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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

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

FULL REPORT PDF

Abstract

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 20% 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 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). 2019. 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. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 96.

Studies

Summary of Findings Considered to Be Toxicologically Relevant in Sprague Dawley (Hsd:Sprague Dawley SD) Rats Administered Perfluoroalkyl Sulfonates by Gavage for 28 Days

PFBSMale Rats

PFBSFemale Rats

PFHxSKMale Rats

PFHxSKFemale Rats

PFOSMale Rats

PFOSFemale Rats

WYMale Rats

WYFemale Rats

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

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

No effect

Triglycerides

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

No effect

Sorbitol Dehydrogenase

No effect

No effect

No effect

No effect

No effect

Bile Acid

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

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 sulfonate 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.