Initial reflections on a way forward to update the REACH Annexes in relation to endocrine disruption properties – OPEN FOR FEEDBACK UNTIL 16 NOVEMBER
The European Commission is looking for comments on its intention to update REACH data requirements for identifying and assessing endocrine disruptors (EDs). The Competent Authorities for REACH and the CLP Expert Group on Endocrine Disrupters recently published their initial reflections on the update of the REACH Annexes to include data requirements on endocrine disruption (Annex I and Annexes VII to X).
Feedback can be provided until 16 November 2020.
REACH Annexes to include data requirements on endocrine disruption
The criteria to identify a substance as an ED include: (i) evidence of endocrine activity (provided by e.g. in vitro methods or in vivo tests informing on the ED mechanism); and (ii) evidence of an adverse effect (provided by existing higher tier in vivo tests); and (iii) a biological plausible link between point (i) and (ii).
The guidance for ED assessment under the Biocidal Products Regulation (BPR) and Plant Protection Product Regulation (PPPR) developed jointly by EFSA and ECHA, with the technical support of European Commission’s Joint Research Centre (JRC), provides assessment schemes for EATS (estrogen, androgen, thyroid, steroidogenic) modalities based on current knowledge and available test methods. It was therefore proposed that the scope of the REACH amendments also be limited to these modalities. However, this does not waive the obligation of manufacturers, importers or downstream users under REACH to assess hazards or risks from adverse effects caused by other, non-EATS, modalities, if such information is available. Also, current ED assessment is limited to vertebrates. Including invertebrate tests as data requirements at this stage may be premature because of the current lack of mechanistic understanding of invertebrate endocrinology.
Under the BPR and the PPPR, there is one set of standard information requirements. The ED assessment strategy as outlined in the ECHA/EFSA Guidance assumes as a starting point that this information is available. In contrast, under REACH, the standard information is dependent upon tonnage band. As a result, the starting point for the ED assessment will vary depending on tonnage. However, there is consensus that the same scientific principles should apply. It is being noted that the ED data requirements should be accompanied with corresponding guidance, because it is not possible to capture all possible scenarios of the ED triggering in the data requirements. There is a need to have some flexibility which will allow the data requirements to be expanded in certain cases.
The proposals foresee to use several in vitro tests in parallel to gather information on the different endocrine modalities. Each in vitro test has a certain rate of false positive results, which trigger unnecessary in vivo tests. The inclusion of several in vitro tests for the different modalities in parallel increases the probability that for a specific substance at least one test provides a false-positive result. Due to that, in vitro tests potentially lead to a number of unnecessary in vivo tests. It is therefore necessary to strengthen triggers for in vivo tests e.g. by using combined information from several sources (e.g. in vitro testing, in silico and literature data).
Assessment of endocrine disrupting properties requires in general information from several tests. Various pieces of information need to be assessed together in a weight-of-evidence approach type assessment. On the other hand, information requirements should be clear and unambiguous as possible.
Explanation of the ED testing strategy explanation
There are different ways to implement an ED testing strategy. Initially, two of these are presented (see below), to trigger discussion and further develop a unique proposal in the next steps. It should also be noted that these are not the only possibilities and other strategies may exist. Therefore, experts of the group can comment on these strategies and, if relevant, send other proposal.
The outlined proposals are meant to introduce standard ED information requirements at each tonnage level, keeping in mind the principle of proportionality. Mammalian tests can inform on endocrine disruption for the environment. Therefore, information from mammalian tests conducted for the human health assessment can be triggers or waivers for further tests on endocrine disruption for the environment.
With regard to non-EATS modalities, the Commission is of the opinion that these cannot be covered by standard information requirements with the current gaps in test methods and knowledge and it is more appropriate that any concern for non-EATS is dealt with via Substance Evaluation. The Registrants are to include all available information on the substance including on non-EATS modalities and to discuss this in the Chemical Safety Report (CSR).
Finally, further consideration will be needed regarding waivers, depending on the inclusion of hazard classes for ED under the CLP Regulation. The waivers will also need to be adapted depending on the inclusion of one or more categories in each class.
Proposal 1:
Annex VII
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | |
| 8.9. | Endocrine Disruption | Information of sections 8.9.1 and 8.9.2 and other relevant available information, including from in silico methods shall be used to assess the endocrine disruptive properties of the substance to the extent it can be derived from that information.
Adequate and reliable documentation shall be provided. |
|
| 8.9.1. | Systematic literature review for endocrine disrupting properties | The systematic review of available literature and studies on mammals and non-mammalian vertebrates shall cover EATS modalities. | |
| 8.9.2. | In vitro mechanistic information | Studies in section 8.9.2.1. to 8.9.2.5. do not need to be conducted if the substance meets the requirements for classification as endocrine disruptor according to the CLP criteria for ED with regard to humans and the environment. | The waiver will need to be adapted depending on the inclusion of hazard classes for ED and one or more categories under the CLP Regulation. [this comment is also valid for similar waivers in other rows]. |
| 8.9.2.1. | Estrogen receptor transactivation assay (OECD TG 455) | The study does not need to be conducted if:
– the output data from the ToxCast ER Bioactivity Model or an Uterotrophic bioassay in rodents (OECD TG 440) are available. |
|
| 8.9.2.2. | Androgen receptor transactivation assay (OECD TG 458) | The study does not need to be conducted if:
– a Hershberger bioassay in rats (OECD TG 441) is available. |
|
| 8.9.2.3. | H295R steroidogenesis assay (OECD TG 456) | ||
| 8.9.2.4. | Aromatase assay (OPPTS 890.1200) | ||
| 8.9.2.5. | << Thyroid assay >> | The study does not need to be conducted if:
– information on the T-modality is available from relevant in vivo mammalian studies. |
In vitro thyroid assays are foreseen to become available in the near future. An in vitro thyroid assay should be included here to complete the screening for EATS modalities. |
Annex VIII
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | |
| 8.9. | Endocrine Disruption for human health | Appropriate in vivo studies in Annex IX or X shall be proposed by the registrant or may be required by the Agency if
– the assessment in Annex VII Section 8.9. indicates the presence of endocrine disrupting properties; – there is indication of endocrine disrupting properties from the information requirements in Annex VIII, Section 8.6 (Repeated dose toxicity), Section 8.7 (Reproductive toxicity) or from higher tier studies in Annex IX, Section 8.6. or 8.7, triggered by those information requirements. Studies do not need to be conducted if – if the substance meets the requirements for classification as endocrine disruptor according to the CLP criteria for ED with regard to humans, or – a substance undergoes immediate disintegration and there are sufficient data on the cleavage products, or – relevant human exposure can be excluded in accordance with Annex XI Section 3. |
OECD TG 407, 408, 409, 414, 421/422, 443, if available. |
| 9.1. | Aquatic toxicity | ||
| 9.1.3. | Short-term toxicity testing on fish | If there are any indications for endocrine disrupting properties long-term toxicity testing (Annex IX Section 9.1.6) instead of short-term toxicity testing on fish, shall be proposed by the registrant or may be required by the Agency. | This has to be read in conjunction with the existing text and the Action 2 points on aquatic toxicity. |
Annex IX
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | |
| 8.9. | Endocrine disruption for human health | ||
| 8.9.3. | Uterotrophic Bioassay in Rodents (OECD TG 440) | The study does not need to be conducted if:
– there is sufficient weight of evidence to conclude on the presence or absence of an estrogenic mode of action. – the output data from the ToxCast ER Bioactivity Model is available, or – there are no indications of estrogen related adversity in a reliable Extended One-Generation Reproductive Toxicity Study (OECD TG 443) – there are indications of estrogenic activity in other in vivo studies, e.g. OECD TG 407, 421/422. |
Waiver based on text in proposal for update of IR under the BPR.
There is overlap of the waivers with the first waiver. |
| 8.9.4. | Hershberger Bioassay in Rats (OECD TG 441) | The study does not need to be conducted if:
– there is sufficient weight of evidence to conclude on the presence or absence of an androgenic mode of action. – if there are no indications of androgen related adversity in a reliable Extended One-Generation Reproductive Toxicity Study (OECD TG 443) – If there are indications of androgenic activity in other in vivo studies, e.g. OECD TG 407, 421/422. |
Waiver based on text in proposal for update of IR under the BPR.
There is overlap of the waivers with the first waiver. |
| 9.1. | Aquatic toxicity | Other long-term toxicity testing than the tests in Section 9.1.5. or 9.1.6. shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41, if the chemical safety assessment according to Annex I indicates the need to investigate further the effects on aquatic organisms.
The choice of the test(s) depends on the results of the chemical safety assessment. |
For information only. This will be discussed during the expert group meeting. The text in the left column corresponds to a current proposal submitted for discussion to the expert group. |
| 9.1.6. | Long-term toxicity testing on fish
The information shall be provided for one of the Sections 9.1.6.1, 9.1.6.3 or 9.6.1.4 |
The test in section 9.1.6.4 shall be proposed by the registrant or may be required by the Agency if
– there is indication of endocrine disrupting properties, and – a Medaka Extended One-Generation Reproduction Test (OECD TG 240) is not available. Fish short-term toxicity tests on embryo and sac-fry stages (OECD TG 212) (Annex IX Section 9.1.6.2) that were initiated before [date of entering into force] shall be considered appropriate to address this standard information requirement in case there is no indication of endocrine disrupting properties from these tests. |
|
| 9.1.6.1. | Fish early-life stage (FELS) toxicity test (OECD TG 210) | ||
| 9.1.6.2 | Fish short-term toxicity tests on embryo and sac-fry stages | Section 9.1.6.2 should be deleted. | |
| 9.1.6.3 | Fish, juvenile growth test (OECD TG 215) | . | |
| 9.1.6.4 | Fish Sexual Development Test (OECD TG 234) | ||
| 9.7. | Endocrine disruption for the environment | ||
| 9.7.1 | Amphibian Metamorphosis Assay (OECD TG 231) | The study does not need to be proposed if:
– there is sufficient weight of evidence to conclude on the presence or absence of a thyroid mode of action in non-mammalian species; – there is no indication for a T-modality – a Larval Amphibian Growth and Development Assay (OECD 241) is available. – a fish study providing information on T-modality is available that has been conducted in accordance with a test method laid down in Council Regulation (EC) 440/2008 or with an international test method recognised by the Commission or the Agency as being appropriate. – the substance can be identified as endocrine disruptor according to the CLP criteria for ED with regard to environment Appropriate in vivo studies in Annex IX and/or X shall be proposed by the registrant or may be required by the Agency in case of a positive result in any of the in vivo mechanistic studies. |
Waiver based on text in proposal for update of IR under the BPR.
There is overlap of the waivers with the first waiver. Waivers require further guidance. Placeholder to prepare for studies that are in the pipeline. Waiver cover the cases where the substance could be identified as ED for the environment based on the mammalian dataset. XETA only to be discussed in the Guidance in alignment with PPPR and BPR. |
Annex X
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | |
| 9.7. | Endocrine disruption for the environment | Further testing according to Sections 9.7.2. or 9.7.3. shall be proposed by the registrant or may be required by the Agency if the chemical safety assessment according to Annex I indicates the need to investigate further the endocrine disrupting properties for the environment, unless the substance meets the requirements for classification as endocrine disruptor for the environment, unless the substance meets the requirements for classification as endocrine disruptor for the environment. The choice of the appropriate test depends on the results of the chemical safety assessment. | Alternatively, the obligation for further testing, if information is not sufficient for classification, could include a trigger system that requires the Medaka EOGR (OECD TG 240) in case of EAS modalities and the LAGDA (OECD TG 241 in case of T-modalities.
The classification-based waiver option will need to be adapted depending on the inclusion of hazard classes for ED and one or more categories under the CLP Regulation. Further discussions might be required on the waiver as regards a possible need of testing for the derivation of PNECs. |
| 9.7.2. | Medaka Extended One-Generation Reproduction Test (OECD TG 240) | The study does not need to be proposed if:
– a Fish Life Cycle Toxicity Test (OPPTS 850.1500; covering all the ‘estrogen-, androgen- and steroidogenic-mediated’ parameters foreseen to be measured in the OECD TG 240 study) is available, or – A Fish Sexual Development Test (OECD TG 234) is available, or – there is no indication for endocrine activity or endocrine related effects from the mammalian data set or from any other relevant information (e.g. literature) and valid in vivo data is available, with no information suggesting that the active substance may elicit endocrine activity or effects potentially related to endocrine activity in either the Fish Short Term Reproduction Assay (OECD TG 229), or the 21-day Fish assay (OECD TG 230) or Fish Sexual Development Test (OECD TG 234) or the Larval Amphibian Growth and Development Assay (OECD 241) If other data are available covering the estrogenic-, androgenic- and steroidogenic- related modalities or parameters investigated in OECD TG 229 or OECD TG 230 or OECD TG 234 or OECD TG 241, then those data can be used instead. |
|
| 9.7.3. | Larval Amphibian Growth and Development Assay (OECD TG 241) | The study does not need to be proposed if:
there is no indication for endocrine activity or endocrine related effects from the mammalian data set, or from any other relevant information (e.g. literature), and valid in vivo data is available, with no information suggesting that the substance may have endocrine disrupting properties in an Amphibian metamorphosis assay (OECD 231). |
PROPOSAL 2:
Annex VII
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | ||
| 10. ENDOCRINE DISRUPTION | ||||
| 10.1. | Assessment of the endocrine disruptive properties of the substance to the extent that can be derived from the relevant available information and other relevant information, including in silico and in vitro methods.
In all cases, adequate and reliable documentation shall be provided. |
|||
| 10.2. | In vitro mechanistic information | 10.2. | Appropriate in vivo mechanistic studies in Annex VIII must be conducted or may be required by the Agency in case of a positive result in any of the in vitro mechanistic studies.
Studies do not need to be conducted if the substance can be identified as endocrine disruptor according to the CLP criteria for ED with regard to humans and the environment. |
|
| 10.2.1. | Estrogen receptor transactivation assay (OECD TG 455) | 10.2.1. | The study does not need to be conducted if:
– the output data from the ToxCast ER Bioactivity Model or an Uterotrophic bioassay in rodents (OECD TG 440) are available. |
|
| 10.2.2. | Androgen receptor transactivation assay (OECD TG 458) | 10.2.2. | The study does not need to be conducted if:
– a Hershberger bioassay in rats (OECD TG 441) is available. |
|
| 10.2.3. | H295R steroidogenesis assay (OECD TG 456) | 10.2.3. | ||
| 10.2.4. | Aromatase assay (OPPTS 890.1200) | 10.2.4. | ||
| 10.2.5. | << Thyroid assay >> | 10.2.5 | In vitro thyroid assays are foreseen to become available in the near future. These should be included here to complete the screening for EATS modalities. | |
Annex VIII
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | ||
| 9.1. | Aquatic toxicity | 9.1. | ||
| 9.1.3. | Short-term toxicity testing on fish (OECD TG 203). The registrant should consider long-term toxicity testing if the substance is poorly water soluble. | 9.1.3. | If there are any indications for endocrine disrupting properties long-term toxicity testing (Annex IX Section 9.1.6) instead of short-term toxicity testing on fish, shall be proposed by the registrant or may be required by the Agency | This has to be read in conjunction with the existing text and the Action 2 points on aquatic toxicity |
| 10. ENDOCRINE DISRUPTION | ||||
| 10.2. | In vivo mechanistic information | 10.2. | Appropriate in vivo studies in Annex IX and/or X must be proposed by the registrant or may be required by the Agency in case of a positive result in any of the in vivo mechanistic studies.
Studies do not need to be conducted: – if the substance can be identified as endocrine disruptor according to the CLP criteria for ED with regard to humans and the environment. |
|
| 10.2.1. | Uterotrophic Bioassay in Rodents (OECD TG 440) | 10.2.1. | The study does not need to be conducted if:
– the output data from the ToxCast ER Bioactivity Model is available, or – there are no indications of estrogen related adversity in a reliable Extended One-Generation Reproductive Toxicity Study (OECD TG 443) – there are indications of estrogenic activity in other in vivo studies, e.g. OECD TG 407, 421/422. |
|
| 10.2.2. | Hershberger Bioassay in Rats (OECD TG 441) | 10.2.2. | The study does not need to be conducted if:
– if there are no indications of androgen related adversity in a reliable Extended One-Generation Reproductive Toxicity Study (OECD TG 443) – If there are indications of androgenic activity in other in vivo studies, e.g. OECD TG 407, 421/422. |
|
| 10.2.3. | Fish Short Term Reproduction assay (OECD TG 229) | 10.2.3. | The study does not need to be conducted if:
– a 21-day Fish Assay (OECD TG 230); or – a Fish Sexual Development Test (OECD TG 234), or – a Medaka Extended One-Generation Reproduction Test (OECD TG 240), or – a Fish Life Cycle Toxicity test (OPPTS 850.1500; covering all the ‘estrogen-, androgen- and steroidogenic-mediated’ parameters foreseen to be measured in the OECD TG 240 study) is available. |
|
| 10.2.4. | Amphibian Metamorphosis Assay (OECD TG 231) | 10.2.4. | The study does not need to be conducted if:
– a Larval Amphibian Growth and Development Assay (OECD 241) is available. – the substance can be identified as endocrine disruptor according to the CLP criteria for ED with regard to environment |
XETA only to be discussed in the Guidance in alignment with PPPR and BPR |
Annex IX
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | ||
| 9.1. | Aquatic toxicity | 9.1. | 9.1. Other long-term toxicity testing than the tests in Section 9.1.5. or 9.1.6. shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41, if the chemical safety assessment according to Annex I indicates the need to investigate further the effects on aquatic organisms.
The choice of the test(s) depends on the results of the chemical safety assessment. |
For information only. This will be discussed during the meeting of expert group. The text in the left column corresponds to a current proposal submitted for discussion to the expert group. |
| 9.1.6. | Long-term toxicity testing on fish | 9.1.6. | OECD TG 234 should be performed instead of OECD TG 210 if LT testing is triggered.
There is an Action 2 (general revision of REACH IR) activity here. |
|
| 9.1.6.1. | Fish Sexual Development Test (OECD TG 234)
(instead of FELS) |
9.1.6.1. | The study does not need to be proposed if:
– a Medaka Extended One-Generation Reproduction Test (OECD TG 240) is available. |
Annex X
| COLUMN 1 STANDARD INFORMATION REQUIRED | COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 | Comments | ||
| 8.6.4. | In contrast to active substances under BPR and PPPR, carcinogenicity studies are normally not available for REACH substances. These studies play an important role in establishing adversity in particular for the T modality. In order to be able to conclude on ED properties for the T modality, there may be a need for additional information which could be requested using 8.6.4., e.g. developmental neurotoxicity (OECD TG 426). However, currently this provision only exists at Annex X. Consider introducing 8.6.4. also, in Annex VIII and IX. | |||
| 10. ENDOCRINE DISRUPTION | ||||
| 10.3.1. | Medaka Extended One-Generation Reproduction Test (OECD TG 240) | 10.3.1. | The study does not need to be proposed if:
– a Fish Life Cycle Toxicity Test (OPPTS 850.1500; covering all the ‘estrogen-, androgen- and steroidogenic-mediated’ parameters foreseen to be measured in the OECD TG 240 study) is available. – there is no indication for endocrine activity or endocrine related effects from the mammalian data set or from any other relevant information (e.g. literature) and valid in vivo data is available, with no information suggesting that the active substance may elicit endocrine activity or effects potentially related to endocrine activity in either the Fish Short Term Reproduction Assay (OECD TG 229), or the 21-day Fish assay (OECD TG 230) or Fish Sexual Development Test (OECD TG 234). If other data are available covering the estrogenic-, androgenic- and steroidogenic- related modalities or parameters investigated in OECD TG 229 or OECD TG 230 or OECD TG 234, then those data can be used instead. |
Further consideration on waiver are needed, depending on the risk management measures that will be implemented in REACH for substances classified as ED in CLP. |
| 10.3.2. | Larval Amphibian Growth and Development Assay (OECD TG 241). | 10.3.2. | The study does not need to be proposed if:
there is no indication for endocrine activity or endocrine related effects from the mammalian data set, or from any other relevant information (e.g. literature) and valid in vivo data is available, and valid in vivo data is available, with no information suggesting that the substance may have endocrine disrupting properties in an Amphibian metamorphosis assay (OECD 231). |
Further consideration on waiver are needed, depending on the risk management measures that will be implemented in REACH for substances classified as ED in CLP. |
General provisions for assessing substances and preparing chemical safety – Annex I
- No change of the legal text is needed if the ED hazard classes is inserted in the CSR under point 2 and 3, then the new hazard classes could be added
- The human health hazard assessment and environmental hazard assessment for the chemical shall consider additionally the endocrine disrupting effects for human health and environment respectively, in addition to existing endpoint effects. Based on all the available information, other effects shall be considered when necessary.
- The Chemical Safety Report shall also include the headings related to endocrine disruption by endocrine modality in both human health hazard assessment and environmental hazard assessment sections
The above-mentioned proposals are intended as a starting point for discussion and should not be regarded as a final proposal.
