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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

Oral

Decane, a read-across substance to Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, was examined for reproductive toxicity in a 28 day combined repeated dose toxicity study with the reproduction / developmental toxicity screening test (OECD TG 422).   The substance was administered oral gavage at a dose of 0, 25, 150, or 1000 mg/kg/day to groups of Sprague-Dawley rats. It was concluded that the substance did not induce reproductive toxicity in the parental animals and no effects on the endocrine system were observed.  Therefore, the NOAEL was determined to be >=1000 mg/kg bw/day. 

 

Undecane, a read-across substance to Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, was examined in a reproduction / developmental toxicity screening test (OECD TG 421).   The substance was administered by oral gavage at a dose of 0 (vehicle), 100, 300, 1000 mg/kg/day to groups of rats. It was concluded that the substance did not induce reproductive toxicity in the parental animals and no effects on the endocrine system were observed.  Therefore, the NOAEL was determined to be >=1000 mg/kg bw/day. 

Based on this study and the lack of systemic toxicity, Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, are not expected to be reproductive toxicants.

 

Inhalation

Hydrocarbons, C9-12, n-alkanes, isoalknes, cyclics, aromatics (2 -25%), a read-across substance to Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, was examined for reproductive toxicity in a reproduction / developmental toxicity screening test (OECD TG 421).   The substances was administered by inhalation at a dose of 0,100, and 300 ppm to groups of rats. It was concluded that the substance did not induce reproductive toxicity in the offspring or in the parental animals.  Therefore, the NOAEL was determined to be >=300 ppm (1720 mg/m3).


Short description of key information:
Reproduction Toxicity

Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) – Oral Administration - The NOAEL for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day.
Reproduction / Developmental Toxicity Screening Test (OECD TG 421) - Oral Administration - The NOAEL for developmental toxicity was 1000 mg/kg/day and the NOAEL for reproductive toxicity was 1000 mg/kg/day.
Reproduction / Developmental Toxicity Screening Test (OECD TG 421) - Inhalation Administration - The NOAEL for developmental toxicity was >=300 ppm (1720 mg/m3).

Effects on developmental toxicity

Description of key information
Developmental Toxicity 
Prenatal Developmental Toxicity Study (OECD TG 414) - Inhalation Administration - The maternal and developmental NOAELs were greater than 900 ppm.
Additional information

Oral:

Decane, a read-across substance to Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids,was examined for reproductive toxicity in a 28 day combined repeated dose toxicity study with the reproduction / developmental toxicity screening test (OECD TG 422).   The substance was administered oral gavage at a dose of 0, 25, 150, or 1000 mg/kg/day to groups of Sprague-Dawley rats. It was concluded that the substance did not induce developmental toxicity in the parental animals and no effects on the endocrine system were observed.  Therefore, the NOAEL was determined to be >=1000 mg/kg bw/day. 

 

Undecane, a read-across substance to Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids,was examined in a reproduction / developmental toxicity screening test (OECD TG 421).   The substance was administered by oral gavage at a dose of 0 (vehicle), 100, 300, 1000 mg/kg/day to groups of rats. It was concluded that the substance did not induce developmental toxicity in the parental animals and no effects on the endocrine system were observed.  Therefore, the NOAEL was determined to be >=1000 mg/kg bw/day.

 

Inhalation:

Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, are not developmental toxicants. In two read-across developmental studies (OECD TG 414), pregnant dams were dosed by inhalation with 0, 300, or 900 ppm during gestational days 6 through 15.  No adverse maternal or fetal effects were noted at any dose level. Thus, Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, are not expected to produce any maternal or fetal toxicity or any developmental effects in rats. Based on the study results, the maternal and developmental toxicity NOAEL is >= 900 ppm (5220 mg/m3). Based on this study and the lack of systemic toxicity, Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, are not expected to be developmental toxicants.

Hydrocarbons, C9-12, n-alkanes, isoalknes, cyclics, aromatics (2 -25%), a read-across substance to Raffinates (Fischer-Tropsch), C10-C25-branchedhydrocarbon fluids, was examined for reproductive toxicity in a reproduction / developmental toxicity screening test (OECD TG 421).   The substances was administered by inhalation at a dose of 0, 100, and 300 ppm to groups of rats. It was concluded that the substance did not induce reproductive toxicity in the offspring or in the parental animals.  Therefore, the NOAEL was determined to be >=300 ppm (1720 mg/m3).

Toxicity to reproduction: other studies

Additional information

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 (summarized above):

 

(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.

 

 

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.

 

, 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,. AFRL-HE-WP-TR-2000-0067.

 

Justification for classification or non-classification

These findings do not warrant classification of Raffinates (Fischer-Tropsch), C10-C25-branched hydrocarbon fluids, as a reproductive or developmental toxin under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.

Additional information