EUROPEAN 
COMMISSION 
Brussels, XXX 
[...](2014) XXX draft 
COMMISSION REGULATION (EU) No 
of XXX 
amending Annexes VIII, IX and X to Regulation (EC) No 1907/2006 of the European 
Parliament and of the Council on the Registration, Evaluation, Authorisation and 
Restriction of Chemicals (REACH) as regards the Extended one-generation 
reproductive toxicity study 
(Text with EEA relevance) 
EN EN COMMISSION REGULATION (EU) No .../. 
of XXX 
amending Annexes VIII, IX and X to Regulation (EC) No 1907/2006 of the European 
Parliament and of the Council on the Registration, Evaluation, Authorisation and 
Restriction of Chemicals (REACH) as regards the Extended one-generation 
reproductive toxicity study 
(Text with EEA relevance) 
THE EUROPEAN COMMISSION, 
Having regard to the Treaty on the Functioning of the European Union, 
Having regard to Regulation (EC) No 1907/2006 of the European Parliament and of the 
Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and 
Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending 
Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission 
Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission 
Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC1, and in particular Article 
13(2) thereof, 
Whereas: 
(1) Article 13(2) of Regulation (EC) No 1907/2006 provides that testing methods used to 
generate information on intrinsic properties of substances required by that Regulation 
is to be regularly reviewed and improved with a view to reducing testing on vertebrate 
animals and the number of animals involved. The principles of replacement, reduction 
and refinement, enshrined in Directive 2010/63/EU of the European Parliament and of 
the Council2 should be taken into account in the design of the test methods, in 
particular when appropriate validated methods become available to replace, reduce or 
refine animal testing. Following that review, Council Regulation (EC) No 440/20083 
and the Annexes to Regulation (EC) No 1907/2006 are to be amended, if relevant, so 
as to replace, reduce or refine animal testing. 
(2) Pursuant to Regulation (EC) No 1907/2006, a two-generation reproductive toxicity 
study is to be used to investigate the reproductive toxicity of chemical substances to 
fulfil the standard information requirements in point 8.7.3. of Annexes IX and X to 
that Regulation. Furthermore, column 2 of point 8.7.1. of Annex VIII to Regulation 
(EC) No 1907/2006 provides that the two-generation reproductive toxicity study is a 
possibility to assess the cases where there are serious concerns about the potential for 
adverse effects on fertility or development. 
OJ L 396, 30.12.2006, p. 1. 
Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the 
protection of animals used for scientific purposes (OJ L 276, 20.10.2010, p. 33). 
Council Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to 
Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, 
Evaluation, Authorisation and Restriction of Chemicals (REACH) (OJ L 142, 31.5.2008, p. 1). 
EN 2 EN (3) The Extended one-Generation Reproductive Toxicity Study4 (EOGRTS) is a new test 
method developed to assess the reproductive toxicity of chemical substances. This test 
method was adopted by the Organisation for Economic Co-operation and 
Development (OECD) in July 2011. EOGRTS is a modular test method, where 
breeding and assessment of a second filial (F2) generation and testing for 
developmental neurotoxicity (DNT) and developmental immunotoxicity (DIT) 
constitute distinct and independent modules. 
(4) EOGRTS is considered to offer a number of advantages in comparison to the two-
generation reproductive toxicity study. It assesses a greater number of animals of the 
first filial (Fl) generation and addresses additional parameters, thus improving the 
sensitivity and level of information that can be obtained from the test. Furthermore, as 
breeding of the F2 generation is not part of the basic test design, a significant 
reduction in the number of animals used is achieved. 
(5) EOGRTS was included in Regulation (EC) No 440/2008 by Regulation (EU) No 
[number and institution and footnote to be inserted]. Annexes IX and X to Regulation 
(EC) No 1907/2006 should be amended to specify how the new test method is to be 
used for the purposes of Regulation (EC) No 1907/2006. To this end, a sub-group of 
the Commission Expert Group consisting of Competent Authorities for the REACH 
and the classification and labelling of chemical substances Regulations (the Expert 
Group) was created in 2011. Based on the scientific recommendations of this Expert 
Group, the EOGRTS should become the preferred test method to address the standard 
information requirement defined in column 1 of point 8.7.3. of Annexes IX and X to 
Regulation (EC) No 1907/2006. 
(6) The standard information requirement in Annexes IX and X to Regulation (EC) No 
1907/2006 should be limited to the basic configuration of EOGRTS. Nevertheless, in 
certain specific cases, where justified, the registrant should be able to propose and the 
European Chemicals Agency (ECHA) should be able to request the performance of F2 
generation, as well as DNT and DIT cohorts. 
(7) It should be ensured that the reproductive toxicity study carried-out under point 8.7.3. 
of Annexes IX and X to Regulation (EC) No 1907/2006 will allow adequate 
assessment of possible effects on fertility. The premating exposure duration and dose 
selection should be appropriate to meet risk assessment and classification and labelling 
purposes as required by Regulation (EC) No 1907/2006 and Regulation (EC) No 
1272/2008 of the European Parliament and of the Council5. 
(8) Considering that the remaining scientific concerns as regards the value of the F2 
generation should be clarified on the basis of empirical data, and that substances 
potentially presenting the highest risk to consumers and professional users should be 
assessed on the basis of a conservative approach, the production and assessment of the 
F2 generation should be triggered for certain substances. The Expert Group 
recommended that an exposure based trigger, associated with uses leading to 
exposures of consumers and professional users should be implemented in the relevant 
points of Annexes IX and X to Regulation (EC) No 1907/2006. Additional criteria, 
based on evidence indicating that a substance is of low concern as a function of the 
4 OECD Test Guideline 443 
5 Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on 
classification, labelling and packaging of substances and mixtures, amending and repealing Directives 
67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 (OJ L 353, 31.12.2008, p. 
1). 
EN 3 EN available toxicity and toxicokinetic information, should be included to further optimise 
the selection of substances for which the F2 generation should be produced and 
subjected to testing. 
(9) Due to technical, economic and practicality reasons the DIT and DNT cohorts, or only 
one of them, should be performed as part of the EOGRTS only in certain cases. 
Consequently, specific rules for the adaptation of the information requirement defined 
in point 8.7.3. of Annexes IX and X to Regulation (EC) No 1907/2006 should be 
introduced, so as to trigger the immunotoxicity and neurotoxicity testing. In cases 
where the available information on a substance indicates a particular concern on 
neurotoxicity or immunotoxicity, the inclusion of the DNT and the DIT cohorts, or 
only one of them, justified on a case-by-case basis, should be possible. Evidence 
supporting these concerns could originate from existing information derived from in 
vivo or non-animal approaches, from the knowledge of relevant mechanisms/modes of 
action of the substance itself, or from existing information on structurally related 
substances. Therefore, if any such particular concerns are justified, the registrant 
should be required to propose, and ECHA should be able to request the performance 
of the DNT and DIT cohorts, or only one of them. 
(10) Point 8.7.3. of Annex IX to Regulation (EC) No 1907/2006 requires performing a 
reproductive toxicity study, only if there are concerns arising from adverse effects 
previously detected on reproductive organs or tissues. That point provides that only 
28- and 90-day repeated dose toxicity studies can be the source of such information. 
Given that also reproductive toxicity screening studies such as OECD Test Guideline 
421 or Test Guideline 422, or other studies with repeated dose administration can 
provide indications on adverse effects on relevant reproductive parameters, which may 
justify the need to follow-up by performing an EOGRTS, column 1 of point 8.7.3. 
should be modified to allow such additional studies to be considered. 
(11) Due account should be taken of the lack of experience in conducting the EOGRTS in 
animal species other than the rat. Therefore, provisions in column 2 of point 8.7.3. of 
Annex IX to Regulation (EC) No 1907/2006, regarding the requirement to test on a 
second species should be deleted. 
(12) In order to avoid imposing a disproportionate burden on the economic operators who 
may have already performed the tests or acquired results of two-generation 
reproductive toxicity study, as well as for animal welfare reasons, the robust study 
summaries of those studies that were initiated before the date of the entry into force of 
this Regulation should be considered appropriate to address the standard information 
requirement in point 8.7.3. of Annexes IX and X to Regulation (EC) No 1907/2006. 
(13) For reasons of consistency, point 8.7.1., column 2 of Annex VIII to Regulation (EC) 
No 1907/2006 should be amended in order to change the cross-reference to the study 
required under point 8.7.3. of Annex IX to Regulation (EC) No 1907/2006 from the 
two-generation reproductive toxicity study to EOGRTS. 
(14) ECHA, in close cooperation with Member States and stakeholders, should further 
develop guidance documents for the application of EOGRTS for the purposes of 
Regulation (EC) No 1907/2006. In doing so, ECHA should take full account of the 
work carried out in OECD, as well as in other relevant scientific and expert groups. 
Furthermore, when determining deadlines by which dossier updates providing results 
of EOGRTS are to be submitted, ECHA should take due account of the market 
availability of this testing service.] 
4 (15) Regulation (EC) No 1907/2006 should therefore be amended accordingly. 
(16) The measures provided for in this Regulation are in accordance with the opinion of the 
Committee established under Article 133 of Regulation (EC) No 1907/2006, 
HAS ADOPTED THIS REGULATION: 
Article 1 
Annexes VIII, IX and X to Regulation (EC) No 1907/2006 are amended in accordance with 
the Annex to this Regulation. 
Article 2 
This Regulation shall enter into force on the twentieth day following that of its publication in 
the Official Journal of the European Union. 
This Regulation shall be binding in its entirety and directly applicable in all Member States. 
Done at Brussels, 
For the Commission 
The President 
[••J 
5 EN 
ANNEX 
Regulation (EC) No 1907/2006 is amended as follows: 
(1) In Annex VIII , in the table setting out the toxicological information, in column 2 
(Specific Rules for Adaptation from Column 1), point 8.7.1. is replaced by the following: 
"8.7.1. This study does not need to be conducted if: 
— the substance is known to be a genotoxic carcinogen and 
appropriate risk management measures are implemented, or 
— the substance is known to be a germ cell mutagen and 
appropriate risk management measures are implemented, or 
— relevant human exposure can be excluded in accordance with 
Annex XI section 3, or 
— a pre-natal developmental toxicity study (Annex IX, 8.7.2) or, 
either an Extended One-Generation Reproductive Toxicity Study 
(B.56, OECD TG 443) (Annex IX, Section 8.7.3) or a two-
generation study (B.35, OECD TG 416), is available. 
If a substance is known to have an adverse effect on fertility, 
meeting the criteria for classification as toxic for reproduction 
category 1A or IB: May damage fertility (H360F), and the 
available data are adequate to support a robust risk assessment, 
then no further testing for fertility will be necessary. However, 
testing for developmental toxicity must be considered. 
If a substance is known to cause developmental toxicity, meeting 
the criteria for classification as toxic for reproduction category 1A 
or IB: May damage the unborn child (H360D), and the available 
data are adequate to support a robust risk assessment, then no 
further testing for developmental toxicity will be necessary. 
However, testing for effects on fertility must be considered. 
In cases where there are serious concerns about the potential for 
adverse effects on fertility or development, either an Extended 
One-Generation Reproductive Toxicity Study (Annex IX, Section 
8.7.3) or a pre- natal developmental toxicity study (Annex IX, 
Section 8.7.2) may, as appropriate, be proposed by the registrant 
instead of the screening study." 
1 (2) In Annex IX, in the table setting out the toxicological information, in column 1 
(Standard Information Requirement) and column 2 (Specific Rules for Adaptation from 
Column 1) point 8.7.3. is replaced by the following: 
"COLUMN 1 
STANDARD 
INFORMATION 
REQUIRED COLUMN 2 
SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 
8.7.3. Extended One-
Generation Reproductive 
Toxicity Study (B.56 of 
the Commission 
Regulation on test 
methods as specified in 
Article 13(3) or OECD 
443), basic test design 
(cohorts 1A and IB 
without extension to 
include a F2 generation), 
one species, most 
appropriate route of 
administration, having 
regard to the likely route 
of human exposure, if 
the available repeated 
dose toxicity studies 
(e.g. 28-day or 90-day 
studies, OECD 421 or 
422 screening studies) 
indicate adverse effects 
on reproductive organs 
or tissues or reveal other 
concerns in relation with 
reproductive toxicity. 8.7.3. An Extended One-Generation Reproductive Toxicity Study 
with the extension of cohort IB to include the F2 generation shall 
be proposed by the registrant or may be required by the Agency in 
accordance with Articles 40 or 41, if: 
(a) the substance has uses leading to significant exposure of 
consumers or professionals, taking into account consumer 
exposure from articles, and 
(b) any of the following conditions are met: 
the substance displays genotoxic effects in somatic cell 
mutagenicity tests in vivo which could lead to classifying it 
as Mutagen Cat. 2, or 
there are indications that the internal dose for the 
substance will only reach a steady state in the test animals 
after an extended exposure, or 
there are indications of one or more relevant modes of 
action related to endocrine disruption from available in 
vivo studies or non-animal approaches. 
An Extended One-Generation Reproductive Toxicity Study 
including cohorts 2A/2B (developmental neurotoxicity) and/or 
cohort 3 (developmental immunotoxicity) shall be proposed by 
the registrant or may be required by the Agency in accordance 
with Articles 40 or 41, only in case of particular concerns on 
(developmental) neurotoxicity or (developmental) immunotoxicity 
justified by any of the following: 
existing information on the substance itself derived from 
relevant available in vivo or non-animal approaches (e.g. 
abnormalities of the CNS, evidence of adverse effects on 
the nervous or immune system in studies on adult animals 
or animals exposed prenatally), or 
specific mechanisms/modes of action of the substance with 
an association to (developmental) neurotoxicity and/or 
(developmental) immunotoxicity (e.g. Cholinesterase 
inhibition or relevant changes in thyroidal hormone levels 
scientifically associated to adverse effects), or 
existing information on effects caused by substances 
2 structurally analogous to the substance being studied, 
suggesting such effects or mechanisms/modes of action. 
Other studies on developmental neurotoxicity and/or 
developmental immunotoxicity instead of cohorts 2A/2B 
(developmental neurotoxicity) and/or cohort 3 (developmental 
immunotoxicity) of the Extended One-Generation Reproductive 
Toxicity Study may be proposed by the registrant in order to 
clarify the concern on developmental toxicity. 
Two-generation reproductive toxicity studies (B.35, OECD TG 
416) that were initiated before [date of the entry into force of this 
Regulation] shall be considered appropriate to address this 
standard information requirement." 
(3) In Annex X, in the table setting out the toxicological information, in column 1 
(Standard Information Requirement) and column 2 (Specific Rules for Adaptation from 
Column 1) point 8.7.3. is replaced by the following: 
"COLUMN 1 
STANDARD 
INFORMATION 
REQUIRED COLUMN 2 
SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 
8.7.3. Extended One-
Generation Reproductive 
Toxicity Study (B.56 of 
the Commission 
Regulation on test 
methods as specified in 
Article 13(3) or OECD 
443), basic test design 
(cohorts 1A and IB 
without extension to 
include a F2 generation), 
one species, most 
appropriate route of 
administration, having 
regard to the likely route 
of human exposure, 
unless already provided 
as part of Annex IX 
requirements. "8.7.3. An Extended One-Generation Reproductive Toxicity Study 
with the extension of cohort IB to include the F2 generation shall 
be proposed by the registrant or may be required by the Agency in 
accordance with Articles 40 or 41, if: 
(a) the substance has uses leading to significant exposure of 
consumers or professionals, taking into account consumer 
exposure from articles, and 
(b) any of the following conditions are met: 
- the substance displays genotoxic effects in somatic cell 
mutagenicity tests in vivo which could lead to classifying 
it as Mutagen Cat. 2, or 
there are indications that the internal dose for the 
substance will only reach a steady state in the test animals 
after an extended exposure, or 
there are indications of one or more relevant modes of 
action related to endocrine disruption from available in 
vivo studies or non-animal approaches. 
An Extended One-Generation Reproductive Toxicity Study 
including cohorts 2A/2B (developmental neurotoxicity) and/or 
cohort 3 (developmental immunotoxicity) shall be proposed by 
the registrant or may be required by the Agency in accordance 
with Articles 40 or 41, only in case of particular concerns on 
3 (developmental) neurotoxicity or (developmental) immunotoxicity 
justified by any of the following: 
existing information on the substance itself derived from 
relevant available in vivo or non-animal approaches (e.g. 
abnormalities of the CNS, evidence of adverse effects on 
the nervous or immune system in studies on adult animals 
or animals exposed prenatally), or 
specific mechanisms/modes of action of the substance with 
an association to (developmental) neurotoxicity and/or 
(developmental) immunotoxicity (e.g. Cholinesterase 
inhibition or relevant changes in thyroidal hormone levels 
scientifically associated to adverse effects), or 
existing information on effects caused by substances 
structurally analogous to the substance being studied, 
suggesting such effects or mechanisms/modes of action. 
Other studies on developmental neurotoxicity and/or 
developmental immunotoxicity instead of cohorts 2A/2B 
(developmental neurotoxicity) and/or cohort 3 (developmental 
immunotoxicity) of the Extended One-Generation Reproductive 
Toxicity Study may be proposed by the registrant in order to 
clarify the concern on developmental toxicity. 
Two-generation reproductive toxicity studies (B.35, OECD TG 
416) that were initiated before [date of the entry into force of this 
Regulation] shall be considered appropriate to address this 
standard information requirement." 
4