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Key value for chemical safety assessment

Effects on fertility

Description of key information
No data identified.
Additional information

Key studies were not available on the reproductive toxicity of 2-methylbutane.  The literature justifies the use of the read-across approach to fill toxicokinetics and reproductive toxicity gaps for 2 -methylbutane using data on cyclohexane.  Cyclohexane is oxidized to cyclohexanol, and excretion and conjugation of cyclohexanol is identical to 2-methylbutane.  Therefore, data on the toxicokinetics and reproductive toxicity of cyclohexane can be used to fill data gaps for 2 -methylbutane when relevant data for this chemical is missing.

 

In a two-generation inhalation reproduction study, cyclohexane was administered to 30 Crl: CD BR rats per sex per dose per group at dose levels of 0, 500, 2000, or 7000 ppm. Whole body exposures were conducted, and animals were exposed 6 hours/day, 5 days/week including holidays. For both generations, animals were exposed prior to mating, and pregnant females were exposed daily during gestation days 0 through 20; exposure ceased from gestation day 21 until lactation day 4. Exposure resumed on lactation day 5 until litters were weaned. Males continued to be exposed 5 days/week until sacrificed. Neonates were not exposed during lactation. Pups were culled on lactation day 4; however, there were no additional details provided on the culling procedure OECD 416. Decreased sound stimulus observed in 2000- and 7000-ppm animals (both sexes in both generations) was considered to be the most sensitive indicator of parental toxicity. This effect was an expected outcome of overexposure. Additional parental effects include decreased mean body weight and mean body weight gain in 7000 -ppm P and F1 rats. Decreased male body weights observed at 7000 ppm were considered to be an artefact of body-weight deficits established as pups. Although not established by the study authors, the parental systemic LOAEC appears to be 2000 ppm (6880 mg/m3) in males and females, based on decreased sound stimulus. The parental systemic NOAEC appears to be 500ppm (1720 mg/m3) in males and females. Mean pup weight was statistically significantly reduced from postpartum day 7 throughout the remainder of the 25-day lactation period for 7000-ppm F1 and F2 litters. The offspring LOAEC is 7000 ppm (24,080 mg/m3) based on decreased litter weights. The offspring NOAEC is 2000 ppm (6880 mg/m3). There were no adverse treatment effects related to reproductive function. Consequently, the parental and reproductive NOAEC appears to be 7000 ppm (24,080 mg/m3). The offspring NOAEC was selected because it is the most health-conservative value.


Short description of key information:
One key two-generation reproductive toxicity study (OECD 416) on cyclohexane was identified. The reported NOAEC was 2000 ppm (6880 mg/m3) for reproductive toxicity. Reproductive toxicity data were not available for 2-methylbutane.

Effects on developmental toxicity

Description of key information
Developmental toxicity data were not available for 2-methylbutane.  A read-across oral developmental study (OECD 414) was identified from n-pentane, in which n-pentane was administered to female rats from days 6 through 15 of gestation. There were no signs of maternal or developmental toxicity. The maternal and developmental NOAEL is 1000 mg/kg/day. Data are also available on the developmental toxicity of cyclohexane. Cyclohexane was not a developmental toxin in female rabbits after exposure to 7000 ppm (24,080 mg/m3) during pregnancy, and cyclohexane was not a developmental toxin in female rats exposed during pregnancy. The foetal NOAEC was 7000 ppm, and the maternal NOAEC was 500 ppm (based upon transient sedation) or 2000 ppm (based upon significant reductions in absolute and adjusted body weight gain). 
Additional information

Developmental toxicity data were not available for 2-methylbutane. One read-across study is available on the developmental toxicity of n-pentane. n-Pentane was orally administered via gavage to 25 Crl: CD BR VAF rats per dose at dose levels of 0, 100, 500, or 1000 mg/kg bw/day from days 6 through 15 of gestation. There were no signs of maternal toxicity at any dose level. There were no treatment-related changes in mean body weight, body weight gain, uterine weight, corrected body weight, food consumption, or uterine implantation data. There were no treatment-related mortalities or clinical signs of toxicity. A maternotoxic dose was not used. However, the highest dose tested was 1000 mg/kg/day, and no adverse effects were observed.  In general, the highest dose tested does not need to exceed 1000 mg/kg/day unless potential human exposure data indicate the need for higher doses. Therefore, the study reported a maternal NOAEL of 1000 mg/kg/day. There were no signs of developmental toxicity at any dose level. There were no treatment-related changes in growth or increased fetal death. There were no changes in total malformations or variations. The developmental NOAEL is 1000 mg/kg/day.

 

In addition, a study was identified on the developmental toxicity of rats and rabbits for cyclohexane. Whole body exposures were used for both rats and rabbits at concentrations of 0, 500, 2000, or 7000 ppm. For rats in the 7000 ppm group, statistically significant reductions were observed in overall and adjusted maternal body weight gain while a transient diminished or absent response to a sound stimulus was apparent at 2000 ppm. Therefore the maternal no-observed-adverse-effect concentration (NOAEC) was 500 ppm (1720 mg/m3) (based upon transient sedation) or 2000 ppm (6880 mg/m3) (based upon significant reductions in overall and adjusted body weight gain).  No compound-related evidence of developmental toxicity was observed at any test concentration, equivalent to a NOAEC of 7000 ppm (24,080 mg/m3). For rabbits, no compound-related maternal effects were observed at concentration levels of 7000 ppm and below. Therefore the maternal NOAEC for rabbits was 7000 ppm. No compound-related evidence of developmental toxicity was observed at any test concentration. The developmental NOAEC for rabbits was 7000 ppm (24,080 mg/m3), the highest concentration tested and the highest concentration permissible under national fire protection association standards.

 

The literature justifies the use of the read-across approach to fill toxicokinetics and reproductive toxicity gaps for 2-methylbutane using data on cyclohexane.  Cyclohexane is oxidized to cyclohexanol, and excretion and conjugation of cyclohexanol is identical to 2-methylbutane.  Therefore, data on the toxicokinetics and reproductive toxicity of cyclohexane can be used to fill data gaps for 2-methylbutane when relevant data for these chemicals are missing.

Justification for classification or non-classification

With a reproductive NOAEL of 7000 ppm, cyclohexane showed no adverse treatment-related effects regarding reproductive function. Therefore, cyclohexane does not meet the criteria for classification as a reproductive toxicant. Based on read-across information from cyclohexane, pentanes also do not meet the criteria for classification as a reproductive toxicant under EU Dangerous Substances Directive 67/548/ECC or CLP EU Regulation 1272/2008 (GHS aligned).

 

With a maternal and developmental NOAEL of 1000 mg/kg/day, n-pentane showed no maternal or developmental treatment-related effect and does not meet the criteria for classification as either a maternal or developmental toxicant. Therefore, pentanesnot meet the criteria for classification as either a maternal or developmental toxicant under EU Dangerous Substances Directive 67/548/ECC or CLP EU Regulation 1272/2008 (GHS aligned).