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Description of key information

No oral or dermal repeated dose toxicity studies were identified for 2-methylbutane.  Additionally, no read-across oral or dermal repeated dose toxicity studies were identified for n-pentane or cyclopentane.  With regard to the inhalation route, the following repeated dose toxicity studies were identified: a supporting subacute inhalation study (OECD 412) from n-pentane, in which the NOAEC was determined to be 1000 ppm based on an increase in calcium and phosphorus levels in male rats; a key 90-day inhalation study (OECD 413) on n-pentane that showed that at concentrations ≤ 20,000 mg/m3 n-pentane did not cause any observable adverse effects in male or female rats; a key 90-day inhalation study (OECD 413) on 2-methylbutane, in which the NOEC of the test substance was found to be > 2220 ppm for subchronic toxicity, and ≥ 6646 ppm for neurotoxicity; and a key 90-day study (non-guideline) on cyclopentane that showed no abnormalities in rats during clinical, neurofunctional, and clinico-pathological examinations in any of the test groups, as well as no changes found during necropsy or in the histo- and neuropathological examinations. 

Key value for chemical safety assessment

Additional information

No oral or dermal repeated dose toxicity studies were identified for 2-methylbutane. Additionally, no read-across oral or dermal repeated dose toxicity studies were identified for n-pentane or cyclopentane. Supporting repeated dose toxicity studies via the oral route were identified for 2-methylbutane and n-pentane. However, several study limitations are noted when comparing each of the study’s methods to OECD 407. First, female rates were not used in the study. Second, the selected dose levels did not cover an appropriate range (only two dose groups were used, and both were at fairly high doses for a substance that can be aspirated). Third, the substance was administered 5 days/week instead of 7. Fourth, body weight measurements were only taken twice during the experiment (prior to dosing and at the scheduled sacrifice). Fifth, the only post-necropsy examinations were of the kidney. Finally, functional observations, haematology analysis, urinalysis and other post-necropsy examinations were not conducted. Consequently, these studies were not considered key. With regard to the inhalation route, the following repeated dose toxicity studies were identified: a supporting subacute inhalation study from n-pentane; a key 90-day inhalation study (OECD 413) on n-pentane; a key 90-day inhalation study (OECD 413) on 2-methylbutane (i.e., 33% 2-methylbutane); and a key 90 -day study (non-guideline) on cyclopentane. Information on these studies is presented below.

One key 90-day inhalation toxicity study on light alkylate naphtha distillate-2 (i.e., 33% 2-methylbutane; CAS number64741-66-8)was identified (Schreiner, 1998). In this study, the test substance was administered to 12 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 668, 2220, or 6646 ppm (0, 2.4, 8.1, and 24.3 mg/m3) for 6 hours per day, 5 days/week for a total of 13 weeks. There were no treatment-related effects in mortality, clinical signs, neurotoxicity, body weight, or food consumption. Significant effects noted in haematology and clinical chemistry were not determined to be toxicologically relevant, and kidney weight increases found in high-dose males were not determined to be relevant to human toxicity risk assessments. The LOEC for subchronic toxicity is6646 ppm, based on haematology, clinical chemistry and organ weights. The NOEC is > 2220 ppm (equivalent to 8.1 mg/m3) for subchronic toxicity and6646 ppm for neurotoxicity. However, because this study tested a substance that is only 33% 2-methylbutane, the results may be of limited value.

One read-across subchronic inhalation toxicity study on n-pentane was available. In this study, n-pentane was administered to 10 rats/sex/concentration by whole body exposure at analytical concentrations of 5097±79; 10,203±151; or 20,483±734 mg/m36 hours a day, 5 days a week for 13 weeks (Whitman, 1997). Animals were sacrificed in the fourteenth week after 3 (males) or 4 (females) exposures. There were no treatment-related effects observed for clinical signs, body weight, food consumption, hematology, clinical chemistry, ophthalmology, gross pathology, organ weights, or histopathology. Based on this information, an NOAEC was established at 20,000 mg/m3. 

An additional supporting, subacute inhalation study on n-pentane was identified (Stadler, 2001). This study was not classified as key because of its short duration (14 days). Overall conclusions regarding the LOAEC and NOAEC values also are in disagreement with the 90 -day inhalation study described above. The only finding was a slight, but statistically significant and dose-related, increase in serum calcium accompanied by increased phosphorous levels in 3000- and 10,000-ppm rats. The NOAEC was 1000 ppm (equivalent to 2951 mg/m3) based on the increase in calcium and phosphorus.

 

One read-across 90 -day repeated dose inhalation study is available for cyclopentane (Gamer, 1998). Fifteen male and 15 female Wistar rats per test group were exposed to cyclopentane vapour (pure) at concentrations of 5, 10, 30 mg/L and cyclopentane vapour (technical grade) at a concentration of 30 mg/L for 6 hours per weekday for 90 days. A concurrent control group was exposed to clean air. General observations were performed twice during weekdays and once during weekends and holidays. Clinical examinations were performed once every weekday and on the day following exposure. Neurofunctional test were performed in 10 animals per sex, once before the exposure period and three times during the exposure period. A hematological and clinicochemical examination was performed in 10 animals per sex at the end of the exposure period. A complete necropsy was performed on 10 animals per sex, which included weighing of selected organs and gross pathological evaluation. Five animals per sex, of those subject to neurofunctional testing, were sacrificed by perfusion fixation and examined neuropathologically. Subchronic inhalation exposure to up to 30 mg/L of cyclopentane vapour (i.e., technical grade or high purity) did not cause a substance related toxic effect. The NOAEC concentration is 30 mg/L (equivalent to 30,000 mg/3) under the conditions of this study.    

Justification for classification or non-classification

Using key and read-across information from repeated dose inhalation toxicity studies performed with pentanes, it can be assumed that 2 -methylbutane does not produce significant systemic toxicity when administered via inhalation. Although there were no key repeated dose toxicity studies identified for either oral or dermal exposure, physiochemical data suggests that absorption via the oral or dermal route is not significant and that oral and dermal toxicity is not a significant cause for concern. Additionally, acute oral toxicity data suggests that absorption via the oral route is not significant and that oral toxicity is not a significant cause for concern. Dermal absorption is also expected to be not significant. Therefore, 2 -methylbutane is not classified under EU Dangerous Substances Directive 67/548/EEC or CLP EU Regulation 1272/2008 for repeated dose toxicity.