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Description of key information

The authors of a GLP, inhalation, carcinogenicity and chronic toxicity study in rats and mice with MIBK equivalent to OECD test guideline 451 did not provide a NOAEC at tested dose up to 1800 ppm due to kidney findings in male rats, and hepatocellular findings in male and female mice, both caused by mechanisms of action that are not relevant to humans. Review of the data from these studies indicates that a NOAEC of 450 ppm (1840 mg/m3) can be established for neoplastic and non-neoplastic lesions in both species.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
1 840 mg/m³
Study duration:
other: rat and mouse

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The development of kidney tumors in male rats in association with chemically induced a2µ-globulin nephropathy is mechanism that is not considered to be a predictor of carcinogenic risk to humans by the IARC (Swenberg & Lehman-McKeeman, 1999) or the US EPA (US EPA, 1991). The lack of relevance of the a2µ-globulin mechanism for the evaluation of carcinogenic risk is based on the absence of the production of an analogous protein in humans. Strict scientific criteria have been outlined to establish the role of a2µ-globulin-associated nephropathy in renal carcinogenesis in male rats (Swenberg & Lehman-McKeeman, 1999), and were used to determine the plausibility of an a2µ-globulin associated nephropathy based on a studies that have been carried out with subchronic and chronic exposures to MIBK. All of the IARC criteria for characterization of the MoA are met (see sections 7.9.4 of IUCLID and 5.10.3 of the CSR). Together these studies provide the weight of evidence that the MIBK induced male rat renal tumors are not relevant to humans. As well, MIBK induced hepatic effects in mice are consistent with a phenobarbital-like MOA where the initiating events are activation of the CAR and PXR nuclear receptors leading to rodent liver tumors (see sections 7.9.4 of IUCLID and 5.10.3 of the CSR); in vivo and in vitro mechanistic studies lend weight to that hypothesis. Therefore, according to the CLP criteria, a classification for the carcinogenic effect is not warranted.

The ECHA Risk Assessment Committee published a CLH opinion on 20 September 2019, which classified MIBK as Carcinogen Category 2, based on the evidence presented in the Annex XV dossier. The key findings of the RAC with regards to the observed effects were: 1) 4-methylpentan-2-one is not genotoxic.
2) CAR-mediated MoA of liver tumours in male and female mice is seen as plausible. Nevertheless, human relevance has not been investigated (in vitro test) leading to some uncertainties on the MoA.
3) α2u-globulin nephropathy MoA of kidney tumours in male rats is plausible but other MoA could have been involved in tumour formation.
4) Mesenchymal malignant kidney tumours in female rats were not statistically significant and only observed in 2/50 animals. Nevertheless, as the tumours were malignant and very rare, this type of tumour could be of concern.

On this basis, MIBK was classified as Carcinogen Category 2 as the human relevance of the findings could not be ruled out.

Additional information

The carcinogenicity of methyl isobutyl ketone (MIBK) was evaluated in 2-year carcinogenicity and chronic toxicity studies in rats and mice (NTP, 1987; Stoutet al., 2008). These GLP studies were equivalent to OECD test guideline 451.

MIBK was administered by inhalation at nominal concentrations of 0, 450, 900, or 1800 ppm to F344N rats for 2 years, 6 hours/day, 5 days/week (50 rats/sex/group). On average, animals were necropsied at week 110. All animals underwent complete gross necropsy and microscopic examinations. Survival was decreased in the 1800 ppm males compared to control males. There were no differences in survival noted in females. Mean body weights in the 900 and 1800 ppm males rats were noted to be 6-8% and 5-8% less, respectively, after week 89 compared to controls; however, there were no differences in mean body weights noted in female rats. Chronic progressive nephropathy (CPN) similar to that which occurs in aged rats was observed in males and females in all groups, including controls, but increased in incidence in 1800 ppm male rats and in all MIBK-exposed female rats, and was more severe in all MIBK-treated male rats and 1800 ppm female rats. The incidence and severity of mineralization of the epithelium of the collecting ducts, a finding commonly accompanying CPN, were increased in male MIBK groups. Hyperplasia of the transitional epithelium lining the renal pelvis was increased in treated males, achieving statistical significance at 900 and 1800 ppm. An increase in adenoma and adenoma or carcinoma (combined) was noted in male rats at 1800 ppm. This increase in renal tubular tumors was considered possibly a result of the increase in severity of CPN and an alpha-2u-globulin-related mechanism by the study authors, the latter which is specific to male rats and is not considered relevant to humans. However, since CPN was exacerbated in females, additional mechanisms may be involved. The authors of the study also indicated that there is no human counterpart to CPN. Renal mesenchymal tumors were identified in 2 female rats in the 1800 ppm group. The relationship of the mesenchymal tumours to MIBK was uncertain. An increase in mononuclear cell leukemias in male rats was noted, achieving statistical significance and exceeding historical ranges for controls in the 1800 ppm group; however, the strength of the response (25/50 at 0 ppmvs35/50 at 1800 ppm) made the finding uncertain. Adrenal medulla hyperplasia also was significantly increased in male rats at 1800 ppm (0 ppm, 13/50; 450 ppm, 18/48; 900 ppm, 18/50; 1800 ppm, 24/50). There also were exposure-related increases in benign or malignant pheochromocytoma (combined) of the adrenal gland in male rats (0 ppm, 8/50; 450 ppm, 9/48; 900 ppm, 11/50; 1800 ppm, 14/50). However, these increases were not significant and were within the historical ranges for chamber controls from inhalation studies fed NTP-2000 diet (69/398, 17±7%; range 10–28%), although the incidence in the 1800 ppm group was at the upper limit of the historical range. Based on these findings a NOAEC was not identified by the study authors. However, 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 (see sections 7.9.4 of IUCLID and 5.10.3 of the CSR). 

Supportive information on the carcinogenicity of MIBK was provided by the 2-year inhalational, carcinogenicity and chronic toxicity study in B6C3F1 mice, involving dose concentrations of 0, 450, 900, and 1800 ppm. No NOAEC was reported in this study due to dose-related histopathological findings of increased eosinophilic foci in the liver in MIBK-treated groups which achieved statistical significance at 450 and 1800 ppm. Treatment-related increases in multiple adenomas were noted in both male and female mice. Hepatocellular adenomas, and adenoma or carcinoma (combined) were increased in both sexes in the 1800 ppm group. As a result of these findings, a NOAEC was not reported by the study authors; however a 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 reported neoplastic effects in the liver of female mice at higher dose levels. Subsequent investigations showed that the carcinogenic effect in mice that can be attributed to Phenobarbital-like activation of CAR is not relevant to humans (see sections 7.9.4 of IUCLID and 5.10.3 of the CSR).

Justification for selection of carcinogenicity via inhalation route endpoint:
The carcinogenicity of methyl isobutyl ketone (MIBK) was evaluated in 2-year carcinogenicity and chronic toxicity studies in rats and mice.

Carcinogenicity: via inhalation route (target organ): digestive: liver; urogenital: kidneys