Thirteen-Week Inhalation Toxicity of 1,4-Dioxane in Rats

Kasai, Tatsuya; Saito, Misae; Senoh, Hideki; Umeda, Yumi; Aiso, Shigetoshi; Ohbayashi, Hisao; Nishizawa, Tomoshi; Nagano, Kasuke; Fukushima, Shoji

doi:10.1080/08958370802105397

Cited by 19 publications

(14 citation statements)

References 16 publications

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“…Greater incidences and malignancy of liver tumors resulting from lesser estimated uptake of 1,4-dioxane by oral administration can be accounted for in terms of the first pass effect of orally administered 1,4-dioxane directly entering the liver after gastrointestinal absorption. The present finding that 1,4-dioxane-induced liver tumors appeared at lower uptake levels by oral administration than by inhalation exposure was consistent with the incidences and severities of nonneoplastic, hepatic lesions reported in the 13-wk inhalation study (Kasai et al, 2008) and in the 13-wk oral administration study (Kano et al, 2008).…”

Section: Discussionsupporting

confidence: 91%

“…Our selection of two higher exposure concentrations of 250 and 1250 ppm resulted in the induction of benign and malignant tumors including nasal squamous cell carcinomas and peritoneal mesotheliomas. The highest exposure concentration of 1250 ppm used in the present study was selected, predicting the MTD on the basis of both body weight change and subchronic toxicity in the 13-wk inhalation study (Kasai et al, 2008). Exposure to 1250 ppm was found to fulfill the MTD criteria (Sontag et al, 1976;OECD, 1981;Bannasch et al, 1986) for the 2-yr bioassay study of rodent carcinogenicity, in that the highest dose of the test agent given during the carcinogenicity study should not exceed the MTD that can be predicted to elicit signs of minimal toxicity without reducing the animals' normal longevity from toxic effects other than carcinogenicity, or no more than a 10% weight decrement, as compared to the concurrent controls.…”

Section: Discussionmentioning

confidence: 99%

“…The highest concentration of 1250 ppm was selected not to exceed the maximum tolerated dose (MTD) criteria (Sontag et al, 1976;OECD, 1981;Bannasch et al, 1986), based on both subchronic toxicity and body weight decrement from our 13-wk inhalation exposure study (Kasai et al, 2008). Our preliminary study showed that 13-wk inhalation exposure of male F344 rats to 1,4-dioxane at a concentration of 1600 ppm did not induce any death, body weight decrement, or toxicity except histopathological changes in the nasal cavity, trachea, and bronchus.…”

Section: Experimental Designmentioning

confidence: 99%

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Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Kasai

Kano

Umeda

et al. 2009

Inhalation Toxicology

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Carcinogenicity and chronic toxicity of 1,4-dioxane were examined by inhalation exposure of 50 male F344 rats to 1,4-dioxane vapor at 0 (clean air), 50, 250, or 1250 ppm (v/v) for 6 h/day, 5 days/wk, and 104 wk. Survival rates of 250 and 1250 ppm-exposed groups were decreased near the end of the 2-yr exposure period, due probably to the occurrence of malignant tumors. A statistically significant but marginal decrement of terminal body weight (<10%) was found in the 1250 ppm-exposed group, suggesting slight systemic toxicity. Significant changes in plasma levels of AST, ALT, ALP, and gamma-GTP and relative weight of the liver occurred in the 1250 ppm-exposed group. Dose-dependent and statistically significant increases in incidences of nasal squamous cell carcinomas, hepatocellular adenomas, and peritoneal mesotheliomas were found primarily in the 1250 ppm-exposed group. The incidences of renal cell carcinomas, fibroadenomas in the mammary gland, and adenomas in the Zymbal gland were also increased dose-dependently. Preneoplastic lesions occurred in the nasal cavity and liver of the 1,4-dioxane-exposed groups. As nonneoplastic lesions, the significantly increased incidences of nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were noted at 50 ppm and above. A LOAEL (lowest observed adverse effect level) was determined at 50 ppm for the nasal endpoint of general chronic toxicity. This study provides clear evidence of carcinogenicity for 1,4-dioxane in male rats. A cytotoxic-proliferative and in vivo genotoxic mode of action is suggested to operate in 1,4-dioxane-induced carcinogenesis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Experimental Designmentioning

confidence: 99%

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Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Kasai

Kano

Umeda

et al. 2009

Inhalation Toxicology

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“…In previous inhalation exposure studies, the mean plasma levels of DX in 52-and 400 ppm-exposed male rats at the end of the exposure period were 7.3 [17] and 48 mg mL À1 [18], respectively. The DX concentration in the blood in the rats of the present study (exposed to 250 ppm DX) at 360 min was 22.0 AE 2.7 mg mL À1 , a value in agreement with the previous studies.…”

Section: Results and Discussion 31 Inhalation Alone Administration Gmentioning

confidence: 99%

“…The plasma concentration of 1,4-dioxane [17,18] and a physiologically based pharmacokinetic (PBPK) model [19][20][21][22][23] of 1,4-dioxane distribution after exposure by a single route have been described. Importantly, the accumulation of a chemical in target tissues and its consequent toxicity can be enhanced when exposure is by multiple routes [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Distribution of 1,4-dioxane by combined inhalation plus oral exposure routes in rats

Take

Ohnishi

Yamamoto

et al. 2011

International Journal of Environmental Analytical Chemistry

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1,4-Dioxane is used in large amounts by industry. Human exposure to 1,4-dioxane is via both air and water. Recently we reported that the toxicity of chloroform is enhanced when exposure is by multiple exposure routes rather than a single exposure route. In this study, rats were exposed simultaneously to 1,4-dioxane by two routes, inhalation and oral, and the distribution of 1,4-dioxane in the blood, lung, liver, brain, kidney and abdominal fat of rats were determined. To assess the contribution of each route, unmodified 1,4-dioxane (DX) was administered by inhalation and deuterated 1,4-dioxane (DX-d 8 ) was administered orally, and DX and DX-d 8 were analyzed by mass spectrometer (MS). Exposure by both inhalation and oral administration resulted in DX and DX-d 8 concentrations in the blood and tissues which were higher than when exposure was by either inhalation or oral administration alone. The distribution of 1,4-dioxane in the combined inhalation plus oral administration conformed with its physicochemical properties and the tissue partition coefficients. Our results support the well accepted tenet that when investigating the toxicity of a chemical, the route of exposure is an important consideration, and in addition, our results suggest that when exposure is by multiple routes, exposure by one route may, to some extent, have an affect on exposure by the second route.

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Ethers of Ethylene Glycol and Derivatives

Kelsey

2023

Patty's Toxicology

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E series Glycol ethers are alkyl ethers of ethylene glycol along with their acetate esters. They are commonly used in paints and cleaners and typically have a higher boiling point in conjunction with the favorable solvent properties of lower‐molecular weight ethers, esters, and alcohols. They are colorless liquids that have mild earthy or fruity odors. The ethers are miscible with water and/or with numerous organic solvents making them useful as solvents in oil‐water compositions. Their relatively slow rate of evaporation also makes them useful as solvents and coalescing agents in paints and inks. The surface tension and solvent properties of the ethers make them useful in cleaners. Other uses of the ethers include process solvents and deicers. The ethers of the higher glycols are used as hydraulic fluids. Occupational exposure to glycol ethers occurs dermally and by inhalation. Most glycol ethers have low acute, single‐dose toxicity to humans. The most notable and well‐known effect relevant to humans is toxicity to male fertility and developmental toxicity produced by those glycol ethers that can metabolize to produce significant amounts of methoxyacetic acid such as methoxy ethanol and the methyl glymes.

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Thirteen-Week Inhalation Toxicity of 1,4-Dioxane in Rats

Cited by 19 publications

References 16 publications

Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats

Distribution of 1,4-dioxane by combined inhalation plus oral exposure routes in rats

Ethers of Ethylene Glycol and Derivatives

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