not been able to identify relevant information on structural analogues. An EOGRTS is not available for 2-ethylanthraquinone.

• Substance-tailored exposure driven testing
Not applicable since the results of the exposure assessment covering all relevant exposures throughout the life cycle of the substance do not demonstrate the absence of or no significant exposure in all scenarios of the manufacture and all identified uses.

• Approaches in addition to above
Not applicable

Considerations that the specific adaptation possibilities of Annexes VI to X (and column 2 thereof) were not applicable. Adaptation options as defined in Annexes VI to X are not applicable for this substance and this endpoint.

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Justification for study design:
The study will be performed in rats according to OECD guideline 443 in compliance with GLP. The test substance will be administered by the oral route. The basic configuration of EOGRTS will be performed as based on the toxicological profile of the substance there are no concern-driven scientific triggers for the performance of the F2 generation (extension of Cohort 1B), developmental neurotoxicity (DNT; cohorts 2A and 2B) and/or developmental immunotoxicity (DIT; cohort 3) cohorts.

1) Extension of Cohort 1B and termination time for F2: extension not justified
According to column 2 (specific rules for adaptation from column 1) point 8.7.3 of the amended REACH Annex X, extension of cohort 1B to include the F2 generation shall be proposed by the registrant based on the following conditions being met (a and any of b(i), b(ii) or b(iii)). See also: Chapter R.7a: Endpoint sepcific guidance Version 5.0 - December 2016:
A. The substance has uses leading to significant exposure of consumers or professionals, taking into account, inter alia, consumer exposure from articles
No – The substance has no uses leading to significant exposure of consumers or professionals. The substance has only industrial use (6 Solvay sites in the European Union).

B (i). The substance displays genotoxic effects in somatic cell mutagenicity tests in vivo which could lead to classifying it as Mutagen Category 2, or
No – The substance is not classified as Mutagen Category 1A or 1B or 2. The substance produced negative results in the reliable combined micronucleus/alkaline Comet assay with rats, suggesting that the substance is not genotoxic in vivo.

B (ii). There are indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure, or
No – The toxicokinetic behaviour of the substance gives no hints for very slow clearance (see results of 90-day study). The results of the 90-day study suggest that 2-amylanthraquinone is readily metabolized in the body, undergoing primarily an oxidation of the aliphatic chain, followed by subsequent sulfonation and glucuronic acid conjugation, followed by excretion in urine. The NOAEC/LOAEC of the subchronic study is not more than 3 times lower than that the NOAEC/LOAEC from a subacute study. Therefore there are no indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure.

B (iii) There are indications of one or more relevant modes of action related to endocrine disruption from available in vivo studies or non-animal approaches
No - There are no indications based on the available study results that endocrine disruption is a relevant mode of action for the substance. In particular, no effects on reproductive organs or tissues or effects on the thyroid were evidenced in the available repeated dose toxicity studies. There were also no effects on gestation in the available developmental toxicity study. The substance also does not have a structural similarity to steroid hormones. Therefore, based on the above considerations, the registrant does not believe that there is a basis for extending cohort 1B to include the F2 generation.

2) Inclusion of Cohorts 2A and 2B (developmental neurotoxicity, DNT): not justified
The registrant does not believe there is a need to include cohorts 2A and 2B in the test design. This is based on:
• Neurobehavioural observations (arena and Functional Observational Battery testing) and motor activity assessment performed as part of the subchronic toxicity study, did not indicate any neurotoxic potential of the test material.

3) Inclusion of Cohort 3 (developmental immunotoxicity, DIT): not justified
The registrant does not believe there is a need to include cohort 3 in the test design. This is based on:
• the substance has not caused biologically significant changes in haematology/clinical chemistry and/or organ weight associated with immunotoxicity such as reduced leucocyte count in combination with reduced spleen weight in repeated dose studies
• the substance has not caused significant effects to immunology organs such as thymus atrophy in repeated dose studies

The highest dose level will be selected in agreement with the testing laboratory and study director with the aim to induce some toxicity, in order to allow a conclusion on whether potential effects on reproduction are considered to be secondary, non-specific consequence of other toxic effects seen.

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): 2-AMYL-ANTHRAQUINONE
- Physical state: Yellow, light brown viscous liquid

Results and discussion

Any other information on results incl. tables

A performance of an extended one-generation reproductive toxicity study is considered to be scientifically not justified, as no evidence of effects on the reproductive organs and tissues was seen in a GLP-compliant guideline 90 -day repeated dose toxicity study(cervix, epididymides, female mammary gland area, prostate gland, seminal vesicles, testes, uterus, vagina).Also no adverse effects on development of progeny or gestation, including early and late resorptions, pre- and post-implantation losses, number of abortions or number of live fetuses were seen in a reliable GLP-compliant guideline developmental toxicity study even at dose levels at which marked maternal toxicity was observed (NOAEL for developmental effects is at least factor three higher than the NOAEL for maternal toxicity). There is no evidence to suggest that the substance will adversely affect reproductive capacity at dose levels that will not cause general toxicity. Furthermore, as the performance of an extended one-generation toxicity study requires the use of a large number of animals and is not expected to provide additional information relevant for risk assessment purposes, the performance of this study is considered to be ethically not justified.

In addition it should be mentioned that the tonnage band of the current dossier is > 1000 tonnes per year but this is based on an average tonnage (sum of manufacturing and import) of only 1016 tonnes per year. However in the beginning of 2018 an update of the REACH dossier is foreseen and very likely the average tonnage of the 3 preceding years will be lower than 1000 tonnes per year. In this case the extended one-generation reproductive toxicity study (EOGRTS) is not an information requirement anymore. This shows that there is no need to initiate an extended one-generation reproductive toxicity study (EOGRTS) at this moment.

Applicant's summary and conclusion