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EC number: 701-175-2 | CAS number: -
Five groups, designated 1,2,3,4 and 5, each containing 10 male and 10 female Crl:CD BR rats, received nose-only inhalation exposures for 6 hours per day, 5 days a week, for four weeks to air or vapors of the test material. Group 1 animlas were exposed to filtered air only. Groups 2,3,4 and 5 were exposed to 2, 19, 129, and 537 mg/m3 of the test material, respectively. All surviving animals from each group were necropsied at the end of the four week exposure period. Body weight, feed consumption, clinical signs, neurology, clinical chemistry, hematology, organ weight and histopathology evaluations were performed on all surviving animals during this study.
All animlas exposed to 537 mg/m3 died by exposure day 11. Prior ro death these animals exhibited treatment-related labored breathing, respiratory noise, gasping, unstable gait, tremors, salivation and lacrimation. At 129 mg/m3 transient occurrences of unstable gait, respiratory noise, salivation and lacrimation were observed. Animals exposed to 19 mg/m3 showed no treatment related signs of toxicity, with the exception of one incident of lacrimation. No treatment-related signs were observed at 2 mg/m3. At the end of the four-week exposure period, neurological evaluations of all surviving animals showed no effect on the nervous system in any group.
Treatment -related decreases in body weight and feed consumption was observed in both sexes at 537 mg/m3. Animlas exposed to 129 mg/m3 showed a decrease in body weights for both sexes, and a decrease in feed consumption in males. Animlas exposed to 19 and 2 mg/m3 showed no treatment-related changes in body weight or feed consumption.
No treatment-related effects were seen in any group for clinical chemistry, hematology or organ weights.
Gross pathologic changes were observed only in animals exposed to 537 mg/m3. These changes consisted of partially or fully blocked nasal cavities and gas-filled stomachs. Microscopic examination of male and female rats exposed to 537 mg/m3 showed chnages in the nasal cavity, larynx, trachea, and lung. The nasal cavity changes were moderate to severe desquamation of the respiratory and olfactory epithelium, epithelial necrosis and inflammation. The larynx and trachea had epithelial necrosis and inflammation. The lungs of two females showed foci of inflammation in the bronchi, bronchioloes and/or alveoli. Male and female rats exposed to 129 mg/m3 showed slight focal lesions of the nasal cavity. Rats exposed to 19 or 2 mg/m3 had no exposure related nasal cavity microscopic changes.
On the basis of the most sensitive indicator of toxicity, the histopathological changes seen in the nasal cavities, the no observed effect level (NOEL) following four weeks of nose-only inhalation exposure to the test material was 19 mg/m3.
A benchmark dose (BMD) analysis of relevant toxicity data for primene was conducted in order to establish BMD and BMDL (lower limit of the 95% confidence interval on the BMD) values. The U.S. EPA’s Benchmark Dose Software (BMDS) was used for the analysis (U.S. EPA 2009). Data from a four week vapor inhalation study in rats was used (Hagan et al., 1994). The exposure doses were 0, 2, 19, 129, and 537 mg/cubic meter of primene.
The key endpoints evaluated were body weight at week four (dose 537 not used due to deaths before the end of the study) and the nasal cavity with both the respiratory and olfactory epithelium. The study report indicated the nasal cavity was the most sensitive target organ with histopathologic changes, particularly desquamation, necrosis and inflammation.
The results for models for a particular response were all within a factor of 3 so the model with the lowest AIC is the most desirable. The plots show that the fits for the models for incidence 0 0 0 2 10 were all very similar except the quantal linear model which had a poorer fit than the others. The response of 0 0 0 2 10 was the most sensitive therefore the BMD value of 80.96 mg/m3 and the BMDL value of 36.20 mg/m3 are chosen corresponding to the multistage model with the lowest AIC.
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