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Description of key information

A repeat-dose oral toxicity study has been conducted on C4 F-isonitrile.  The results of the study are: 
A 28 day inhalation study resulted in a NOAEC of 516 ppm when tested according to OECD 412.

Key value for chemical safety assessment

Additional information

The repeat-dose inhalation toxicity potential of the test article was evaluated in male and female Sprague-Dawley rats via whole-body inhalation for 6 hours/day, 5 days/week, for 4 weeks (20 total exposures). The study was performed in compliance with EPA GLP 40 CFR 792 (1989) and OECD GLP (1997). The study method was based on OECD Guideline 412 (2009). Main phase rats (5/sex/group) were exposed to filtered air (control) or filtered air containing 0, 250, 500, 1000, or 1500 ppm (nominal) of the test article, for 6 hour exposures, 5 days per week for 4 weeks (20 total exposures). Recovery rats (5/sex/group) were exposed to filtered air or 1500 ppm test article in the same manner followed by a 2 week recovery period after the exposure period. Mean analyzed exposure concentrations were 252, 516, 1033, and 1512 ppm test article.  Clinical observations were performed daily, prior to exposure, during exposure, and 0-1 hour following the end of exposure and detailed physical examinations were performed weekly. Body weights were recorded within 4 days of receipt, the week prior to randomization, on the day of randomization, on Study Day 0, and twice weekly thereafter. Blood and urine were collected at necropsy for all animals (Day 28 for main group animals, Day 42 for recovery animals) and hematology and urinary parameters were evaluated. Macroscopic examinations were performed on all animals upon necropsy. Selected tissues were examined microscopically from all animals in the control and high concentration groups at the primary necropsy (Day 28). Target tissues were examined from all animals in the 250, 500 and 1000 ppm groups at the primary necropsy.  No mortality or test substance related clinical observations were noted during the study. Test substance related lower body weight gains and/or losses resulting in lower body weights were noted in the 500, 1000, and 1500 ppm group males and in all test substance treated females during the exposure period. These effects were statistically significant in the 1000 and 1500 ppm group males and females. There were no treatment related effects noted during the recovery period. Test substance related lower food consumption was noted in the 1000 and 1500 ppm group males and females during the exposure period. No treatment related effects were noted during the recovery period. On Study Day 28, mean erythrocytic parameters (RBC count, hemoglobin, and hematocrit values) were slightly higher than controls with a generally dose related response in the 500, 1000, and 1500 ppm group males and females. Mean absolute reticulocyte counts were lower than controls in the 1000 and 1500 ppm group males (28% and 39%, respectively). Mean hemoglobin distribution width was slightly lower (6%) than controls in the 1500 ppm group males. Following the recovery interval, there were no meaningful consistent alterations in hematology parameters. No clinical chemistry or urinalysis parameters were altered with a dose response relationship. Test substance related lower thymus weights were noted in the 1500 ppm group males at the Study Day 28 primary necropsy. Lower mean absolute thymus weights were also noted in the 500 and 1000 ppm group males and lower mean thymus to body weight and thymus to brain weight ratios in the 1000 and 1500 ppm group males were also noted but the differences were not statistically significant. Mean thymus weights were higher than the control group at the Study Day 42 recovery necropsy. There were no correlating histopathologic finding within the thymus. No test substance related gross lesions were observed upon necropsy. Test-substance related microscopic findings were noted in the nasal cavity in the 250, 500, 1000, and 1500 ppm group males and females from the Study Day 28 primary necropsy, and in the 1500 ppm group males and females from the Study Day 42 recovery necropsy. Findings were also noted in the pharynx in the 500, 1000, and 1500 ppm group males and females and in the 250 ppm group males from the Day 28 primary necropsy and in the 1500 ppm group females from the study day 42 recovery necropsy. Hyperplasia of the transitional epithelium, degeneration and regeneration of the respiratory epithelium, and/or degeneration and regeneration of the olfactory epithelium were observed in the nasal cavity in males and females from all test substance exposed groups at the Day 28 primary necropsy aside from the 250 ppm group males. Degeneration of the respiratory epithelium was characterized by loss of cilia, presence of cytoplasmic vacuolation and/or bleb formation, and sparse inflammatory cell cell infiltration. In addition, decreased mucous cells and hyperplasia of the submucosal glands were observed in the rostral levels. The olfactory epithelium was most severely affected in all groups except in the 250 ppm group. In the 250 ppm group animals, the transitional and respiratory epithelia of nasal cavity level II were often most severely affected. Degeneration and regeneration were almost always present concurrently within the same sections, indicating repetitive injury to the epithelial cells. No toxicologically relevant microscopic findings were observed in the larynx, trachea or lungs. Based on the results of the study, the No Observed Adverse Effect Concentration (NOAEC) is 516 ppm for the test article.

Justification for classification or non-classification

The results of the test do not meet the requirement to classify C4 F-isonitrile as dangerous.