2-methylbutan-1-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Several data were used in a weight of evidence approach for the assessment of developmental toxicity. The whole database was considered reliable and suffcient for assessment.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction

No data exist for 2 -methylbutan-1 -ol on toxicity to reproduction. Therefore read-across was performed to two other members of the category. A detailed read-across justification is attached in IUCLID chapter 13.

 

The substance 3-methylbutan-1-ol was tested in a modified extended one-generation study according to OECD 443 and in compliance with GLP regulations (BASF 2020).  The test substance was administered continuously to groups of 25 male and female Wistar rats in drinking water of different concentrations (0, 1250, 3750 and 12500 ppm). Pups of the F1 litter were selected and assigned to 2 different cohorts. There were no test substance-related mortalities, adverse clinical observations or effects on food consumption in any of the groups. Body weights and body weight change of low and mid-dose F0 males and females, as well as all male and female F1 rats, were not affected by treatment.The body weights of the high-dose F0 males were below the concurrent control values from premating day 28 onwards until the end of the study, most of the time the difference was statistically significant. The average final in-life weight of these males was 7% below control. Accordingly, body weight gain was decreased compared to control during premating days 0 - 7 and 0 - 70 (about 8% and 9%, respectively). It was suggested that it was treatment-related and was considered as a sign of an adverse systemic effect. Regarding clinical pathology, pathology, organ weights, macroscopy, microscopy, and differential ovarian follicle count no treatment-related adverse findings were noted. No effects on fertility, reproductive performance, and developmental toxicity were reported.A statistically significant delay in vaginal opening of about one day beyond the concurrent control was observed in the female F1 offspring of the high-dose group (12500 ppm). The delay is also slightly (less than a day) beyond the historical control range of the test facility. However, pubertal age in test groups 01 (1250 ppm) and 02 (3750 ppm) as well as in concurrent control were all above the upper limit of the historical range, while the statistically significantly higher value in test group 03 (12500 ppm) was again only slightly above concurrent control. This apparent delay was solely due to 4 high-dose individuals entering puberty after the age of 36 days. This and the still rather small average difference to the control of about one day indicates that the later onset of puberty in test group 03 is not a specific effect on the timing of puberty. In addition, none of the other endocrine-sensitive parameters like anogenital distance, or estrous cyclicity in the F1A and B offspring brought beyond puberty, or the integrity of sexual organs in these females including differential ovarian follicle count, indicated any effect of the test item. Thus, the apparently later entry of test group 03 into female puberty is likely to be incidental.Thus, the NOAEL for general, systemic toxicity is 3750 ppm (about 405 mg/kg bw/d) and 12500 ppm (about 1221 mg/kg bw/d in males and 1521 mg/kg bw/d in females) in F0 parental males and in F0 parental females as well as adolescent and adult F1 offspring, respectively. The NOAEL for fertility and reproductive performance for parental rats and developmental toxicity for F1 progeny is 12500 ppm, the highest tested dose.

 

3-methylbutan-1-ol was also tested in a Combined 28-Day Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD TG 422 and in compliance with GLP regulations (Kuraray Co. Ltd. 2008). The substance was administered to male and female Sprague-Dawley strain SPF rats by gavage at dose levels of 0 (control group), 30, 100 or 300 mg/kg bw for a total of 42 days to males (for 14 days before mating throughout the mating period up to the day before necropsy) and for a total of 41 to 53 days to females (for 14 days before mating throughout the mating and gestation periods up to day 4 of lactation) to examine its repeated dose toxicity and reproductive and developmental toxicity. For the males and females in the 0 and 300 mg/kg bw groups, a 14-day recovery period was provided after administration for 42 days to examine reversibility of the toxic changes. The females in the recovery group were not subjected to mating. There were no test article-related effects on estrous cycle, number of days until copulation, copulation index, insemination index or fertility index. There were no test substance-related effects on delivery index, length of gestation period, number of corpora lutea, number of implantation sites, implantation index, index of pre-implantation loss, index of post-implantation loss, index of stillborn pups, parturition index, number of liveborn pups, live birth index or sex ratio and there were no abnormalities in the lactation condition during the lactation period. In live born pups, there were no test substance-related changes in body weight, external observation, gross pathological findings or viability index on day 4 of lactation. Based on the results described above, it was judged that the no adverse effect levels for reproductive and developmental toxicity in male and female parent animals and pups were 300 mg/kg bw/day.

 

In another GLP-compliant OECD 422 study (BASF 2018), reaction mass of 2-methylbutan-1-ol and pentan-1-ol (EC 903 -139 -3) was administered daily as addition to the drinking water in different concentrations to groups of 10 male and 10 female Wistar rats to screen for potential systemic, reproductive and developmental toxicity. After a two-week premating period, these parental animals were paired and the females were allowed to give birth and bring up the offspring until sacrifice on PND 4 or PND 13. In males the overall mean dose of the test substance throughout the study was approx. 77 mg/kg body weight/day (mg/kg bw/d) in the 1250 ppm group, approx. 254 mg/kg bw/d in the 3750 ppm group and approx. 842 mg/kg bw/d in the 12500 ppm group; in females it was approx. 117 mg/kg body weight/day (mg/kg bw/d) in the 1250 ppm group, approx. 372 mg/kg bw/d in the 3750 ppm group and approx. 1239 mg/kg bw/d in the 12500 ppm group. In the clinical examinations of the F0 parental animals no clinical symptoms were caused by the test compound up to the high-concentration of 12500 ppm. In the in-depth investigations including the detailed clinical observation, the functional observational battery and the measurement of motor activity no treatment-related differences to control were observed at any concentration. Water consumption, food consumption and body weights / body weight gain did not show important test substance-related changes. A small decrease in food consumption of high-dose males as well as temporary increase of water consumption in high-dose females were not accompanied by any body weight changes or other clinical findings and thus not noteworthy enough to be considered adverse. Concerning clinical pathology (including thyroid hormone measurement) no treatment-related, adverse effects were observed up to a concentration of the compound of 12500 ppm in the drinking water. Regarding pathology, there were no treatment-related organ weight changes, gross lesions, and histopathological findings in male and female Wistar rats. Regarding fertility and reproductive performance, as well as pre-postnatal development no signs of toxicity were observed in male or female parental animals or their offspring of all test groups (1250, 3750, and 12500 ppm) during the entire study. Most F0 parental animals across all test groups proved to be fertile and those individuals failing to generate offspring did not show any specific gross or histopathological findings. There were no test article-related effects on estrous cycle, number of days until copulation, copulation index, insemination index, or fertility index. There were no test article-related effects on delivery index, length of gestation period, number of corpora lutea, number of implantation sites, implantation index, index of pre-implantation loss, index of post-implantation loss, index of stillborn pups, parturition index, number of liveborn pups, live birth index or sex ratio, and there were no abnormalities in the lactation condition during the lactation period. In live born pups, there were no test article-related changes in body weight, external observation, gross pathological findings or viability index on day 4 of lactation. Neither determination of anogenital distance/index not the count of nipple/areola anlagen revealed any treatment-related changes up to and including a concentration of the test item of 12500 ppm in the drinking water. This results in a calculated NOAEL of 1000 mg/kg bw for the assessment of adverse effects on reproduction at the screening level. 

This assessment is supported by a publication describing a subchronic study performed with pentan-1-ol and a study report of a subchronic study conducted with 3-methylbutan-1-ol:

 

In a subchronic repeated dose toxicity study conducted equivalent to OECD guideline 408, 15 ASH/CSE rats per sex and dose received doses of 50, 150, 1000 mg/kg bw/day pentan-1-ol in corn oil by gavage for 13 weeks (Butterworth et al. 1978). At necropsy all tissues were examined for gross abnormalities including the reproductive organs. No abnormalities in the reproductive organs were found by histological analysis. Therefore, the highest dose of 1000 mg/kg bw can be seen as the NOAEL regarding reproductive toxicity of pentan-1-ol.

 

In addition, repeated dose toxicity was investigated in a 90 day drinking water study performed according to OECD guideline 408 with 3-methylbutan-1-ol (BG-Chemie 1990). Ten Wistar rats per sex and dose received nominal doses of 80, 340 and 1250 mg/kg bw /day 3-methylbutan-1-ol in the drinking water for 3 months. At the end of the 3-month administration period all animals were sacrificed by decapitation and were assessed by gross pathology. Subsequently, a histopathological examination was carried out including the reproductive organs. Regarding toxicity to reproductive organs, no abnormalities were found by histological analysis. Thus, the highest dose level tested, 1250 mg/kg bw/day, was the NOAEL under the conditions of the study.

 

Taken together, there are no hints for a reproductive toxic potential, nor was any relevant systemic toxicity observed up to at least 1000 mg/kg bw subchronic exposure.  The available experimental data are sufficient to assess the potential toxicity to reproduction by 2-methylbutan-1-ol. No additional information nor a lower NOAEL would be expected. 

 

A detailed read across justification is atatched in IUCLID chapter 13.

Short description of key information:
Toxicity to reproduction (fertility):
- oral: NOAEL = 1000 mg/kg bw /day (Sprague-Dawley rat, OECD TG 443, drinking water, Read-across to CAS No. 123-51-3)
- No effects on reproductive organs after subchronic exposure (NOAEL 1000mg/kg, RA to CAS 71-41-0; NOAEL 1250 mg/kg, RA to CAS 123-51-3)

Effects on developmental toxicity

Description of key information

Toxicity to reproduction (development):
- inhalative: NOAEC = 14 mg/L air (maternal and developmental) (Sprague-Dawley rat, vapour inhalation, GD 1-19) - RA to 71-41-0
- inhalative: NOAEC = 10mg/L air (developmental toxicity) = sat. vapour conc. (rat and rabbit, OECD 414) - RA to 123-51-3

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

14 000 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Several data were used in a weight of evidence approach for the assessment of developmental toxicity. The whole database was considered reliable and sufficient for assessment.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity

No data from 2-methylbutan-1-ol studies on developmental toxicity is available. Therefore read-across with its structural analogues was done.

Developmental toxicity of 3-methylbutan-1-ol was investigated in a prenatal developmental study performed according to OECD test guideline 414 (BG-Chemie 1990). 25 Wistar rats were exposed to test substance vapours at 0.5, 2.5 and 10 mg/L air for 6 hours/day on days 6 - 15 of gestation. The number of corpora lutea, implantations, resorption sites and live fetuses per sex was recorded. Fetuses were examined for skeletal malformations or visceral abnormalities. As a result, a marginal and transient (days 6-9) retardation of bodyweight gain was observed in the dams of the highest dose group, while the fetuses did not show any embryo-/fetotoxic or teratogenic effects in all dose groups. Thus, the NOAEC was 2.5 mg/L air for maternal toxicity and 10 mg/L air for developmental toxicity.

In a similar study also performed according to OECD TG 414, Himalayan rabbits as second species were exposed to 3-methylbutan-1-ol substance vapours at 0.5, 2.5 and 10 mg/L air, 6 hours/day, on days 7 - 19 of gestation (BG-Chemie 1990). Animals were sacrificed on gestation day 29. Gravid uterus weight, number of copora lutea, implantation sites, early and late resorptions and live foetuses were recorded. All foetuses were examined for visceral and skeletal changes, including a head examination. The only effect was a decreased body weight in the high dose animals between gestation days 7 and 10, comparable to the findings in rats. In addition, signs of beginning eye irritation were observed in this group. Thus, the NOAEC was 2.5 mg/L air for maternal toxicity and 10 mg/L air for developmental toxicity in rabbits.

Developmental toxicity of pentan-1-ol was examined in a study, where 15 female, sperm-positive Sprague-Dawley rats were exposed to a concentration of 14 mg/L air, the highest vapour concentration technically achievable (Nelson et al. 1989). Thereby, the exposure duration was 7 hour/day on days 1 - 19 of gestation. At the end of the exposure period, the dams were sacrificed and ovaries and uterine content as well as fetuses were examined. The number of corpora lutea, implantations, resorption sites and live fetuses was recorded. One-half of the fetuses were examined for skeletal malformations, while the remaining fetuses were examined for visceral abnormalities. At 14 mg/L air, no overt maternal toxicity was observed. Overall feed consumption was lower than in controls, but water consumption remained unchanged. Although the weight gain was slightly decreased, this effect did not reach statistical significance. The number of corpora lutea, resorptions, gender ratio and fetal weights were also not affected by treatment. Although small reversible delays in ossification of the caudal vertebrae, the sternum, the metacarpals and the hind paw phalanges were reported, these effects were not statistically significant. In addition, no malformations of the fetuses were observed. Thus, the dose of 14 mg/L air can be seen as the NOAEC regarding maternal as well as developmental toxicity of pentan-1-ol.

Thus, no indications of a developmental toxic or teratogenic effect were seen in animal studies with two members of the pentanol category. A detailed justification for this read-across is attached in IUCLID chapter 13.

Justification for classification or non-classification

The available data are considered reliable and suitable for classification purposes under Regulation (EC) No 1272/2008 (CLP). As a result, no classification for toxicity to reproduction or developmental toxicity under Regulation (EC) No 1272/2008 is required for 2 -methylbutan-1 -ol.