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Repeat-dose oral and inhalation studies have been conducted on HFE-7300.  The results of the studies are: 
A 28 day oral gavage study resulted in a NOAEL of 150 mg/kg/day.
A 10 day inhalation study resulted in a NOAEL of 143 mg/L.
A 5 day inhalation study resulted in a NOAEL of 143 mg/L.

Key value for chemical safety assessment

Additional information

The subacute oral toxicity of the test article was evaluated in Sprague Dawley rats following 28 consecutive days of dosing. This study was performed in compliance with OECD GLP (1997) and Japanese MHLW, METI, and MOE GLP guidelines (2003). The study design was based on Japanese testing guidelines (2003), OECD 407 (1995), and Council Directive B.7 (1996). The test article was prepared in olive oil (vehicle) once weekly. Rats (6/sex/group) received 0, 25, 150, or 1000 mg/kg test article via oral gavage at dose volume of 10 mL/kg once daily for 28 consecutive days. One vehicle control group and one 1000 mg/kg/day dose group served as recovery groups and were observed for 14 days following the last dose. All dose groups, except for the recovery groups, were euthanized after the last dose. The recovery groups were euthanized after the 14 day observation period. Parameters measured: clinical observations (at least once daily), body weight (twice weekly), food intake (approximately weekly), functional observation battery (week 4), gross necropsy (termination), clinical chemistry (termination), urinalysis (termination), and weight and histopathology of select organs (termination). All animals survived. During the dosing period, mottled teeth (15/24) and salivation (18/24) were observed in the 1000 mg/kg dose group. Salivation, loss of hair, scab formation, and/or exudate were observed in the 25 and 150 mg/kg dose groups. Salivation and mottled teeth were also observed among vehicle control group animals. During the recovery period, mottled teeth (12/12) and partial loss of lower incisors (3/12) were observed in the 1000 mg/kg dose group. There were no abnormal changes in body weight or food intake. Absolute and relative liver weights were increased in males in the 150 and 1000 mg/kg groups. Relative liver weights were increased in females in the 150 and 1000 mg/kg groups. Absolute liver weights were increased in females in the 1000 mg/kg group. Enlargement of the liver was observed in males at 150 and 1000 mg/kg and in females at 1000 mg/kg. In the liver, centrilobular hypertrophy of the hepatocytes was noted in males of the 150 and 1000 mg/kg groups and in the females of the 1000 mg/kg group. Focal necrosis of the hepatocytes was noted in males of the 1000 mg/kg group. At termination of the dosing period, total bilirubin was decreased in males and females of the 150 and 1000 mg/kg groups. Increased albumin was noted in 1000 mg/kg-treated females and in 150 and 1000 mg/kg-treated males. AST was decreased in 1000 mg/kg-treated females and in 25 mg/kg-treated males and females. In addition, 1000 mg/kg-treated males had increased ALT, alkaline phosphatase, A/G ratio, and BUN. The females in the 1000 mg/kg group had increased A/G ratio and decreased creatinine. At the termination of the recovery period, ALT was increased in 1000 mg/kg-treated males, and A/G ratio was increased in 1000 mg/kg-treated females. Based on the results of the study, the NOAEL for the test article is 150 mg/kg/day.

This study evaluated the 10-day inhalation toxicity of the test article in male Sprague Dawley rats following a custom protocol. Four rats were whole body exposed to 10000 ppm (143 mg/L) test article vapor for 6 hour exposures on 10 consecutive days. A second group of four rats was not exposed to any test atmosphere and served as the negative control. Clinical observations were performed continually during exposure and at least daily after the last exposure. Body weights were recorded daily. Urine was collected every day after each exposure and on days 4, 7, 12, and 14 after the last exposure. Selected urine samples were analyzed for metabolites by NMR. A gross necropsy was performed at 14 days after the last exposure. No clinical abnormalities occurred during the study or at gross necropsy. There were no abnormalities in body weight or body weight gain. Urine concentrations of both acid and fluoride metabolites were comparable among all test material treated animals. Based on the results of the study, the NOAEL for the test article is 143 mg/L, vapor.

The 5-day inhalation toxicity of the test article was evaluated in male Sprague Dawley rats. This study was performed in the spirit of GLP. The study method was based on a custom protocol. A group of 4 rats were exposed, whole body, to an atmosphere of 10000 ppm (143 mg/L, vapor) for 6 hours per day for 5 days. A second group of 4 rats served as a control and was not exposed to atmosphere containing the test material. Clinical observations were made continually during the study. Body weights were recorded at pretest, daily, and at termination. Immediately after the last exposure, all animals were euthanized and examined for gross pathology. The liver, kidneys, lungs, and testes were collected for histology. Serum was collected and analyzed for blood chemistries. All animals survived. There were no abnormal clinical observations, body weight changes, or necropsy findings. Based on the results of the study, the NOAEL for the test article is 143 mg/L, vapor.

Justification for classification or non-classification

The results of these tests do not meet the requirement to classify HFE-7300 as dangerous.

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