Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study planned
Study period:
03/01/2012 to 03/01/2014

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
Principles of method if other than guideline:
Title: Two Generation Reproductive Toxicity Test of C9-C20 aliphatic Hydrocarbon Solvent

Background

Substances Covered by the Proposal

These aliphatic hydrocarbon solvents are complex hydrocarbon substances with carbon numbers ranging from approximately C9 to C20 and aromatic contents of up to 30%. For purposes of REACH registration, there are approximately 45 of these substances in 4 categories (C9-C14 aliphatic solvents, 2-25% aromatics; C9-C14 aliphatic solvents < 2% aromatics; C14-C20 aliphatic solvents, 2-30% aromatics; C14-C20 aliphatic solvents, < 2% aromatics). The aliphatic constituents of these solvents include normal paraffins, iso (i.e., branched) paraffins and cycloparaffins in varying proportions as indicated in the substance descriptors. The aromatic molecules present in the C9-C14 solvents would be primarily C9 isomers. Higher molecular weight solvents could include more highly branched alkyl benzenes, naphthalene, and alkylated naphthalenes. The specific substances covered by this proposal are listed in Attachment 1.

Regulatory Issues

REACH Reguirements/Guidance

As stipulated in the REACH regulation (Regulation (EC) No. 1907/2006 of the European Parliament and of the Council of December 2006), the standard information requirements for substances manufactured or imported in quantities of 1000 tonnes or more includes the stipulation that a two generation reproductive toxicity study must be carried out (Annex X). More specifically, there is a stipulation that a ¿two-generation reproductive toxicity study, one species, male and female, most appropriate route of administration, having regard to the likely route of human exposure [must be carried out] unless already provided as part of Annex IX requirements.¿ The guidance goes on further to stipulate that the test must be carried out unless:

The substance is known to be a genotoxic carcinogen and appropriate risk management measures are implement ¿ this does not apply as these substances are not genotoxic.

The substance is known to be a germ cell mutagen and appropriate risk management measures are implemented ¿ as above, this does not apply as these substances are not genotoxic.

The substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure¿and there is no or no significant human exposure ¿ This does not fully apply as, although the toxicological studies provide little if any evidence for systemic toxicity, the substances may be absorbed and exposure may occur.

The guidance goes on to state that:

If a substance is known to have an adverse effect on fertility, meeting the criteria for classification as Repr Cat 1 or 2:R60 and the available data are adequate to support a robust risk assessment, then no further testing for fertility will be necessary ¿ This does not apply as the substances are not classified for reproductive effects and there are no data suggesting that they adversely affect fertility, and

If a substance is known to cause developmental toxicity, meeting the criteria for classification as Repr Cat 1 or 2:R61 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. ¿ This does not apply since the substances have been tested for developmental toxicity and show no effects in studies conducted up to limit dose levels (e.g., 1000 mg/kg).

Accordingly, in accordance with REACH guidelines, it is proposed that either a modified one generation reproductive toxicity study (OECD 415) or a two generation reproductive toxicity test (OECD 416) as is most consistent with guidance on testing strategies be conducted. However, as described in more detail below, it seems unlikely that these substances would have any effect on fertility, so a scientific justification for such testing, is less clear.


Review of data summarized in IUCLID:

(1) Reproductive Toxicity Data ¿ Although two generation toxicity studies of substances in these categories have not been conducted, there are data from related studies of several types.

(i) There is a dominant lethal study of a C9-C14, 2-25% aromatics substance. The study produced negative effects. Accordingly, there is no evidence of transmissible effects associated with exposure to this substance.

(ii) There are two reproductive toxicity screening tests of substances in the C9-C14 <2% aromatics category. In both cases the substances were tested at limit doses, and neither produced an effect on fertility. Finally, a two generation reproductive toxicity study was conducted on C9 aromatic hydrocarbons, a group of constituents equivalent to the aromatic fraction of C9-C14, 2-25% aromatic solvents (McKee et al., 1990). There were no effects on fertility and no other effects which were not secondary to systemic toxicity at the highest exposure level used in this study.

(iii) There have been two generation reproductive toxicity studies on other hydrocarbon solvents and key constituents including cyclohexane (Kreckman et al., 2000) and commercial hexane (Daughtrey et al., 2006). There were no effects on fertility in these studies. Similarly there were no effects on fertility in reproductive toxicity studies of other complex hydrocarbon substances including gasoline and jet fuel (McKee et al., 2000; Mattie et al., 2000). The available evidence suggests that hydrocarbons of this type are not reproductive toxicants.

(2) Developmental toxicity tests of substances in the C9-C14, 2-25% aromatics; C9-C14, < 2% aromatics and C14-C20 < 2% aromatics have been conducted. None of these substances has produced any evidence of developmental effects in studies conducted to limit doses. There is no evidence that hydrocarbon solvents of this type are developmental toxicants.

(3) Repeated Dose Studies ¿ There have been numerous repeated dose studies of hydrocarbon solvents in all of these categories. In none of these was there any evidence of toxicity to the reproductive organs. Thus it is apparent that the male and female reproductive tracts are not affected by exposure to these hydrocarbon solvents.

(4) Mutagenicity Testing ¿ Data for representative substances from all of these solvent categories indicates that they are not mutagenic. Thus effects on sperm production resulting from exposure to these solvents, is not expected.

Interim Risk Measures

It is indicated in the guidance for testing proposals (8.1.3.4), that ¿ the registrant has to implement and/or recommend to downstream users, interim risk management measures while awaiting the outcome of the Agency decision regarding the test proposal and the subsequent conduction of the test proposed.

Based on the information for these and similar substances summarized above, it does not appear that these substances would be reproductive toxicants or that the reproductive system would be a target organ. Accordingly, classification for effects on fertility is not proposed, and there is currently no reason to believe that the proposed risk management measures which are based on the existing data would not also be appropriate as interim measures to be used until the testing is completed.

Specific Proposal:

It is proposed to conduct a two generation reproductive toxicity test on a substance selected from category 3 (C9-C14 aliphatic solvents, 2-25% aromatics) (see attachment 1). A substance of this type seems an appropriate choice in that it represents a large production volume and widespread use both in industry and in the general population. It also seems reasonable that a substance of this type would be a reasonable worst case with respect to other high molecular weight aliphatic solvents in that it is more volatile (i.e., potentially leading to higher exposures) than substances in categories 4 (C14-C20 aliphatic solvents, 2-30% aromatics) and 9 (C9-C14 aliphatic solvents, < 2% aromatics) and it has a higher aromatic content than substances in categories 8 (C9-C14 aliphatic solvents, <2% aromatics) and 9.

The test would be in accordance with the test guidelines for studies of this type (either a modified OECD 415 test or an OECD 416 test) and in accordance with Good Laboratory Practice (GLP). The submitters will make every effort to initiate this test within 6 months of the acceptance of this testing proposal by ECHA.

The submitters propose that the results of this test would apply to other substances in category 3 and would normally be used to read across to all of the other substances in categories 3 as well as those in categories 4, 8 or 9. However, as reproductive toxicity would not be expected, should it be observed, the submitters reserve the right to conduct additional testing as necessary to clarify the results and to understand the extent to which these results apply to substances in the other categories.

References

McKee, R. et al. (1990). The reproductive and developmental toxicity of high flash aromatic naphtha. Toxicology and Industrial Health 6:441-460.

McKee, R. et al. (2000). Assessment in rats of the reproductive toxicity of gasoline from a gasoline vapor recovery unit. Reproductive Toxicology 14:337-353.

Daughtrey, W.C. et al. (1994). Two-generation reproduction study on commercial hexane solvent. J. Appl. Toxicol. 14(5), 387-393.

Kreckman, K. et al. (2000). Inhalation developmental toxcity and reproduction studies with cyclohexane. Drug, Chem, Toxicol. 23(4):555-573.

Mattie DR, Marit GB, Cooper JR., Sterner TR, Flemming CD. (2000). Reproductive effects of JP-8 Jet Fuel on Male and Female Sprague-Dawley Rats After Exposure by Oral Gavage. Human Effectiveness Directorate, Air Force Research Laboratory. Wright Patterson AFB, Ohio. AFRL-HE-WP-TR-2000-0067.

Attachment 1 ¿ Substances covered by Testing Proposal

(i) Category 3 - C9-C14 Aliphatics (2-25% aromatics)

Hydrocarbons, C9-C10, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)
Hydrocarbons, C10-C13, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)
Hydrocarbons, C8-12, nalkanes, isoalkanes, cyclics, aromatics (2-25%)
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)
Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)

(ii) Category 4 ¿ C14-C20 Aliphatics (2-30% aromatics)

Hydrocarbons, C14-C18, n-alkanes, isoalkanes, cyclics, aromatics (2-30 %)
Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, aromatics (2-30 %)

(iii) Category 9 ¿ C9-C14 Aliphatics (< 2% aromatics)

Hydrocarbons, C9-C11, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C9-C10, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C10-C13, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C10-C13, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C13-C15, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C11-C14, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C10-C12, isoalkanes, <2% aromatics
Hydrocarbons, C11-C12, isoalkanes, <2% aromatics
Hydrocarbons, C11-C13, isoalkanes, <2% aromatics
Hydrocarbons, C10-C13, n-alkanes, < 2% aromatics
Hydrocarbons, C11-C14, n-alkanes, < 2% aromatics
Hydrocarbons, C9-C11, cyclics, <2% aromatics
Decane
Undecane
Dodecane
Tridecane
Tetradecane
Isododecane
Hydrocarbons, C10-C14, n-alkanes, <2% aromatics
Hydrocarbons, C10-C14, n-alkanes, isoalkanes, < 2% aromatics
Hydrocarbons, C12-C15, n-alkanes, isoalkanes, cyclics, < 2% aromatics
Hydrocarbons, C12-C16, isoalkanes, cyclics, <2% aromatics

(iv) Category 9 ¿ C14-C20 Aliphatics (< 2% aromatics)

Hydrocarbons, C13-C18, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C14-C18, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C16-C20, n-alkanes, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C16-C20, n-alkanes, isoalkanes, <2% aromatics
Hydrocarbons, C13-C16, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C14-C19, isoalkanes, cyclics, <2% aromatics
Hydrocarbons, C14-C17, n-alkanes, < 2% aromatics
Hydrocarbons, C14-C20, n-alkanes, < 2% aromatics
Pentadecane
Hexadecane
Isohexadecane
Heptadecane
Octadecane
Nonadecane
Icosane
Isoeicosane
Hydrocarbons, C14-C20, n-alkanes, isoalkanes, <2% aromatics

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion