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Description of key information

Three repeat dose toxicity studies have been conducted on HFP Kinetic Dimer:
28 Day Repeat Dose Oral Toxicity according to OECD 407 (1995): NOAEL 450 mg/kg/day
28 Day Repeat Dose Inhalation Toxicity according to OECD 412 (1981): NOAEC 249.9 ppm (3.07 mg/L, vapor)
28 Day Combined Repeated Dose Inhalation Toxicity and Reproductive/Developmental Screening according to OECD 421 (1995): NOAEC: 360 ppm (4.29 mg/L)

Key value for chemical safety assessment

Additional information

The subacute oral toxicity of the test article (clear, colorless liquid; CASRN 84650-68-0, purity 98.5%; Lot 4, with spikes) was evaluated in Wistar Rats. METHODS: This study was performed under OECD GLP (1997) conditions. The study method was based on OECD 407 (1995), MHLW No. 1039 and METI No. 1014 (1986), U.S. EPA OPPTS 870.3050 (2000), and EC Directive 96/54/EC, Annex IV.D (1996). Rats (5/sex/dose) received 0, 50, 150, or 450 mg/kg-day test article via oral gavage for 28 days followed by a 14-day recovery period. The test article was diluted in perfluorohexane (PF-5060, FC-72) for dosing. Body weights and clinical and functional observations were recorded. Clinical hematological and biochemical parameters were measured. Microscopic examinations were performed on all animals from the control and 450 mg/kg-day dose groups and on animals of all dose groups that died spontaneously or were sacrificed in extremis. All animals survived to scheduled necropsy. No adverse clinical signs were noted in any animals in any dose group. Females in the 450 mg/kg group had statically significantly higher mean body weights compared to controls at the end of treatment. Body weights were not statistically significantly different between the control 450 mg/kg groups at the end of the recovery period in males or females. Upon hematological analysis, males had statistically significantly lower RBC (450 mg/kg group), HGB (150 and 450 mg/kg groups), HCT (450 mg/kg group), MCH (50, 150, 450 mg/kg groups), MCHC (50, 150, 450 mg/kg groups), and PT (450 mg/kg group) and statically significantly higher RDW (450 mg/kg group) compared to controls. At the end of the recovery period MCHC, and RDW were still statistically significantly elevated in the 450 mg/kg group compared to controls. Upon hematological analysis, females had statistically significantly lower RBC (450 mg/kg group), HGB (50 and 450 mg/kg groups), HCT (450 mg/kg group), MCV (450 mg/kg group), MCHC (50 and 450 mg/kg groups), and statically significantly higher RDW (150 and 450 mg/kg group) compared to controls. At the end of the recovery period HGB was still statistically significantly higher than controls in the 450 mg/kg group. Males had statistically significantly elevated bilirubin (150, 450 mg/kg groups) and potassium (450 mg/kg group) compared to controls. At the end of the recovery period, ASAT was statistically significantly decreased in 450 mg/kg-treated males and total protein was elevated compared to controls. Females had statistically significantly elevated ALAT (450 mg/kg group), GGT (450 mg/kg group), cholesterol (150, 450 mg/kg groups), potassium (450 mg/kg group), calcium (450 mg/kg group), chloride (450 mg/kg group) compared to controls. At the end of the recovery period, ALAT and calcium were statistically significantly decreased and creatinine was increased compared to controls in females. At the end of treatment, males had statically significantly decreased brain and testes weights compared to controls that had lost statistical significance by the end of the recovery period compared to controls. At the end of treatment, females had statistically significantly increased liver weight and spleen weight that had lost statistical significance by the end of recovery compared to controls. No abnormal findings were noted upon gross necropsy of all animals or histopathological examination of the control and 450 mg/kg-day groups. Based on the results of the study, the No Observed Adverse Effect Level (NOAEL) of the test article is 450 mg/kg-day.

 

The subacute inhalation toxicity of the test article (supplied as a liquid, purity 98.5%; Lot 4, with spikes) was evaluated in Wistar rats. This study was performed under OECD GLP (2004) conditions. The study method was based on OECD 412 (1981), Japanese ITI Guidelines for Screening Toxicity testing of Chemicals, II (1986), and EEC Directive 92/69/EEC, L383A, part B8. Rats (5/sex/concentration) were exposed whole body to target concentrations of 0, 50, 100, or 250 ppm test article (administered as a vapor) 6 hours/day, 5 days/week for 28 days, for a total of 20 exposure days (Main study group). In addition, to study the persistence and/or reversibility of possible effects, two groups of rats (5/sex) were added to the control and high exposure groups and kept for a 28-day recovery period (Recovery group). Rats were necropsied 1-day (Main study) and 28-days (Recovery) following their final exposure. Mean actual test article concentrations of test atmosphere were 49.9, 99.4, and 249.9 ppm, which are equivalent to vapor concentrations of 0.61, 1.22, and 3.07 mg/L, respectively. To evaluate the toxicity of the test article clinical observations, body weights food consumption parameters, hematology, clinical chemistry, organ weights and microscopic histopathology examinations were performed. All test article treated animals survived through the end of the study period. No adverse effects were noted in the clinical observations, body weights, food consumption parameters, hematology, clinical chemistry or organ weight end points. Histopathological changes were limited to increased striation of the dentine of the upper incisors of three male and two female animals in the high concentration group which was reversed following the 28-day recovery period. The increased dentin is not considered an adverse effect since no changes were noted in the molar (non-growing teeth) of the rats; rather, this finding is considered indicative of exposure to a fluoride-containing test article. No other microscopic changes were noted upon histopathological examination. Based on the results of the study, the No Observed Adverse Effect Concentration (NOAEC) is 249.9 ppm (3.07 mg/L, vapor) test article.

 

The repeat dose toxicity and reproductive and developmental toxicity potential of the test article was evaluated in male and female Wistar rats. The study was conducted in compliance with OECD GLP (1997) regulations. The test method was based on OECD 421 (1995). The test article was administered by inhalation at 0 (control), 150, 350, and 750 ppm (nose only, 6 hours per exposure per day) to groups of 12 male and 12 female rats during a premating period of 2 weeks and during mating and gestation up to gestation day 19. Male animals were sacrificed after a total of 25 exposure days. Dams and pups were sacrificed four or five days after delivery. In-life parameters recorded included clinical signs, body weight, food consumption, mating parameters, gestational and parturition parameters and litter parameters. At necropsy, testes and epididymides were weighed for male animals and liver and lung weight was determined for all animals. Liver and respiratory tract were preserved for all animals but not examined histopathologically. Reproductive organs were examined histopathologically for animals of the mid exposure group (350 ppm) and the control group. Animals exposed to 750 ppm exhibited hunched posture, piloerection, appeared thin, had muscle weakness and encrustations of the eyes. Incidence and severity of signs increased over two weeks of exposure. One female in the high-exposure group (750 ppm) was found dead on Day 4 without the preceding clinical observations. One female in the 750 ppm group was found dead on Day 18. One male animal in the 750 ppm group was sacrificed moribund on Day 22. Based on the early mortalities, clinical signs and body weight loss observed in the 750 ppm group animals, it was decided to discontinue exposure for the group from Day 23 onwards. All remaining animals in the 750 ppm group were sacrificed on Day 24. No abnormal clinical signs or mortality was observed in other exposure groups. Males in the 750 ppm group showed progressing body weight loss from the start of exposure onwards and mean body weights were statistically significantly lower at the end of premating and during post-mating. Females in the 750 ppm group showed a more limited decrease in body weight gain, although weight changes were statistically decreased at the end of the pre-mating period. There were no statistically significant differences in body weights of the 150 or 350 ppm animals compared to controls. In the 750 ppm group, 11 females were places with males. Due to the unscheduled death of one male and one female during mating and the deteriorating conditions of the other animals in this group, exposure was discontinued and the animals were sacrificed after 9 days of cohabitation. At the time of unscheduled sacrifice, 4 out of 11 females were sperm-positive and considered mated. In the control, 150 and 350 groups, 12 females were placed with males for mating. In the control group, one female was not mated and another female did not deliver, resulting in 10 litters. In the 150 ppm and 350 ppm groups, all females were mated and this resulted in 12 litters in the 150 ppm group and 11 litters in the 350 ppm group. There were no relevant differences in pre-coital time, mating index, male or female fertility index between the 150 ppm, 350 ppm and control groups and no treatment-related effects were observed in the mean number of corpora lutea and the mean number of implantation sties. Reproductive performance was not affected by treatment. In each group, the duration of gestation was comparable. The mean number of pups was comparable in all groups and there were no stillborn pups. As the 750 ppm group was discontinued, organ weights are not comparable to the control group. In the 150 and 350 ppm groups, there were no significant changes in the weight of male reproductive organs and the liver. Relative lung weight was slightly, but statistically significantly increased in both males and females in the 350 ppm group. In absence of a statistically significant difference in absolute lung weight, this effect was considered non-adverse. Males from the 750 ppm group that were sacrificed early revealed three animals with small prostate glands, four with small seminal vesicles, four with cryptochidism, and one with small testes and epididymis. Three males and one female in the 750 ppm group had pale kidneys. Two males and two females in the 750 ppm group had a small thymus and one male had a small spleen. No abnormal findings were observed in the 150 and 350 ppm groups upon gross necropsy. Microscopic analysis of the male animals revealed minimal unilateral seminiferous tubular atrophy in both the control group (two animals) and the 350 ppm group (three animals). In addition two animals of the 350 ppm group showed mild seminiferous tubular atrophy. In agreement with this observation, minimal unilateral cellular debris was observed in the epididymis of two animals of both the control group and the 350 ppm group. In addition, three animals of the 350 ppm group showed mild cellular debris in the epididymis. No statistical significance was reached for these findings in treatment groups compared to controls. A Unilateral sperm granuloma was found in the epididymis of an animal of the 350 ppm group. The liver of one male animal of the 350 ppm group showed multifocal hepatocellular degeneration and hemorrhages. The number of pups born and the sex ratio were comparable between the treatment groups and controls. The viability index was not affected by treatment. The viability index was 99% in the control group, 98.3% in the 150 ppm group, 89.9% in the 350 ppm group. There were no treatment-related signs in pups during the lactation period. There were no differences in mean pup weight between the test groups and the controls on Day 0 or Day 4 or lactation. No gross abnormalities were observed in any pups when examined externally. Based on the results of the study, the parental No Observed Adverse Effect Concentration (NOAEC) of the test article is 350 ppm (4.29 mg/L, vapor).

Justification for classification or non-classification

HFP Kinetic Dimer does not meet the CLP criteria for classification as a target organ toxicant after repeated exposure.