4-methylpentan-2-ol

Endpoint summary

Description of key information

Repeated dose studies with MIBC and its primary metabolites, MIBK and HMP, indicated that systemic toxicity is minimal.  The NOAEC for subchronic inhalation exposure was 886 ppm (3700 mg/m3) for MIBC (6-weeks with rats) and 450 ppm (1840 mg/m3) for MIBK (2-year with rats).  The NOAEL for the ultimate metabolite, HMP, via gavage dosing for 45 days was 30 mg/kg/day for males (based on hyaline droplet nephropathy) and 100 mg/kg/day for females. There were no organ-specific toxic effects for either chemical relevant for human risk assessment.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

3 698 mg/m³

Study duration:

subacute

Species:

rat

Additional information

MIBC inhalation toxicity study

A non-GLP 6-week inhalation study was conducted in male and female Wistar rats with methyl isobutyl carbinol (MIBC) (Blair, 1982). Animals were exposed to concentrations of MIBC at 0 (control), 211, 825, or 3698 mg/m³for 6 hours per day for 5 days per week for 6 weeks. There were no adverse effects reported for the following parameters evaluated: mortality and clinical signs, hematology, gross pathology, and histopathology. The mean alkaline phosphatase value was increased in females exposed to 3698 mg/m³. Mean concentrations of ketone bodies in urine samples from all the exposed groups (except males exposed to 211 mg/m³) showed a significant increase above those of the control groups. The mean concentrations of protein were increased in all the exposed female groups and in the male group exposed to 3698 mg/m³. The mean specific gravities of both male and female groups exposed to 3698 mg/m³were increased compared to the control values as was the female group exposed to 825 mg/m³. The mean pH of urine from the male group exposed to 3698 mg/m³was reduced, and the mean glucose content of the urine of females exposed to the same concentration was increased compared to the control values. Finally, the mean urine volumes of females exposed to 211 and 3698 mg/m³were reduced compared to the control values.Although significantly increased kidney weights were noted in males exposed to 3698 mg/m³as compared to controls, there were no macroscopic or microscopic correlates associated with this finding.Although the authors did not define the NOAEC for this study, NOAEC can considered to be the highest exposure concentration of 3698 mg/m3.

Read across

Metabolic data demonstrate that MIBC is rapidly and extensively converted to the methyl i-butyl ketone (MIBK) via oxidation of the alcohol functional group by alcohol dehydrogenase in the liver (Guillaumat, 2004). MIBK is subjected to further oxidative metabolism (hydroxylation) by the hepatic microsomal mixed function oxidase system to produce 4-hydroxymethyl-4-methyl-2-pentanone (HMP or diacetone alcohol), which is the major metabolite formed from both MIBC and MIBK exposures.Thus, MIBK may be used as an appropriate surrogate for MIBC and vice versa considering that the alcohol is rapidly metabolized to the ketone and that exposure to either substance ultimately results in the rapid formation of HMP.

MIBK

In a whole body 2-year inhalation study in Fischer 344 rats, animals (50/sex/group) were administered the read-across substance, MIBK, at concentrations of 0 (control), 450, 900 or 1800 ppm for 6 hours per day, 5 days per week for 2 years (NTP,2007; Stout et al., 2008). This GLP study was equivalent to OECD Test Guideline 453. Mortality was observed in all groups administered test article. However, survival was significantly decreased in males administered MIBK at 1800 ppm as compared to controls. Mean body weights also were decreased in males administered 900 ppm and 1800 ppm as compared to controls. The mean body weights and survival in treated females were similar to controls. The primary target of MIBK toxicity was the kidney in rats. Briefly, chronic progressive nephropathy (CPN) similar to that which occurs in aged rats also was observed in all rats (including controls). There were treatment related significant increases in both the incidence (1800 ppm) and severity in all exposed groups. Kidney lesions that typically accompany CPN also were reported in males exposed to 900 ppm and 1800 ppm MIBK. The kidney lesions observed were suggestive of α2μ-globulin nephropathy (specific to male rat), a mechanism of xenobiotic-induced renal carcinogenesis for which there is no human counterpart. A NOAEC was not identified by the authors.Review of the study data suggests that a NOAEC of 450 ppm (1840 mg/m3) can be derived for neoplastic and non-neoplastic lesions, based on the non-neoplastic lesions observed in the kidneys at higher dose levels and the irrelevance to humans of the tumour types observed in the kidneys of male rats.

Groups of 14 male and 14 female Fischer 344 rats were exposed to measured mean concentrations of 0, 50, 252, and 1002 ppm (0, 205, 1033, and 4106 mg/m3) MIBK for 6 hrs/day, 5 days/week, for 14 weeks and sacrificed the animals following their final exposure day (Dodd and Eisler, 1983; Philips et al., 1987).The following endpoints were evaluated: clinical signs, body weights, organ weights (kidneys, heart, liver, lungs, and testes), urinalysis, hematology, serum chemistry (including glucose and hepatic enzyme levels), complete gross pathology, targeted histopathology (nasal cavity, trachea, liver, kidneys, and lungs) in all animals and complete histopathology in control and high-exposure groups.No effects of any kind were observed in rats of either sex at 205 mg/m3. Terminal body weights were significantly increased in female rats at >=1033 mg/m3. Platelet numbers in male rats were significantly increased at 4106 mg/m3by 13% over controls, and eosinophil number in female rats was significantly decreased at 4106 mg/m3by 57% as compared to controls. Serum cholesterol in male rats was significantly increased at the 1033 and 4106 mg/m3exposure levels by 23 and 35%, respectively, as compared to controls. Male rats showed a significant increase in absolute (+13) and relative (+9%) liver weight at 4106 mg/m3. No histological lesions were observed in the liver and no changes were seen in serum liver enzymes and bilirubin in any exposure group; thus, the observed liver enlargement may have been an adaptive response to increased hepatic metabolic activity rather than a toxic effect. Urine glucose was significantly increased in male rats at 1033 mg/m3(+37%) and 4106 mg/m3(+55%) and in female rats at 4106 mg/m3(+26%). Significantly increased urine protein (+28%) was also observed in male rats at 4106 mg/m3. The only renal histological lesion observed was hyaline droplet formation in all male rats; the severity of the lesion generally increased with exposure level. The U.S. EPA has concluded that renal alpha2u-globulin hyaline droplet formation is unique to male rats and is not relevant to humans for the purposes of risk assessment (U.S. EPA. (1991) Alpha2u-globulin: Association with chemically induced renal toxicity and neoplasia in the male rat. Risk Assessment Forum.EPA/625/3-91/019F). The NOAEL was assigned as 1002 ppm (4106 mg/m3) and the NOEC at 50 ppm (205 mg/m3).

HMP

A repeated dose study according to OECD TG 422 was conducted with 4-hydroxy-4-methyl-2-pentanone (diacetone alcohol, or HMP) (MHW, 1997). In this study, 10 rats/sex/group were dosed by gavage with 0, 30, 100, 300, or 1000 mg/kg/day of 4-hydroxy-4-methyl-2-pentanonein distilled water for approximately 45 days. Decreased locomotor activity and stimulation response were observed at 300 and 1000 mg/kg/day for both sexes. Altered blood parameters, dilatation of the distal tubules of the kidneys, hepatocellular hypertrophy, and vacuolization of the zona fasciculata of the adrenals were observed in males from the 1000 mg/kg/day group. Females at 300 mg/kg/day showed dilatation of the distal tubules and fatty degeneration of the proximal tubular epithelium in the kidneys. At 1000 mg/kg/day, female body weight gain was reduced, liver weight was increased, hepatocellular hypertrophy was noted, and kidney lesions similar to those at 300 mg/kg/day were also recorded. In addition, increased incidence and/or severity of hyaline droplets in the tubular epithelium was noted in males at 100 mg/kg/day and greater. The LOAEL for this study was 100 mg/kg/day for males and 300 mg/kg/day for females. The NOAEL was 30 mg/kg/day for males (based on hyaline droplet nephropathy) and 100 mg/kg/day for females.

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.