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https://ntp.niehs.nih.gov/go/tox096abs

Abstract for TOX-96

Toxicity Studies of Perfluoroalkyl Sulfonates Administered by Gavage to Sprague Dawley (Hsd:Sprague Dawley SD) Rats (Revised)

Substances:

  • Perfluorobutane sulfonic acid (CASRN 375-73-5)
  • Perfluorohexane sulfonate potassium salt (CASRN 3871-99-6)
  • Perfluorooctane sulfonic acid (CASRN 1763-23-1)
  • WY-14643 (CASRN 50892-23-4)

Report Date: August 2019; July 2022 (Revised)

FULL REPORT PDF

Abstract

[July 28, 2022] Transcription errors were identified in the TOX-96 NTP report, and an audit was conducted. The report was revised and is republished with an appendix that identifies the corrections. Please note that the final data tables are available in the Chemical Effects in Biological Systems (CEBS) database.

Widespread exposure to several per/polyfluorinated alkyl substances (PFAS) is associated with a variety of toxicities that include liver and endocrine toxicity. The National Toxicology Program (NTP) conducted 28-day toxicity studies in male and female Sprague Dawley (Hsd:Sprague Dawley SD) rats (n = 10/dose; five doses per chemical) to compare the toxicities of seven PFAS (three sulfonic acids or salt: perfluorobutane sulfonic acid [PFBS], perfluorohexane sulfonate potassium salt [PFHxSK], and perfluorooctane sulfonic acid [PFOS], and four carboxylates) via gavage in deionized water with 2% Tween 80. This report describes the studies for the two sulfonic acids (PFBS and PFOS) and salt (PFHxSK); a companion report (NTP Toxicity Study Report 97) describes the studies for the PFAS carboxylates. Doses were 0 to 1,000 mg/kg/day for PFBS, 0 to 10 mg/kg/day for PFHxSK males, 0 to 50 mg/kg/day for PFHxSK females, and 0 to 5 mg/kg/day for PFOS.

A peroxisome proliferator-activated receptor alpha (PPARα) agonist (Wyeth‑14,643) was used for qualitative comparison to the PFAS evaluated (0 to 25 mg/kg/day). These studies evaluated clinical pathology, thyroid hormones, liver expression of PPARα- (Cyp4a1, Acox1) and constitutive androstane receptor (CAR)-related genes (Cyp2b1, Cyp2b2), liver acyl-CoA oxidase enzyme activity (males only), plasma and liver (males only) parent compound concentrations, and histopathology.

There was no effect on survival in PFOS or PFHxSK rats, but reduced survival was observed in the PFBS rats. Lower body weights were observed in PFBS rats and to a lesser extent in PFOS rats. Plasma and liver concentrations normalized to dose were the highest in male and female PFOS rats and the lowest in PFBS rats with apparent sex differences in plasma concentrations observed in PFHxSK rats. Findings that occurred in two or more PFAS were increased liver weights (absolute and relative to body weight), increased Cyp4a1, Acox1, Cyp2b1, Cyp2b2 expression, increased acyl-CoA oxidase activity. Several clinical chemistry endpoints were altered in PFBS and PFOS including increased liver enzyme activities; increased total bile acid and direct bilirubin concentrations; and decreased globulin, cholesterol, and triglyceride concentrations. In PFHxSK males, globulin, cholesterol, and triglyceride concentrations were decreased. Reticulocyte counts were decreased in all but the PFHxSK females. Histopathologic findings included hepatocellular hypertrophy and/or cytoplasmic alteration, bone marrow hypocellularity, and lesions of the nose. Decreases in thyroid hormones were present across these chemicals and occurred at almost all doses administered, but thyroid stimulating hormone did not increase in response.

In bacterial mutagenicity tests, PFBS was equivocal in Salmonella typhimurium strain TA98 with or without exogenous metabolic activation; all other results for PFBS and PFOS were negative. In vivo, no increases in micronucleated reticulocytes were observed in male or female rats administered PFBS, PFHxSK, or Wyeth-14,643. In male rats administered PFOS in vivo, no increases were observed; an equivocal result was observed in female rats administered PFOS.

In general, the effects in male and female rats administered PFHxSK were of lower magnitude (e.g., liver or clinical pathology findings) or not apparent compared to the effects in rats exposed to PFBS and PFOS. This corresponded, to some degree, with limited to no increases in liver Acox1 and Cyp gene expression changes. Several of the effects observed in the liver were also observed in rats administered Wyeth-14,643, but effects observed outside the liver by the PFAS were not observed with Wyeth-14,643. These data provide a basis for comparisons across the PFAS class, either using external (e.g., mol/kg/day) or internal (e.g., plasma μM) dose.

National Toxicology Program (NTP). 2022. NTP technical report on the toxicity studies of perfluoroalkyl sulfonates (perfluorobutane sulfonic acid, perfluorohexane sulfonate potassium salt, and perfluorooctane sulfonic acid) administered by gavage to Sprague Dawley (Hsd:Sprague Dawley SD) rats (revised). Research Triangle Park, NC: National Toxicology Program. Toxicity Report 96. https://doi.org/10.22427/NTP-TOX-96

Studies

Summary of Findings Considered to Be Toxicologically Relevant in Sprague Dawley (Hsd:Sprague Dawley SD) Rats Administered Perfluoroalkyl Sulfonates by Gavage for Twenty-Eight Days
  PFBS
Male
PFBS
Female
PFHxSK
Male
PFHxSK
Female
PFOS
Male
PFOS
Female
WY
Male
WY
Female
Doses in deionized water with Tween 80 (mg/kg/day) 0–1,000 [a] 0–1,000 [a] 0–10 0–50 0–5 0–5 0–25 0–25
Survival rates No effect No effect No effect No effect No effect No effect
Body weights No effect No effect No effect
Organ weights  
R. adrenal gland
Absolute
No effect No effect No effect No effect No effect
Relative
No effect No effect No effect No effect No effect No effect
Heart
Absolute
No effect No effect No effect
Relative
No effect No effect No effect No effect No effect No effect
R. kidney
Absolute
No effect No effect No effect No effect No effect
Relative
No effect No effect No effect
Liver
Absolute
Relative
Lung
Absolute
No effect No effect No effect No effect No effect No effect No effect No effect
Relative
No effect No effect No effect No effect No effect No effect No effect
Spleen
Absolute
No effect No effect No effect No effect No effect
Relative
No effect No effect No effect No effect No effect No effect No effect No effect
Thymus
Absolute
No effect No effect No effect No effect
Relative
No effect No effect No effect No effect No effect No effect
Hematology
Erythrocytes No effect No effect No effect No effect No effect No effect No effect
Hemoglobin No effect No effect No effect No effect No effect No effect No effect
Hematocrit No effect No effect No effect No effect No effect No effect No effect
Reticulocytes No effect No effect No effect
Leukocytes No effect No effect No effect No effect No effect No effect No effect
S. neutrophils No effect No effect No effect No effect No effect No effect No effect
Clinical chemistry
Total protein No effect No effect No effect No effect
Albumin No effect No effect No effect No effect
Globulin No effect No effect No effect
Albumin/globulin ratio No effect No effect
Total bilirubin No effect No effect No effect No effect No effect No effect
Direct bilirubin No effect No effect No effect
Cholesterol No effect No effect
Triglycerides No effect No effect No effect No effect
Alanine aminotransferase No effect No effect
Alkaline phosphatase No effect No effect
Aspartate aminotransferase No effect No effect No effect
Sorbitol dehydrogenase No effect No effect No effect No effect No effect
Total bile acids No effect No effect No effect
Thyroid stimulating hormone No effect No effect No effect No effect No effect No effect
Total thyroxine No effect
Free thyroxine No effect
Total triiodothyronine No effect No effect
Testosterone No effect No effect No effect No effect No effect No effect
Gene expression
Acox1 No effect
Cyp4a1 No effect
Cyp2b1
Cyp2b2
Acyl-CoA oxidase NA NA NA NA
Reproductive toxicity
Altered estrous cyclicity NA Yes NA No effect NA Yes NA Yes
Altered sperm parameters No effect NA No effect NA No effect NA Yes NA
Nonneoplastic effects
Liver:
Hepatocyte, cytoplasmic alteration
No effect No effect No effect
Hepatocyte, hypertrophy
No effect
Hepatocyte, vacuolization cytoplasmic
No effect No effect No effect No effect No effect No effect No effect
Necrosis
No effect No effect No effect No effect No effect No effect
Bone marrow:
Hypocellularity
No effect No effect No effect No effect
Kidney:
Papilla, necrosis
No effect No effect No effect No effect No effect No effect
Nose:
Olfactory epithelium, degeneration
No effect No effect No effect No effect No effect
Olfactory epithelium, hyperplasia
No effect No effect No effect No effect No effect
Olfactory epithelium, inflammation, suppurative
No effect No effect No effect No effect No effect
Olfactory epithelium, necrosis
No effect No effect No effect No effect No effect No effect
Spleen:
Extramedullary hematopoiesis, decreased
No effect No effect No effect No effect No effect No effect
Stomach, forestomach:
Epithelium, hyperplasia
No effect No effect No effect No effect No effect No effect No effect
Thymus:
Atrophy
No effect No effect No effect No effect No effect No effect
Genetic toxicology
Bacterial gene mutations Equivocal in S. typhimurium strain TA98, with and without S9 mix; negative in TA100 and E. coli strain WP2 uvrA/pKM101, with and without S9 Not tested Negative in S. typhimurium strains TA98 and TA100 and E. coli strain WP2 uvrA/pKM101, with and without S9 Not tested
Micronucleated erythrocytes
Rat peripheral blood in vivo Negative Negative Negative Negative Negative Equivocal Negative Negative


PFBS = perfluorobutane sulfonic acid.

PFHxSK = perfluorohexane sulfonic acid potassium salt.

PFOS = perfluorooctane sulfonic acid.

WY = Wyeth-14,643.

NA = not applicable; reproductive hazard calls were not considered appropriate.

[a] One-half the dose was administered daily.