AMMONIUM PERFLUOROOCTANOATE

CAS number: 3825-26-1

Synonyms: Ammonium pentadecafluorooctanoate; FC-143^®; Octanoic acid; Pentadecafluoroammonium salt

Molecular formula: C₈F₁₅O₂H₄N

Structural formula: C₇F₁₅COONH₄

TLV–TWA, 0.01 mg/m³

Skin

A3 — Confirmed Animal Carcinogen with Unknown Relevance to Humans

Summary

A TLV–TWA of 0.01 mg/m³ is recommended for occupational exposure to ammonium perfluorooctanoate. This value is intended to minimize the potential for chronic asymptomatic accumulation of ammonium perfluorooctanoate in the blood; liver damage, reported in several animal studies, and testicular cancer, reported only in animals. A Skin notation is assigned, based on liver damage and elevated blood organofluoride levels in dermally treated rats. An increased incidence of testicular tumors (Leydig cell adenomas) in rats fed ammonium perfluorooctanoate warrants the A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans, notation. Sufficient data were not available to recommend a SEN notation.

Chemical and Physical Properties

Ammonium perfluorooctanoate is a white, free-flowing powder composed of various C-8 isomers. Chemical and physical properties include:⁽¹⁾

Molecular weight: 431
Density: 0.6 to 0.7 g/cc
Boiling point: sublimes above 125°C
Vapor pressure: 7 x 10^-5 torr at 20°C
Solubility: highly soluble in water

Major Uses

Ammonium perfluorooctanoate is commonly used commercially in the polymerization of fluorinated

Acute

Ammonium perfluorooctanoate has moderate oral toxicity with an LD₅₀ in rats of 540 mg/kg body weight.⁽¹⁾ The material was nonirritating to rabbit skin but produced moderate eye irritation in rabbits characterized by iridal and conjunctival effects that persisted for at least 7 days.⁽¹⁾ The reported dermal LD₅₀ values were 4300 mg/kg for rabbits, 7000 mg/kg for male rats, and > 7500 mg/kg for female rats.⁽²⁾

Single 4-hour inhalation exposures in rats produced lethality at concentrations of 800 mg/m³ or greater; ammonium perfluorooctanoate was considered moderately to highly toxic on an acute basis.⁽³⁾

Subchronic

Repeated dermal doses of 20 to 2000 mg ammonium perfluorooctanoate/kg body weight to rats produced liver damage in a dose-related fashion and elevated blood organofluoride levels. Circulating blood concentrations were reduced but still remained 42 days after cessation of exposure.⁽²⁾

Repeated oral dietary doses of ammonium perfluorooctanoate to rats and mice showed the liver to be the target organ with the response in males being greater than in females.⁽¹⁾ Rats tolerated feeding of up to 3000 ppm for 28 days, although body weight gain was reduced at levels of 1000 ppm or greater. Liver weights of males and females were elevated at 30 and 300 ppm, respectively. Hepatocellular changes consisted of multifocal cytoplasmic hypertrophy at lower dose levels and degeneration or necrosis of hepatocytes and focal bile duct proliferation at the higher doses. Mice fed 30 ppm for 28 days showed increased liver weight; feeding 300 ppm or greater was not tolerated.⁽¹⁾

Rats fed 10, 30, or 100 ppm ammonium perfluorooctanoate for 13 weeks showed hepatocellular hypertrophy, increased relative liver weights, and increased hepatic palmitoyl CoA oxidase activity. These effects were reversible and no effects were produced by feeding of 1 ppm. Rats fed 10 ppm or greater also showed a slight increase in estradiol concentration; however, the effect was greater following calorie restriction than was that produced by the chemical per se.⁽³⁾ Serum estradiol levels were elevated in rats gavaged for 14 days with 10, 25, or 50 mg ammonium perfluorooctanoate/kg, but no change was seen at 1 mg/kg. Hepatic B oxidation activity was elevated in rats treated at 10 mg/kg or greater; the latter appeared related to testicular lesions and resultant endocrine imbalance.⁽⁴⁾ Rats and mice given a single intraperitoneal injection of 100 mg/kg showed a fourfold increase in peroxide generating acyl-CoA oxidase activity measured in hepatic homogenates; however, increases were not observed either in vivo or in an intact perfused liver.⁽⁵⁾

Monkeys treated by oral intubation of 3 to 100 mg ammonium perfluorooctanoate/kg/day for 90 days⁽¹⁾ died at 30 and 100 mg/kg/day. The gastrointestinal tract and the reticuloendothelial systems were affected at the two higher doses; no tissue changes were seen in monkeys given either 3 or 10 mg/kg/day.⁽¹⁾

Repeated inhalation by male rats showed no ammonium perfluorooctanoate-related effects at 1 mg/m³. Liver damage was encountered at 7.6 and 84 mg/m³.⁽⁶⁾ These liver effects were reversible, although the retention of ammonium perfluorooctanoate in the blood was prolonged. Clearance from the blood of female rats was much more rapid than that in males, apparently due to an active secretory mechanism in the kidney.⁽⁷⁾

Chronic/Carcinogenicity

There was a dose-related reduction in body weight gain in a 2-year feeding study in which rats received either 30 or 300 ppm ammonium perfluorooctanoate (approximately 1.5 or 15 mg/kg).⁽⁶⁾ Increased liver weights, hepatocyte hypertrophy with vacuolated cytoplasm, and some evidence of hepatocellular degeneration with occasional signs of necrosis were recorded. Tumor incidence was relatively low; the types were similar to those found in geriatric Sprague–Dawley rats.

However, the incidence of Leydig cell adenomas in rats fed 300 ppm, but not 30 ppm, was significantly elevated. The incidence of adenomas in this study was 0% in controls, 6% at 30 ppm, and 14% at 300 ppm. The historical incidence in this strain of rat ranges from 1.4% to 10% with a mean of 4.68%.⁽⁸⁾ No increase in neoplasms for any other tissue or organ was observed.⁽⁹⁾The incidence of malignant hepatocellular carcinomas produced by diethylnitrosamine was increased following either 12 months of feeding 200 ppm or 23 weeks of feeding 150 ppm ammonium perfluorooctanoate in the diet.⁽¹⁰⁾

Reproductive/Developmental

Ammonium perfluorooctanoate was not teratogenic in the rat after inhalation of concentrations up to 25 mg/m³ or by oral doses up to 100 mg/kg/day throughout organogenesis.⁽¹¹⁾

Genotoxicity Studies

Ammonium perfluorooctanoate failed to cause mutagenesis when assayed in the Ames Salmonella typhimurium strains TA1535, TA1537, TA1538, and TA100. It was nonrecombinogenic in the Saccharomyces cerevisiae yeast assay. All assays were with and without metabolic activation.⁽¹²⁾ In the C3H 10T1/2 colony cell line transformation assay, ammonium perfluorooctanoate showed no evidence of cell transformation. The LC₅₀ for the cell line was approximately 50 μg/ml.⁽¹²⁾

Human Studies

Organic fluoride concentrations were found in the blood of workers exposed to ammonium perfluorooctanoate in an industrial environment; these levels were higher in the industrial workers than in individuals who had no industrial exposure.⁽¹³⁾ The material is not readily cleared from the blood and has a half-life of more than 1 to 2 years. No adverse health effects attributable to exposure were found among the exposed workers. Exposure levels encountered in that setting ranged from 0.032 to 7.6 mg/m³ with average concentrations for various process steps being related to the specific job assignments.

TLV Recommendation

A TLV–TWA of 0.01 mg/m³ is based on the data from the human studies and the extended half-life in the human blood system,⁽¹³⁾ the no-observed-effect levels found in rats exposed to ammonium perfluorooctanoate by various routes including inhalation,^(2,3,6) and the carcinogenic response following lifetime feeding of rats at 300 ppm.⁽⁶⁾ The systemic effects (liver and blood organofluoride levels) from percutaneous studies in animals⁽²⁾ warrant the Skin notation. Based on testicular (Leydig cell) cancer in rodents,⁽⁶⁾ an A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans, notation is considered appropriate.

Sufficient data were not available to recommend a SEN notation. The reader is expected to be familiar with the section on Excursion Limits in the “Introduction” of the current edition of the Documentations of the Chemical Substance TLVs for the guidance and control of excursions above the TLV–TWA, even when the 8-hour TWA is within the recommended limit.

Historical TLVs

1986: Proposed: TLV–TWA, 0.1 mg/m³; Skin
1988–1993: TLV–TWA, 0.1 mg/m³; Skin
1993: Proposed: TLV–TWA, 0.01 mg/m³; Skin; A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans
1994–present: TLV–TWA, 0.01 mg/m³; Skin; A3

References

1.  Griffith, F.D.; Long, J.E.: Animal Toxicity Studies with Ammonium Perfluorooctanoate. Am. Ind. Hyg. Assoc. J. 41:576–583 (1980).
2.  Kennedy, Jr., G.L.: Dermal Toxicity of Ammonium Perfluorooctanoate. Toxicol. Appl. Pharmacol. 81:348– 355 (1985).
3.  Perkins, R.G.: Investigation of Ammonium Perfluorooctanoate Effect on Hormone Levels and Peroxisomal Proliferation in the Rat. Toxicologist 12:38 (1992).
4.  Cook, J.C.; Murray, S.M.; Frame, S.R.; Hurtt, M.E.: Induction of Leydig Cell Adenomas by Ammonium Perfluorooctanoate: A Possible Endocrine-Related Mechanism. Toxicol. Appl. Pharmacol. 113:209–217 (1992).
5.  Handler, J.A.; Seed, C.B.; Bradford, B.U.; Thurman, R.G.: Induction of Peroxisomes by Treatment with Perfluorooctanoate Does Not Increase Rates of H₂O₂ Production in Intact Liver. Toxicology Lett. 60:61–68 (1992).
6.  Kennedy, Jr., G.L.; Hall, G.T.; Brittelli, M.R.; et al.: Inhalation Toxicity of Ammonium Perfluorooctanoate. Food Chem. Toxicol. 24:1325–1329 (1986).
7.  Hanijarvi, H.; Ophaug, R.H.; Singer, L.: The Sex-Related Difference in Perfluorooctanoate Excretion in the Rat. Proc. Soc. Exp. Biol. Med. 171:50–55 (1982).
8.  Long, P.L.: Spontaneous Neoplastic Lesions and Selected Non-Neoplastic Lesions in the Crl: CD^® BR Rat. Charles River, Inc., Kingston, NY (1992).
9.  Riker Laboratories, Inc./Three M Company: Two-Year Oral (Diet) Toxicity/Carcinogenicity Study of Fluorochemical FC-143 in Rats. Riker Experiment No. 0281CR0012. Riker Laboratories, Inc., St. Paul, MN (May 1983).
10.  Abdellatif, A.G.; Preat, V.; Taper, H.S.; Roberfroid, M.: The Modulation of Rat Liver Carcinogenesis by Perfluorooctanoic Acid, A Peroxisome Proliferator. Toxicol. Appl. Pharmacol. 111:530–537 (1991).
11.  Staples, R.E.; Burgess, B.A.; Kerns, W.D.: The Embryo-Fetal Toxicity and Teratogenic Potential of Ammonium Perfluorooctanoate (APFO) in the Rat. Fund. Appl. Toxicol. 4:429–440 (1984).
12.  Three M Company: Product Toxicity Summary–Fluorad^® Brand Fluorochemical Surfactant FC-143. Three M Company, St. Paul, MN (August 1984).
13.  Ubel, F.A.; Sorenson, S.D.; Roach, D.E.: Health Status of Plant Workers Exposed to Fluorochemicals—A Preliminary Report. Am. Ind. Hyg. Assoc. J. 41:584–589 (1980)