4-methylpentan-2-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

300 mg/kg bw/day

Effect on fertility: via inhalation route

Dose descriptor:

NOAEC

4 093 mg/m³

Additional information

The reproductive toxicity of methyl isobutyl carbinol was evaluated on the basis of data on the read across substances, methyl isobutyl ketone (MIBK) and 4-hydroxymethyl-4-methyl-2-pentanone (i.e., diacetone alcohol, HMP).

The reproductive toxicity of 4-hydroxymethyl-4-methyl-2-pentanone was evaluated in a combined oral repeated-dose toxicity and reproductive/developmental toxicity screening test in rats (MHW, 1997). This study was conducted in accordance with OECD test guideline 422 (GLP status unknown). DAA was administered at dose levels of 0 (water vehicle), 30, 100, 300, or 1000 mg/kg bw/day. Findings in parental animals included decreased locomotion and decreased response to stimulation at 300 and 1000 mg/kg bw/day males. Results of hematology and blood chemistry revealed increases in platelet count, glutamic oxalacetic transaminase, choline esterase, total protein, total cholesterol, total bilirubin, blood urea nitrogen, creatinine, and calcium, as well as a decrease in glucose, at 1000 mg/kg bw/day. Increased kidney weights were noted at 300 and 1000 mg/kg bw/day in males, and increased liver and adrenal weights were noted in the 1000 mg/kg bw/day males. Histological evaluation of kidney tissues confirmed the presence of hyaline droplets in the proximal tubular epithelium in males at 100 mg/kg bw/day or more, and basophilic tubules in the 300 and 1000 mg/kg bw/day males. Hepatocellular hypertrophy was noted in the liver in the 1000 mg/kg bw/day males, and vacuolizaiton of the cells of the zona fasciculata were noted in the adrenals of the 300 and 1000 mg/kg bw/day males. In females, one animal in the 1000 mg/kg bw/day group was euthanized during delivery. Reduced premating body weight gain was noted in the high-dose females. Histopathological changes to the liver and adrenals also were noted, as well as an increase in liver weight. Dilatation of the distal tubules and fatty degeneration of the proximal tubule epithelium in the kidneys was noted in the 300 and 1000 mg/kg bw/day females. Reproductive effects included decreased fertilization rate, number of implantations, and implantation rate at the 1000 mg/kg bw/day dose level. Offspring effects included reduced overall birth rate, delivery rate, number of live pups, live birth weight, number of live pups at day 4 of lactation, and survival at day 4 of lactation at 1000 mg/kg bw/day. In one 1000 mg/kg bw/day litter, no pups survived due to death or cannibalism. Based on these findings, the NOAEL for reproductive function in males and females, as well as for development of offspring, is considered to be 300 mg/kg bw/day.

The reproductive toxicity of methyl isobutyl ketone (MIBK) was evaluated in a GLP-compliant multi-generation toxicity study in Crj: CD(SD) rats (Nemec, 2000; Nemec et al., 2004). The study design was equivalent to OECD test guideline 416. Rats were administered MIBK at target concentrations of 0, 500, 1000 and 2000 ppm (mean measured concentrations were 0, 491, 999, and 1996 ppm or 0, 2012, 4093, and 8178 mg/m3) by whole body inhalation. Parental (F0) findings included transient decreased body weight during the first 2 weeks of exposure at the 2000 ppm dose concentration and increases in absolute and relative liver weights at 2000 ppm. Significant increases in parental F0 and F1 mean absolute and relative kidney weights were observed for males in all MIBK-treated groups relative to the control group; however, mean kidney weights of female rats were unaffected. These increases in mean kidney weight were attributed to an alpha2µ-mediated mechanism and are not considered relevant to human risk identification (see Section 5.10). Offspring findings included a single mortality and signs of CNS depression in the F1 group following MIBK exposure on postnatal day (PND) 22 to 25. As a result, F1 MIBK exposure was suspended until PND 27. CNS depressive effects were observed until PND 31, but not after. F1 animals in the 1000 and 2000 ppm groups showed reduced reactivity to novel stimulus during exposure, which was attributed to a sedative effect. There were no effects on reproductive parameters reported. Based on these findings the NOAEL for parental systemic toxicity and neonatal toxicity was considered to be 1000 ppm (4093 mg/m3). The NOAEL for reproductive toxicity was considered to be 2000 ppm (8178 mg/m3), the highest dose tested.

Short description of key information:
Information on the reproductive toxicity of methyl isobutyl carbinol was based on data read across substances, methyl isobutyl ketone (MIBK) and 4-hydroxymethyl-4-methyl-2-pentanone (HMP).
A GLP inhalation multi-generation study in rats (equivalent to OECD Guideline 416) performed with MIBK reported a parental and neonatal toxicity of 1000 ppm (4093 mg/m3 at 20 °C), and a reproductive toxicity of 2000 ppm (8330 mg/m3 at 20 °C; the highest dose tested).
Slight changes in reproductive performance (decreased fertility and implantations) and pup viability following high oral exposure to HMP (1000 mg/kg/day) in an OECD TG 422 study may have occurred in the presence of maternal toxicity (reduced weight gain, statistically significant changes in hematology, clinical biochemistry and relative organ weights; renal and hepatic histopathological lesions). The NOAEL for reproductive function in males and females, as well as for development of offspring, is considered to be 300 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Information on the developmental toxicity of methyl isobutyl carbinol was based on data read across substance, methyl isobutyl ketone (MIBK). In inhalation developmental toxicity studies in rats and mice, maternal toxicity and fetotoxicity were seen at 3000ppm (12292 mg/m3). Effects in the dams included decreased body weight gain, increased liver and kidney weights, decreased food consumption, and in mice, maternal deaths. Reduced fetal body weights and delayed ossification were noted in both species and increased resorptions were noted for mice. 1000ppm (4106 mg/m3) was considered to be the NOEL for both maternal animals and offspring.

Effect on developmental toxicity: via inhalation route

Dose descriptor:

NOAEC

4 106 mg/m³

Additional information

Information on the developmental toxicity of methyl isobutyl carbinol was based on data read across substance, methyl isobutyl ketone (MIBK).

Developmental and maternal toxicity were evaluated in groups of 35 pregnant Fischer 344 rats and 30 pregnant CD-1 mice exposed by inhalation to 0, 300, 1000, or 3000 ppm (0, 1229, 4106, 12,292 mg/m3) MIBK for 6 hrs/day on gestation days 6 through 15 (Tyl et al., 1987). Animals were sacrificed on gestation day 21 (rats) or 18 (mice). Dams were evaluated for exposure-related changes in clinical signs, body weight, food consumption, organ weights (kidney, liver, and gravid uterus), and reproductive parameters; fetuses were evaluated for exposure-related changes in body weight and viability, and for external, skeletal, and thoracic and peritoneal visceral alterations. Maternal mean body weight, weight gain, and food consumption were significantly decreased in rats exposed to 12,292 mg/m3 (but not to 4106 mg/m3 or lower ) during the exposure period, but they had recovered to control levels by the day of sacrifice; maternal body weight was not affected in mice. Maternal clinical signs observed in rats or mice included coordination loss, hindlimb weakness, paresis, irregular gait, hypoactivity, ataxia, unkempt fur, negative tail or toe pinch, piloerection, lacrimation, or red perioral encrustation. These clinical signs were observed only during the exposure period and only at 12,292 mg/m3. Three maternal deaths (12% of the animals in the group) occurred in mice exposed to 12,292 mg/m3 after the first exposure on gestation day 6; no further deaths occurred in that group, and no exposure-related deaths occurred in the other mouse or rat exposure groups. Neonates from those dams were not considered in the final evaluation. Statistical analyses by the authors were per dam or per litter. No exposure-related effects were observed in rats or mice with respect to numbers of corpora lutea, total implants, percent implantation loss, live fetuses per litter, nonviable implants per litter, percent live fetuses, and sex ratio. In mice, there was an increased mean number of dead fetuses per litter at 12,292 mg/m3 (0.6 per litter compared to 0.1 in controls). Fetal body weights (litter weight, male weight per litter, and female weight per litter) were significantly reduced in rats exposed to 1229 (the mean by 3%) and 12,292 mg/m3 (the mean by 6%) but not to 4106 mg/m3; and in mice, fetal body weights were statistically significantly reduced at 12,292 mg/m3 (the mean by 13%) but not at 4106 mg/m3 or below. The authors indicated that the reduction in rat fetal body weight was confounded by a skewed distribution of litter size, whereby higher doses had very small litters and smaller litters had varied mean weights across dose, while lower-dosed dams appeared to have larger litters and larger litters showed a dose-dependence in mean weight. There was no statistically significant increase in the number of rat or mouse fetuses per litter. The authors decided the reductions in rat fetal body weight was not treatment-related. No exposure-related change in the incidence of malformations of any type were observed in rat and mouse fetuses. The number of litters with observations indicating retarded skeletal ossification was significantly increased to various degrees in both rats and mice at 12,292 mg/m3 relative to controls for a variety of skeletal endpoints, with scattered increases in litters with retarded ossification at lower exposure levels that were not considered to be exposure-exposure-related. 1000ppm (4106 mg/m3) was considered to be the NOEL for both maternal animals and offspring.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) NO. 1272/2008.