Tetraethylammonium heptadecafluorooctanesulphonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented and scientifically acceptable

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Reference 2

Reference Type:

publication

Title:

A 90-day repeated dose oral (gavage) toxicity study of perfluorohexanoic acid (PFHxA) in rats (with functional observational battery and motor activity determinations)

Author:

Chengelis CP, Kirkpatrick JB, Radovsky A, Shinohara M

Year:

2009

Bibliographic source:

Reprod Toxicol 27, 342-351

Materials and methods

Principles of method if other than guideline:

Fluorochemical Surfactant FC 95 (potassium perfluoroctane sulfonate) was fed in the diet at levels of 30, 100, 300, 1,000 and 3,000-ppm to Charles River CD rats for 3 months. Five male and 5 female rats were initiated at each dosage level and in the control group. The rats were observed twice daily for overt signs of toxicity and mortality. Individual body weights and sex group food consumptions were recorded weekly. Hematological, biochemical and urinalysis studies were conducted at the beginning of the study and after 30 and 90 days of treatment. The rats were scrificed after 90 days and a gross and histopathological examination was conducted.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Potassium heptadecafluorooctane-1-sulphonate

EC Number:

220-527-1

EC Name:

Potassium heptadecafluorooctane-1-sulphonate

Cas Number:

2795-39-3

IUPAC Name:

potassium 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctane-1-sulfonate

Details on test material:

Fluorad FC-95 (potassium perfluoroctane sulfonate)

Test animals

Species:

rat

Strain:

other: CD

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: feed

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 30, 100, 300, 1,000 and 3,000-ppm (=0, 2, 6, 18, 60, and 200 mg/kg d)
Basis:
nominal in diet

No. of animals per sex per dose:

5/sex/group

Control animals:

yes, plain diet

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

All of the rats in the 300, 1000 and 3000 ppm groups died. Death occurred between days 13-25 and days 18-28 for the males and females, respectively, in the 300 ppm group. At 1000 ppm, death occurred between days 8-14, and at 3000 ppm, the rats died between days 7-8 of treatment. The rats in all groups showed signs of toxicity including emaciation, convulsions following handling, hunched back, red material around the eyes, yellow material around the anogenital region, increased sensitivity to external stimuli, reduced activity and moist red material around the mouth or nose. Three males and two females in the 100 ppm group died prior to scheduled sacrifice. Two of the males and the two females died during week 5 and the third male died during week 11 of the study. At study termination, mean body weights were reduced by 16.7% and 16.3% in the male and female groups, respectively. Average food consumption during the entire study period (g/rat/day) was significantly reduced for males and females at 100 ppm. After 30 days of treatment, hematologic values were comparable among the control and 100 ppm groups. Clinical chemistry analyses at one month showed a significant increase in mean glucose in males, blood urea nitrogen values in males and females, and creatinine phosphokinase and alkaline phosphatase values for females. After 90 days of treatment at 100 ppm, the two surviving males had significantly reduced erythrocyte, hemoglobin, hematocrit and leukocyte counts; the three surviving females had significantly reduced hemoglobin and reticulocyte counts, as well as slightly lower erythrocyte, hematocrit and leukocyte counts. Two of the surviving females showed slight to moderate increases in plasma glutamic oxalacetic and pyruvic transaminase activities. Urinalysis results were comparable among treated and control groups at 30 and 90 days. Relative liver weight was significantly increased in the males and absolute and relative liver weights were significantly increased in the females. Relative kidney weights were significantly increased in both sexes.

All rats in the 30 ppm group survived until the end of the study. At study termination, mean body weights were reduced by 8.7 and 8% in the males and females, respectively. Average food consumption during the entire study period (g/rat/day) was significantly reduced for the males at 30 ppm. Hematologic values were comparable among the control and 30 ppm group at 30 and 90 days. One female showed a slightly elevated glucose level and one male showed a slightly increased alkaline phosphatase level at 30 days. At 90 days, one male showed moderate increases in glucose, blood urea nitrogen and y-glutamyl transpeptidase activity. The females had significant increases in absolute and relative liver weights. The males had significant decreases in absolute and relative adrenal weights, absolute thyroid/parathyroid weight and absolute pituitary weight. The biological significance of the changes in male organ weights is unclear since similar changes were not noted in higher dose groups. At necropsy, treatment related gross lesions were present in all treated groups and included varying degrees of discoloration and/or enlargement of the liver and discoloration of the glandular mucosa of the stomach. Histologic examination also showed lesions in all treated groups. Centrilobular to midzonal cytoplasmic hypertrophy of hepatocytes and focal necrosis was observed in the liver; the incidence and relative severity were greater in the males. In addition, especially among rats in the 300, 1000 and 3000 ppm groups, treatment related histologic lesions were noted in the primary (thymus, bone marrow) and secondary (spleen, mesenteric lymph nodes) lymphoid organs, stomach, intestines, muscle and skin. In the thymus, this consisted of depletion in the number and size of the lymphoid follicles and in the bone marrow hypocellularity was noted. The spleen was slightly atrophied with a corresponding decrease in the size and number of lymphoid follicles and cells and a similar depletion was noted in the mesenteric lymph nodes. Mucosal hyperkeratosis and/or acanthosis was observed in the forestomach and mucosal hemorrhages were noted in the glandular portion of the stomach. Decreases in the height and thickness of the villi were noted in the small intestine. Atrophy of the skeletal muscle was noted, as well as epidermal hyperkeratosis and/or acanthosis was noted in the skin.

Applicant's summary and conclusion

Executive summary:

Fluorochemical Surfactant FC 95 (potassium perfluoroctane sulfonate) was fed in the diet at levels of 30, 100, 300, 1,000 and 3,000-ppm to Charles River CD rats for 3 months. Five male and 5 female rats were initiated at each dosage level and in the control group. The rats were observed twice daily for overt signs of toxicity and mortality. Individual body weights and sex group food consumptions were recorded weekly. Hematological, biochemical and urinalysis studies were conducted at the beginning of the study and after 30 and 90 days of treatment. The rats were scrificed after 90 days and a gross and histopathological examination was conducted.

At dosage levels of 300, 1,000 and 3,000 ppm, all rats died prior to scheduled termination of the study. Overt signs of toxicity including: emaciation, convulsions, altered posture, red material (right eye and/or mouth), yellow material (anogenital region), - increased sensitivity to external stimuli and reduced ,motor activity were evident prior' to most deaths. Time of death was directly related to the dosage level with the earliest deaths seen in the 3,000-ppm treatment group. At the 30-ppm dosage level, neither male nor female rats showed any compound related changes in appearance or behavior. Mean body weights were slightly lower for the rats at the 30-ppm dosage level when compared to the controls. At the 30-ppm dosage level, one female rat showed a slightly elevated glucose level and one male rat showed a slightly elevated alkaline phosphatase value at 1 month of study. At 3 months of study, one male rat at the 30-ppm dosage level showed slight to moderate elevations in glucose, blood urea nitrogen and gamma- glutamyl transpeptidase activity. At the 100-ppm dosage level at 3 months, body weight means when compared to the controls were lower for males and for females. Food consumption means when compared to the controls were lower (statistically significant) for males and females.

At the 100-ppm dosage level, slight increases in creatinine phosphokinase (CPK) and alkaline phosphatase activity, slight to moderate increases in glucose and blood urea nitrogen, and slight to marked increases in plasma glutamic oxalacetic and pyruvic transaminase activities (PGOT and PGPT) were seen at 1 month of study. At 3 months of study. slight to moderate decreases in hemoglobin, hematocrit and erythrocyte counts were seen for male and female rats and slight to moderate increases in PGOT and PGPT activities were seen for two, of the three surviving female rats at the 100-ppm dosage level. Compound-related gross changes such as emaciation, areas of discoloration involving ths stomach and liver were observed among treated rats that died prior to sacrifice. Similar changes were also observed in the liver of a few rats sacrificed at termination of study from the 30- and 100-ppm groups. Microscopically, compound-related lesions were observed among all test groups. Morphological changes consisting of centrilobular to midzonal cytoplasmic enlargement (hypertrophy) of hepatocytes were observed in the livers. Necrosis of liver cells was also present among these rats. The incidence and relative severity of the above lesions were more evident among male test rats. In addition, especially among rats from the 300-, 1,000-, and 3,000- ppm dosage level that died prior to sacrifice, changes involving the primary (thymus, bone marrow) and secondary (spleen, mesenteric lymph nodes) lymphoid organs, stomach, intestines, muscle and skin, were observed and were all considered as compound related. The other changes described in the tissues of these rats were lesions of naturally occurring diseases.