Inhalation Two-Generation Reproductive Toxicity Study of Methyl Isobutyl                Ketone in Rats

Nemec, Mark D.; Pitt, Jeffrey A.; Topping, Douglas C.; Gingell, Ralph; Pavkov, Kenneth L.; Rauckman, Elmer J.; Harris, Stephen B.

doi:10.1080/10915810490436351

Cited by 22 publications

(8 citation statements)

References 16 publications

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“…The spectrum of kidney lesions described in the literature after short-term exposures to MIBK (Phillips, et al, 1987;Nemec, et al, 2004) supports the observation that the kidney is the primary target in rats. In the 3-month study of MIBK (Phillips, et al 1987), there were doserelated increases in the severity of hyaline droplet formation and regeneration of PCT cells in male rats, although the highest dose tested in the 13-week study was 1,000 ppm.…”

Section: Discussionsupporting

confidence: 79%

“…There was also a positive trend for increases in benign or malignant pheochromocytomas (combined); however increases were neither statistically significant nor exceeded the historical control range. Nemec et al (2004) reported significant changes in adrenal gland weights of female Sprague-Dawley rats exposed to 2,000 ppm MIBK for 70 days, which were the F0 generation of a two generation reproductive study.…”

Section: Discussionmentioning

confidence: 99%

“…Male and female 7 week old Sprague-Dawley rats were exposed to 0, 500, 1,000 or 2,000 by inhalation for at least 70 days as part of a two-generation reproductive study (Nemec, et al, 2004). There were increases in both absolute and relative kidney weights in males.…”

Section: Introductionmentioning

confidence: 99%

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Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure

et al. 2008

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Methyl isobutyl ketone (MIBK) is primarily used as a denaturant for rubbing alcohol, as a solvent and in the manufacture of methyl amyl alcohol. Inhalation of vapors is the most likely route of exposure in the work place. In order to evaluate the potential of MIBK to induce toxic and carcinogenic effects following chronic exposure, groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to MIBK at concentrations of 0, 450, 900, or 1800ppm by inhalation, 6h/day, 5 days per week for 2 years. Survival was decreased in male rats at 1800ppm. Body weight gains were decreased in male rats at 900 and 1800ppm and in female mice at 1800ppm. The primary targets of MIBK toxicity and carcinogenicity were the kidney in rats and the liver in mice. In male rats, there was increased mineralization of the renal papilla at all exposure concentrations. The incidence of chronic progressive nephropathy (CPN) was increased at 1800ppm and the severity was increased in all exposed groups. There were also increases in renal tubule hyperplasia at all exposure concentrations, and in adenoma and adenoma or carcinoma (combined) at 1800ppm; these lesions are thought to represent a continuum in the progression of proliferative lesions in renal tubule epithelium. These increases may have resulted from the increased severity of CPN, either through alpha2micro-globulin-dependent or -independent mechanisms. An increase in mononuclear cell leukemia at 1800ppm was an uncertain finding. Adrenal medulla hyperplasia was increased at 1800ppm, and there was a positive trend for increases in benign or malignant pheochromocytomas (combined). In female rats, there were increases in the incidence of CPN in all exposure concentrations and in the severity at 1800ppm, indicating that CPN was increased by mechanisms in addition to those related to alpha2micro-globulin. There were renal mesenchymal tumors, which have not been observed in historical control animals, in two female rats at 1800ppm. The relationship of these tumors to exposure to MIBK was uncertain. Hepatocellular adenomas, and adenoma or carcinoma (combined) were increased in male and female mice exposed to 1800ppm. There were also treatment-related increases in multiple adenomas in both sexes.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure

et al. 2008

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“…Spermatogenic endpoints were evaluated using the methods described by Nemec et al (2004). Immediately after euthanasia the right epididymis of each F 0 and F 1 male was exposed, excised, and weighed.…”

Section: Methodsmentioning

confidence: 99%

Two‐generation reproduction study of di‐2‐ethylhexyl terephthalate in Crl:CD rats

Faber¹,

Deyo

Stump

et al. 2007

Birth Defects Research Pt B

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Increases in liver weights were found in the male and female animals exposed to 0.6% or 1.0% DEHT in the diet. Because there were no accompanying histopathologic changes, this effect was not considered adverse. Significant decreases in feed consumption in the female animals from the groups consuming 1.0% DEHT in the diet during lactation accompanied reduced postnatal pup body weights and rate of weight gain. Reductions in pup body weights later in lactation may also have been due to direct consumption of the treated feed by the pups or taste aversion to the same. Reduced relative spleen weight was found in male weanling pups from the 1.0% group in both generations and reduced relative spleen and thymus weights were found in female pups from the 1.0% group in the F(2) generation at necropsy on PND 21. Therefore, for parental and pup systemic toxicity, 0.3% DEHT in the diet (182 mg/kg/day) was considered no-observed-effect level (NOEL). The 1.0% DEHT (614 mg/kg/day) in the diet exposure concentration was considered a NOEL for F(0) and F(1) reproductive toxicity endpoints.

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“…Spermatogenic endpoints were evaluated using the methods described by Nemec et al (2004). Immediately upon euthanasia, the right epididymis of each F 0 and F 1 male was exposed, excised, and weighed.…”

Section: Methodsmentioning

confidence: 99%

Two generation reproduction study of styrene by inhalation in Crl‐CD rats

Cruzan

Faber²,

Johnson

et al. 2005

Birth Defects Research Pt B

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This study was conducted to evaluate the potential adverse effects of styrene on reproductive capability from whole‐body inhalation exposure of F0 and F1 parental animals. Assessments included gonadal function, estrous cyclicity, mating behavior, conception rate, gestation, parturition, lactation, and weaning in the F0 and F1 generations, and F1 generation offspring growth and development. Four groups of male and female Crl:CD(SD)IGS BR rats (25/sex/group) were exposed to 0, 50, 150, and 500 ppm styrene for 6 hr daily for at least 70 consecutive days prior to mating for the F0 and F1 generations. Inhalation exposure for the F0 and F1 females continued throughout mating and gestation through gestation day 20. Inhalation exposure of the F0 and F1 females was suspended from gestation day 21 through lactation day 4. On lactation days 1 through 4, the F0 and F1 females received styrene in virgin olive oil via oral gavage at dose levels of 66, 117, and 300 mg/kg/day (divided into three equal doses, approximately 2 hr apart). These oral dosages were calculated to provide similar maternal blood peak concentrations as provided by the inhalation exposures. Inhalation exposure of the F0 and F1 females was re‐initiated on lactation day 5. Styrene exposure did not affect survival or clinical observations. Rats in the 150‐ and 500‐ppm groups in both parental generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either the F0 or F1 generation. Male and female mating and fertility indices, pre‐coital intervals, spermatogenic endpoints, reproductive organ weights, lengths of estrous cycle and gestation, live litter size and postnatal survival were similar in all exposure groups. Additionally, ovarian follicle counts and corpora lutea counts for the F1 females in the high‐exposure group were similar to the control values. No adverse exposure‐related macroscopic pathology was noted at any exposure level in the F0 and F1 generations. A previously characterized pattern of degeneration of the olfactory epithelium that lines the dorsal septum and dorsal and medial aspects of the nasal turbinates occurred in the F0 and F1 generation animals from the 500‐ppm group. In the 500‐ppm group, F2 birthweights were reduced compared to the control and F2 offspring from both the 150‐ and 500‐ppm exposure groups gained weight more slowly than the controls. Based on the results of this study, an exposure level of 50 ppm was considered to be the NOAEL for F0 and F1 parental systemic toxicity; the NOAEL for F0 and F1 reproductive toxicity was 500 ppm or greater. Birth Defects Res B 2005. © 2005 Wiley‐Liss, Inc.

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Inhalation Two-Generation Reproductive Toxicity Study of Methyl Isobutyl Ketone in Rats

Cited by 22 publications

References 16 publications

Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure

Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure

Two‐generation reproduction study of di‐2‐ethylhexyl terephthalate in Crl:CD rats

Two generation reproduction study of styrene by inhalation in Crl‐CD rats

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