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Effects on fertility

Description of key information
No other concerns identified.
Additional information

Two reproductive/developmental screening studies were identified, one within category and the other a read-across study from isomerised olefins; alpha, internal, linear and branched - single carbon number. In key a reproductive/developmental screening study (Thorsud, 2003a), alkenes, C6 dissolved in corn oil were administered via oral gavage to F0 male and female Sprague-Dawley rats at dose levels of 100, 500 and 1000 mg/kg/day for at least 4 weeks. There was no mortality or adverse signs of toxicity observed at any dose level and F0 mating, fertility indices, mean gestation lengths, mean number of pups delivered, F1 live birth index, F1 viability index, F1 pups per litter, and F1 pup sex ratios were comparable between control and treatment groups. Gross necroscopy of F0 females revealed no significant treatment-related findings. Organ weight determinations in F0 rats did not reveal any significant difference between treatment and control animals. Based on the lack of significant adverse clinical effects, the reproductive toxicity NOAEL for alkenes, C6 was reported as 1000 mg/kg. No adverse fertility effects were reported in either screening study; therefore the NOAEL was 1000 mg/kg bw/day for both studies (highest dose tested). 

 

In a read-across reproductive/developmental screening study from single carbon number isomerised olefins, octadecene, dissolved in corn oil, was administered to Sprague-Dawley rats (12 sex/dose) by gavage at dose levels of 0, 100, 500, or 1000 mg/kg/day for 42 days (Thorsud, 2003b). There was no mortality observed in animals in the control, 100, 500, or 1000 mg/kg dose group. No treatment-related or dose-dependant signs of clinical toxicity were noted in rats at any dose level. Mean body weight, body weight change and food consumption was observed to be normal in all treatment animals when compared with the controls. Parent female mating, fertility, and mean gestation lengths were observed to be comparable with controls as were the mean number of pups delivered and live birth and viability indices. Mean live pups/litter and sex ratio/litter were also found to be normal and comparable to those observed in control animals. Gross necroscopy revealed no remarkable differences between octadecene-treated and control animals. There were no microscopic lesions observed in male or female rats treated with octadecene and no statistically significant differences in absolute or relative epididymides weight were noted in treated males when compared with control males. Based on the lack of adverse systemic effects observed in the study, the reproductive toxicity NOAEL for octadecene was reported as 1000 mg/kg.

 

No adverse fertility effects were reported in either screening study (OECD 421 and/or OECD 422); therefore the NOAEL was 1000 mg/kg bw/day for both studies (highest dose tested). The weight of evidence presented by these studies suggests that higher olefin substances, as a group, are unlikely to present a significant hazard potential to fertility; therefore a DNEL for this endpoint is not necessary.  However, although reassuring, such information does not fully meet the REACH information requirement for this endpoint; therefore a two-generation study (OECD 416) is proposed in the registration dossier.  Results from this study, when available, will be reviewed, and if justified, a DNEL will be proposed at that time.

 

Justification for Read Across:

Several criteria justify the use of the read across approach to fill data gaps for multiple carbon number isomerised olefin substances using single carbon number isomerised olefinsubstance analogues. Studies indicate that changing the carbon number, the location of the double bond, or adding branching does not measurably alter the effects on mammalian health endpoints. There is a consistent toxicity potency pattern for isomerised olefins with a range of carbon numbers and they are considered to have minimal acute toxicity potential. Genotoxicity studies indicate that these materials are not mutagenic. No adverse systemic toxicity was observed in a combined 28 -day systemic and reproductive/developmental screening study in which rats were exposed to octadecene. The toxicological profile of single carbon number isomerised olefins described above indicates a low hazard potential for human health. Since multiple carbon number isomerised olefins are comprised of a mixture of single carbon number isomerised olefins, no significant toxicological differences are expected between the two categories of substance and read across between these two categories can be justified.


Short description of key information:
A key reproductive/developmental screening study (OECD 422) from alkenes, C6 (isomerised olefins; alpha, internal, linear and branched – multiple carbon numbers) was identified. Based on the lack of significant adverse effects, the reproductive toxicity NOAEL for alkenes, C6 was reported as 1000 mg/kg. One read-across reproductive/developmental screening study (OECD 421) from octadecene was identified. Based on the lack of adverse systemic and reproductive effects observed in the study, the reproductive toxicity NOAEL for octadecene was reported as 1000 mg/kg.

Effects on developmental toxicity

Description of key information
A key reproductive/developmental screening study (OECD 422) from alkenes, C6 (isomerised olefins; alpha, internal, linear and branched – multiple carbon numbers) was identified. Based on the lack of significant adverse foetal effects, the developmental NOAEL for alkenes, C6 was reported as 1000 mg/kg. One read-across reproductive/developmental screening study (OECD 421) from octadecene was identified. Based on the lack of adverse effects observed in the study, the developmental NOAEL for octadecene was reported as 1000 mg/kg.  Alkenes, C11/C13/C14 are not expected to cause developmental toxicity.
Additional information

Two reproductive/developmental screening studies were identified, one within category and the other a read-across study from single carbon number isomerised olefins.

 

In a key reproductive/developmental screening study, alkenes, C6 dissolved in corn oil were administered via oral gavage to F0 male and female Sprague-Dawley rats at dose levels of 100, 500 and 1000 mg/kg/day for at least 4 weeks. There were no adverse signs of toxicity observed at any dose level and the mean number of pups delivered, F1 live birth index, F1 viability index, F1 pups per litter, and F1 pup sex ratios were comparable between control and treatment groups. Based on the lack of significant adverse clinical effects, the developmental toxicity NOAEL for alkenes, C6 was reported as 1000 mg/kg.

 

In a read-across reproductive/developmental screening study fromsingle carbon number isomerised olefins, octadecene, dissolved in corn oil, was administered to Sprague-Dawley rats (12 sex/dose) by gavage at dose levels of 0, 100, 500, or 1000 mg/kg/day for 42 days. Mean live pups/litter and sex ratio/litter were also found to be normal and comparable to those observed in control animals. Gross necroscopy revealed no remarkable differences between octadecenes-treated and control animals. There were no statistically significant differences observed in pup weights on lactation days 1 and 4 and gross necroscopy on lactation day 4 revealed no treatment-related effects. Based on the lack of adverse systemic effects observed in the study, the developmental toxicity NOAEL for octadecene was reported as 1000 mg/kg.

 

No adverse developmental effects were reported in either screening study (OECD 421 and/or OECD 422); therefore the NOAEL was 1000 mg/kg bw/day for both studies (highest dose tested).  The weight of evidence presented by these studies suggests that higher olefin substances, as a group, are unlikely to present a significant hazard potential to foetal development; therefore a DNEL for this endpoint is not necessary.  However, although reassuring, such information does not fully meet the REACH information requirement for this endpoint; therefore a developmental study (OECD 414) is proposed in the registration dossier.  Results from this study, when available, will be reviewed, and if justified, a DNEL will be proposed at that time.

 

Justification for Read Across:

Several criteria justify the use of the read across approach to fill data gaps for multiple carbon number isomerised olefin substances using single carbon number isomerised olefinsubstance analogues. Studies indicate that changing the carbon number, the location of the double bond, or adding branching does not measurably alter the effects on mammalian health endpoints. There is a consistent toxicity potency pattern for isomerised olefins with a range of carbon numbers and they are considered to have minimal acute toxicity potential. Genotoxicity studies indicate that these materials are not mutagenic. No adverse systemic toxicity was observed in a combined 28 -day systemic and reproductive/developmental screening study in which rats were exposed to octadecene. The toxicological profile of single carbon number isomerised olefins described above indicates a low hazard potential for human health. Since multiple carbon number isomerised olefins are comprised of a mixture of single carbon number isomerised olefins, no significant toxicological differences are expected between the two categories of substance and read across between these two categories can be justified.

Justification for classification or non-classification

No developmental or 2-generation reproductive toxicity data were available for alkenes, C11/C13/C14. Two screening reproductive/developmental toxicity studies from structural analogues related to alkenes, C11/C13/C14 (i. e., octadecene and alkenes, C6) showed no effects on reproductive parameters. Although results from the developmental reproductive screening study for octadecene and alkenes, C6 showed no reproductive or developmental effects at the highest dose tested, and while the data in combination present a reasonable weight of evidence upon which to judge the reproductive and developmental toxicity of themultiple carbon number isomerised olefins, these study results cannot meet the requirement for results from a complete developmental or two-generation reproductive study. Nonetheless, the results are considered adequate and do not raise concern with regard to classification of alkenes, C11/C13/C14 as toxic for reproduction or as developmental toxicants under EU Dangerous Substances Directive 67/548/ECC or CLP EU Regulation 1272/2008 (GHS aligned).