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Description of key information

Two repeat dose studies have been conducted on perfluoro–N-methylmorpholine. A 28 day oral study and a 90 day inhalation study have been conducted on perfluoro-N-methylmopholine. Additionally, four repeat dose studies have been conducted on Fluoroinert Category Members. A 28 Day Oral study has been conducted on perfluoroisopropylmorpholine, a 90 Day Inhalation study has been conducted on perfluorohexane, a 28 day oral study was conducted on perfluorohexane and a 28 Day Inhalation study was conducted on perfluorotributylamine. 

NOAEL in the 28 day oral study on perfluoro-N-methylmorpholine is 2000 mg/kg/day.
NOAEL in the 90 day inhalation study on perfluoro-N-methylmorpholine is 49589 ppm.
Tests on other Fluoroinert Category members
NOAEL in the 28 day oral study on perfluoroisoproplymorpholine is 1000 mg/kg/day
NOAEL for the 90 Day Inhalation study on perfluorohexane study is 49821 ppm
NOAEL in the 28 Day Inhalation study on perfluorotributylamine was 7.28 ml/m3 (single dose tested, which represents saturation)
NOAEL in the 28 Day Oral study on perfluorohexane was >2000 mg/kg
These results are considered applicable to perfluoro-N-methylmorpholine.

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

Additional information

Perfluoro-N-methylmorpholine studies:

In the 90 day inhalation study, perfluoro-N-methylmorpholine was tested in Sprague-Dawley CD rats. Rats were whole-body exposed to the test article for 6 hour a day, 5 days a week, for 13 weeks at dose levels of 4971, 15094, and 49589 ppm. Control rats were similarly exposed to air on the same schedule. A satellite group was observed for an additional 4 weeks after sacrifice of the main group. Clinical signs were recorded twice daily, usually prior to loading and immediately following unloading from the chambers on exposure days. Body weights were recorded at group allocation, then weekly commencing one week prior to the start of exposures until the end of study. The quantity of food consumed by each cage of rats was recorded weekly commencing one week prior to the start of exposures until the end of the study. The eyes of all rats were examined prior to allocation and at study conclusion. Blood samples (fasted) were taken from all main group rats during week 13 and from the satellite group on week 17. Haematology and clinical chemistry parameters were examined from the blood samples. At week 13 (main group) and week 17 (satellite group) the animals were sacrificed and subject to gross necropsy. Microscopic examination of the tissues listed in Table 11 was also conducted. No treatment related changes in any parameters were observed due to test article exposure. The No Observed Adverse Effect Level for the test article under the conditions of the study was 49589 ppm.

The 28 day study evaluated the potential short-term toxicity of perfluoro-N-methylmorpholine when administered daily at 200, 1000, and 2000 mg/kg of body weight by oral gavage to male and female Crl:CDBR VAF/Plus rats for 30 days. Animals (5/sex/group) were administered the test material at a dose volume of 0.118, 0.59, and 1.18 mL/kg, respectively. Control animals were administered 0.9% sodium chloride at a dose volume of 1 mL/kg. Rats were observed twice daily (a.m. and p.m.) for mortality and moribundity, and predose and 1.5 hours postdose for indications of toxic effects. Blood samples were collected from all animals before terminal sacrifice for hematology and clinical chemistry analyses. After 4 weeks of treatment, the animals were fasted overnight, anesthetized with sodium pentobarbital, weighed, exsanguinated, and necropsied. At necropsy, all animals were examined macroscopically and selected tissues were weighed and preserved in 10% phosphate buffered formalin. Tissues from all animals in control and high-dose groups were sectioned, stained, and examined microscopically. No significant treatment-related effects were observed. The NOAEL for perfluoro-N-methylmorpholine is 2000 mg/kg/day.

Repeat Dose studies on other category members:

In the 28 Day Oral study on perfluoroisopropylmorpholine, animals were dosed at 250, 500 and 1000 mg/kg/day. At 1000 mg/kg/day, no effects were noted for body weight gain, food consumption, organ weight changes, gross pathology, neurobehavior, clinical chemistry or hematology. The NOAEL was determined to be 1000 mg/kg/day, which was the highest dose tested.

In the 28 Day Oral study on perfluorohexane, 20 male and 20 female Crl:CDBR VAF/Plus rats were assigned at random to one control group and three treated groups (five/sex/group). The control group was given 0.9% sodium chloride at 1 mL/kg body weight. The test groups received 200, 1000, and 2000 mg/kg body weight at a volume of 0.104, 0.520, and 1.04 mL/kg respectively. The animals received their respective doses daily (A.M.) for a total of 32 days. Rats were observed twice daily (A.M. and P.M.) for mortality and moribundity and pre-dose and approximately 1.5 hours post-dose for obvious indications of a toxic effect. Blood samples were collected from all animals before terminal sacrifice for hematology and clinical chemistry analyses. After 4 weeks of treatment, the animals were fasted overnight, anesthetized with sodium pentobarbital, weighed, exsanguinated, and necropsied. All animals were examined macroscopically and selected tissues were weighed and preserved. Tissues from all animals in the control and high-dose groups were sectioned, stained, and examined microscopically. There were no test article related clinical observations or changes in body weights or food consumption noted for males or females. Oral administration of the test article had no effect on clinical pathology or anatomical pathology. Based on the results of this study, the no-observable-effect level/no-observable-adverse-effect level for the test article in male and female rats was greater than 2000 mg/kg as described in the study report. IN the absence of any adverse findings, it can also be considered that the NOAEL is > 2000 mg/kg.

In the 90 day study, perfluorohexane was tested at nominal concentrations of 5000, 15000 and 50000 ppm. There were no toxicologically significant treatment-related signs of mortality, clinical signs of toxicity, bodyweight, food consumption, ophthalmoscopy, biochemistry, macroscopic pathology, organ weights and microscopic pathology. No effects of exposure were observed. From this study, a no observed adverse effect level (NOAEL) of 49821 ppm (the highest measured dose) was determined.

 

In the 28 Day Inhalation study on perfluorotributylamine, twenty-seven male and fifteen female Sprague-Dawley rats were used in the assay, eleven males and five females were used as control animals. The experimental group was exposed to an atmosphere saturated with respect to the test article for sever hours per day, five days per week, for a total of 30 exposures over 6 weeks. A 0.3 cubic meter enamel coated inhalation chamber was supplied with 30 liters/min of filtered air from a pressure line regulated by a rotameter. Before entering the chamber the air was bubbled through a large flask containing 250 ml of the test article heated to 125 degrees Celsius by an oil bath to saturate the air with vapor. Control rats were placed in an exposure chamber on the same schedule as the test rats, but were exposed to room air only. The male test rats gained less weight during the study period than the male control rats. However, the female test rat weight pattern was similar to the female controls. The female test rats had lower mean corpuscular volumes than the female control rats. A reduced serum glutamic oxaloacetic transaminase level was observed in the female test rats. The male test rats exhibited an elevated blood iron level and the female test rats exhibited a lower blood iron level than controls. The lack of any pattern or trend in the above deviations indicated that there is no direct dose-response relationship and questions the significance of the observed changes. No pathology was observed which was attributed to the exposure experience.

Because these substances exhibit similarity in their physicochemical properties and toxicological properties in mammals, and because available data indicates that parent molecules are not reactive toward biological molecules and cannot undergo bioactivation by normal enzymatic processes, they can be considered members of a chemical category. Data gaps for partitioning properties, mammalian and ecological toxicity can therefore be addressed by read-across and/or trend analysis between category members. Please see IUCLID section 13 for the category justification and a matrix of repeated dose toxicity data for members of the Perfluorinated Organic Chemicals C5-C18 category.

Justification for classification or non-classification

The results of these tests do not meet the requirement to classify perfluoro-N-methylmorpholine as dangerous.