API TR 404-1995

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An Inhalation Oncogenicity Study of Commercial Hexane in Rates and Mice

Published By	Publication Date	Number of Pages
API	1995	152

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Description

This study, conducted for the American Petroleum Institute, was designed to assess the oncogenic effect of commercial hexane. The test substance was administered by whole-body inhalation as a vapor to Fischer 344 rats and B6C3F1 mice (50/sex/group/species). This report presents the results from the rat portion of the study. The mouse results are presented in a separate report. The test substance was administered for six hours per day, five days per week, for approximate two years at target concentrations of 900, 3000 and 9000 parts per million (ppm) of air. The 9000 ppm high exposure level was based upon the results of a 90-day subchronic study. In addition, 9000 ppm is approximately 80% of the lower explosive limit. Exposures were initiated on 23 January 1990 and completed on 29 January 1992. Exposure levels were analyzed hourly using an infrared spectrophotometer (IR). Gas chromatographic (GC) confirmation of the commercial hexane chamber exposure levels as well as analysis for the six major components were also conducted. Particle size distribution measurements of any background aerosol were made monthly. Detailed physical examinations were conducted weekly on all animals. Ophthalmoscope examinations were performed on all animals pretest, and prior to sacrifice. Body weight measurements were recorded pretest on Test Days -11, -5 and O, weekly through Week 13, monthly through Week 101 and just prior to sacrifice. Differential white blood cell counts were analyzed pretest for all animals and at Month 12, Month 18 and prior to termination of Group I and IV survivors. Following the two years of exposure, all survivors were sacrificed. Complete macroscopic examinations were conducted for all animals. Microscopic examinations were performed of the lungs in all animals and of selected tissues in all Group I and IV animals and for all animals which died or were sacrificed moribund prior to their scheduled sacrifice.

The cumulative mean exposure concentrations as determined by IR were 900, 3000 and 9016 ppm. GC analyses confirmed these exposure levels and indicated commercial hexane was stable over the duration of the study with a mean composition (%) of: n-hexane (51.5), methylcyclopentane (16.0), 3-methylpentane (16.1), 2-methylpentane (12.9), cyclohexane (3.3) and 2,4-dimethylpentane . Particle size distribution determinations indicated that no significant test substance aerosol was present in the exposure chambers.

At termination of the study the control group survivorship was males and 76% in the females. There was no significant difference in survivorship among the control or exposure groups.

Physical observations, hematological and ophthalmoscope examinations found no signs of any commercial hexane related effects except for excess lacrimation which was increased in the commercial hexane exposed males at 3000 and 9016 ppm.

Body weight gain was significantly reduced in the 3000 and 9016 ppm exposure At study termination, the mean male and female body weights in the 9016 & up were 7 and 11 percent lower than control values respectively. In the 3000 ppm group, mean male and female body weights were 5 and 3 percent lower than control values, respectively, at study termination. Food consumption was reduced in the commercial hexane exposure groups but was not dose related.

There were no macroscopic morphologic abnormalities which were considered to be related to exposure to commercial hexane.

Microscopic morphologic abnormalities which were considered related to commercial hexane were found in the nasal turbinate and the larynx.

Hyperplasia of the respiratory epitheliums was seen most frequently in males and females from Group IV (9016 ppm). Hypertrophy/hyperplasia of goblet cells was seen most frequently in males and females from Group IV, followed by Group III (3000 ppm); the severity, greater in the exposure groups than in the controls, was severe in Group IV. Both findings were considered to be an expected response to mucosal irritation and injury.

Intracytoplasmic eosinophilic material in the respiratory epithelial cells and sustentacular cells of the olfactory epitheliums was seen in almost all of the males and females from the exposure groups for which the nasoturbinal tissues were examined, and in numerous control animals. When compared to controls, the severity was increased and com arable in Groups III (3000 ppm) and IV (9016 ppm), followed by Group II (900 ppmf. While a common finding in aging and aged rats, the exact nature of this material (presumed to be secretory) and reasons for its increase following exposure to irritants are not known.

The following changes were also seen: Inflammatory cells/cell debris in the nasal lumen [males, Groups II (900 ppm), 111 (3000 ppmY and IV (9016 ppm); and females, Group III]; and subacute (chronic active)/chronic inflammation in the nasal mucosa, the incidence of which was greatest in males and females from Group IV.

Squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium was seen in a small number of animals from the exposure and control groups. In the males, the incidence was highest in Group IV (9016 ppm), followed by Group III (3000 ppm). In the females, the incidence in Groups IIIand IV was comparable and greater than that seen in Group I (O ppm). This finding was considered to be a localized response indicative of irritation. There was no indication of any oncogenic effect.

In conclusion, under the exposure conditions of this study, commercial hexane is not an oncogen in the rat.

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