Mutagenicity of para-substituted α-methylstyrene oxide derivatives with Salmonella

Rosman, L. B.; Beylin, Vladimir G.; Gaddamidi, Venkatswamy; Hooberman, Barry H.; Sinsheimer, Joseph E.

doi:10.1016/0165-1218(86)90036-4

Cited by 28 publications

(15 citation statements)

References 20 publications

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“…The stereochemistry of urinary metabolites from cumene-treated rabbits suggested that S-(ϩ)-2-phenylpropionic acid was not from oxidation of R-(ϩ)-2-phenyl-1-propanol (Ishida and Matsumoto, 1992). Rapid rearrangement of AMS oxide to phenylpropionaldehyde was observed in this and other studies (Rosman et al, 1986); therefore, formation of M16 from this pathway is highly feasible. However, R-(Ϫ)-2-phenylpropionic acid has been shown to partially isomerize to its S-(ϩ)-isomer in rats (Yamaguchi and Nakamura, 1985); therefore, formation of M16 from oxidation of M14 cannot be FIG.…”

Section: Discussionmentioning

confidence: 67%

“…AMS oxide is mutagenic in Salmonella assays (Rosman et al, 1986) and reacts with GSH, forming a mercapturic acid conjugate (M12) excreted in urine. Therefore, AMS oxide might play a role in the higher incidence of alveolar/bronchiolar adenoma and carcinoma observed in the lung of cumene-treated mice in the National Toxicology Program toxicity studies.…”

Section: Disposition and Metabolism Of Cumene In Micementioning

confidence: 99%

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Disposition and Metabolism of Cumene in F344 Rats and B6C3F1 Mice

Chen

Wegerski²,

Kramer³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Cumene is a high-production volume chemical that has been shown to be a central nervous system depressant and has been implicated as a long-term exposure carcinogen in experimental animals. The absorption, distribution, metabolism, and excretion of [ 14 C]cumene (isopropylbenzene) was studied in male rats and mice of both sexes after oral or intravenous administration. In both species and sexes, urine accounted for the majority of the excretion (typically >70%) by oral and intravenous administration. Enterohepatic circulation of cumene and/or its metabolites was indicated because 37% of the total dose was excreted in bile in bile duct-cannulated rats with little excreted in normal rats. The highest tissue 14 C levels in rats were observed in adipose tissue, liver, and kidney with no accumulation observed after repeat dosing up to 7 days. In contrast, mice contained the highest concentrations of 14 C at 24 h after dosing in the liver, kidney, and lung, with repeat dosing accumulation of 14 C observed in these tissues as well as in the blood, brain, heart, muscle, and spleen. The metabolites in the expired air, urine, bile, and microsomes were characterized with 16 metabolites identified. The volatile organics in the expired air comprised mainly cumene and up to 4% ␣-methylstyrene. The major urinary and biliary metabolite was 2-phenyl-2-propanol glucuronide, which corresponded with the main microsomal metabolite being 2-phenyl-2-propanol.

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Section: Discussionmentioning

confidence: 67%

Section: Disposition and Metabolism Of Cumene In Micementioning

confidence: 99%

Disposition and Metabolism of Cumene in F344 Rats and B6C3F1 Mice

Chen

Wegerski²,

Kramer³

et al. 2010

Drug Metab Dispos

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“…An alternative theory is that DNA damage could contribute to lung cancer (Hong et al 2008), suggesting that the results of these rodent studies could be relevant to humans. With respect to the alternative theory, it should be noted that cumene was not mutagenic in studies conducted by the NTP (2009), but one of its metabolites (a-methylstyrene oxide) has been shown to be mutagenic in vitro (Rosman et al 1986). However, the separate observation that a-methylstyrene, a direct precursor to a-methylstyrene oxide, did not induce the mouse lung and rat nasal tumors that are associated with cumene (NTP 2007) seems more compatible with the hypothesis that cumene acts via a non-genotoxic mode of action.…”

Section: Carcinogenicitymentioning

confidence: 99%

Characterization of the toxicological hazards of hydrocarbon solvents

McKee

Adenuga

Carrillo

2015

Critical Reviews in Toxicology

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Hydrocarbon solvents are liquid hydrocarbon fractions derived from petroleum processing streams, containing only carbon and hydrogen atoms, with carbon numbers ranging from approximately C5-C20 and boiling between approximately 35-370°C. Many of the hydrocarbon solvents have complex and variable compositions with constituents of 4 types, alkanes (normal paraffins, isoparaffins, and cycloparaffins) and aromatics (primarily alkylated one-and tworing species). Because of the compositional complexity, hydrocarbon solvents are now identified by a nomenclature ("the naming convention") that describes them in terms of physical/ chemical properties and compositional elements. Despite the compositional complexity, most hydrocarbon solvent constituents have similar toxicological properties, and the overall toxicological hazards can be characterized in generic terms. To facilitate hazard characterization, the solvents were divided into 9 groups (categories) of substances with similar physical and chemical properties. Hydrocarbon solvents can cause chemical pneumonitis if aspirated into the lung, and those that are volatile can cause acute CNS effects and/or ocular and respiratory irritation at exposure levels exceeding occupational recommendations. Otherwise, there are few toxicologically important effects. The exceptions, n-hexane and naphthalene, have unique toxicological properties, and those solvents containing constituents for which classification is required under the Globally Harmonized System (GHS) are differentiated by the substance names. Toxicological information from studies of representative substances was used to fulfill REACH registration requirements and to satisfy the needs of the OECD High Production Volume (HPV) initiative. As shown in the examples provided, the hazard characterization data can be used for hazard classification and for occupational exposure limit recommendations. Introduction Scope and purpose of the documentThe present document summarizes information on the physical/ chemical properties and toxicological hazards of hydrocarbon solvents and provides examples of the ways in which the information on hazard characterization can be used for hazard classification and to set occupational exposure limits. Many of the toxicological studies were published separately, but the results are summarized herein and referenced in the appendices.Hydrocarbon solvents are liquid hydrocarbon fractions that are primarily produced by the distillation of petroleum feed stocks or their synthetic analogs (e.g., Fischer-Tropsch derived materials), sometimes followed by additional processing steps such as solvent extraction, hydrodesulfurization, or hydrogenation. 1 Most hydrocarbon solvents are complex substances with variable compositions and are best described as UVCB 2 (unknown and variable composition) substances, but some are single constituent (mono-constituent) substances. The complex and variable nature of these solvents is the consequence of their manufacturing processes. In short, most hydroca...

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“…α-Methylstyrene α-Methylstyrene is a metabolite of isopropyl benzene that has been found in the exhaled air of mice after oral administration, but was practically absent in that of rats (see Section 3.2). As α-methylstyrene can be converted to α-methylstyrene oxide, which is genotoxic in Salmonella mutagenicity tests, it is suspected that αmethylstyrene plays a role in the induction of isopropyl benzene-induced lung tumours in mice (Chen et al 2011;Rosman et al 1986). After inhalation exposure of mice and rats to α-methylstyrene, effects similar to those that occur after inhalation of isopropyl benzene are observed, for example hyperplasia of the olfactory epithelium.…”

Section: Relevance Of the Nasal Tumours For Humansmentioning

confidence: 99%

Isopropyl benzene (cumene) [MAK Value Documentations, 2013]

Jahnke

Hamann²,

Laube³

et al. 2016

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated isopropyl benzene to derive a maximum concentration at the work place (MAK value), considering all toxicity endpoints. Available publications are described in detail. Isopropyl benzene caused adenomas in the nose of rats, and in mice adenomas and carcinomas in the lungs and adenomas in the liver. Genotoxic effects do not seem to be responsible for the carcinogenicity. Concerning the lung tumours of mice, it is assumed that ring hydroxylated metabolites stimulate cell proliferation, which can lead to tumour formation. In humans, the metabolism of aromatic molecules in the respiratory tissues is not yet clarified in detail and therefore carcinogenic effects of isopropyl benzene in humans cannot be excluded. Isopropyl benzene is therefore classified in Carcinogen Category 3B. Isopropyl benzene is not genotoxic, therefore, the derivation of a MAK value is possible. In agreement with the procedures used by the Commission, a MAK value of 10 ml/m 3 was set, derived from a calculated BMDL of 35 ml/m 3 for liver weight increase in the 14‐week study with rats and from the calculated BMDL of 42 ml/m 3 for nasal adenomas in the 2‐year study in rats. On the basis of the mainly systemic effects, the classification in Peak Limitation Category II is retained. The half‐life in humans is considerably longer than 2 hours, so that the excursion factor of 4 is also retained. No foetotoxic or teratogenic effects were found in rats and rabbits up to 1200 and 2300 ml/m 3 , respectively. As the difference between the NOAEC for developmental toxicity and the MAK value is sufficiently large, damage to the embryo or foetus is unlikely when the MAK value is observed. The assignment to Pregnancy Group C is confirmed. Skin contact may contribute significantly to systemic toxicity and the designation with an “H” notation is retained. Sensitisation is not expected based on the result of a maximisation test.

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Mutagenicity of para-substituted α-methylstyrene oxide derivatives with Salmonella

Cited by 28 publications

References 20 publications

Disposition and Metabolism of Cumene in F344 Rats and B6C3F1 Mice

Disposition and Metabolism of Cumene in F344 Rats and B6C3F1 Mice

Characterization of the toxicological hazards of hydrocarbon solvents

Isopropyl benzene (cumene) [MAK Value Documentations, 2013]

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