Skip to Main Navigation
Skip to Page Content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Share This:
https://ntp.niehs.nih.gov/go/tox097abs

Abstract for TOX-97

Toxicity Studies of Perfluoroalkyl Carboxylates Administered by Gavage to Hsd: Sprague Dawley SD Rats

Substances:

  • Perfluorohexanoic acid (CASRN 307-24-4)
  • Perfluorooctanoic acid (CASRN 335-67-1)
  • Perfluorononanoic acid (CASRN 375-95-1)
  • Perfluorodecanoic acid (CASRN 335-76-2)
  • 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 wide array of toxicities. 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) to compare the toxicities of seven PFAS chemicals (three sulfonic acids or salt: perfluorobutane sulfonic acid, perfluorohexane sulfonate potassium salt, and perfluorooctane sulfonic acid; and four carboxylates: perfluorohexanoic acid [PFHxA], perfluorooctanoic acid [PFOA], perfluorononanoic acid [PFNA], and perfluorodecanoic acid [PFDA]) via gavage in deionized water with 20% Tween® 80. This report describes the studies of the four carboxylates (PFHxA, PFOA, PFNA, and PFDA); a companion report (NTP Toxicity Study Report 96) describes the studies of the three PFAS sulfonates. Doses were 0 to 1,000 mg/kg/day for PFHxA, 0 to 5 mg/kg/day for PFOA males, 0 to 100 mg/kg/day for PFOA females, 0 to 5 mg/kg/day for PFNA males, 0 to 25 mg/kg/day for PFNA females, and 0 to 2.5 mg/kg/day for PFDA.

A peroxisome proliferator-activated receptor alpha (PPARα) agonist (Wyeth-14,643) was used at a dose of 0 to 25 mg/kg/day for qualitative comparison to the PFAS evaluated. 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) concentrations, and histopathology.

There was no effect on survival in animals administered PFHxA, PFOA, or PFDA, but treatment-related reduced survival was observed in males and females administered PFNA. Lower body weights were observed in male rats treated with PFHxA, PFOA, PFNA, and PFDA; lower body weights were also observed in females administered PFNA and PFDA. Plasma and liver concentrations normalized to dose were generally higher in animals administered the longer-chain PFAS. PFHxA and PFOA females had lower plasma concentrations than did males when normalized to dose. Common findings across two or more of the PFAS presented in this report included increased liver weights (absolute and relative to body weight); increased Acox1, Cyp4a1, Cyp2b1, and Cyp2b2 expression; and increased acyl-CoA oxidase activity. Clinical chemistry endpoints were altered in several PFAS, including increased liver enzyme activities (aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase, and sorbitol dehydrogenase); decreased globulin and cholesterol concentrations; and increased bile acids and direct bilirubin concentrations. PFHxA male and female rats had a dose-dependent hypochromic, macrocytic, regenerative decrease in the red blood cell mass characterized by a decrease in erythrocyte count, hemoglobin concentration, and hematocrit with an increase in reticulocyte counts. In most PFAS, total thyroxine (T4) and free T4 were decreased with no compensatory increase in thyroid stimulating hormone. Histopathologic findings observed in more than one PFAS were in the liver (hepatocyte hypertrophy, hepatocyte cytoplasmic alteration, and hepatocyte necrosis), nose (olfactory epithelium degeneration and hyperplasia), bone marrow (hypocellularity), thymus (atrophy), testes (germinal epithelium degeneration, interstitial cell atrophy, and spermatid retention), and epididymis (exfoliated germ cell).

PFHxA, PFOA, PFNA, and PFDA were negative in bacterial mutagenicity tests. In vivo, no increases in micronucleated reticulocytes were seen in male or female rats exposed to PFHxA, PFNA, or PFDA; a small increase in micronucleated reticulocytes was observed in male rats exposed to PFOA.

In general, the effects in male and female rats administered PFHxA were of lower magnitude (e.g., liver or clinical pathology findings) or not apparent compared to the effects in animals exposed to PFNA or PFDA. Several of the effects observed in the liver were also observed in Wyeth-14,643 animals, but some extrahepatic effects were not observed with Wyeth-14,643, suggesting that PFAS chemicals induce toxicity by a variety of pathways apart from PPARα. 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 carboxylates (perfluorohexanoic acid, perfluorooctanoic acid, perfluorononanoic acid, and perfluorodecanoic acid) administered by gavage to Sprague Dawley (Hsd:Sprague Dawley SD) rats. Research Triangle Park, NC: National Toxicology Program. Toxicity Report 97.

Studies

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

PFHxA
Male Rats

PFHxA
Female Rats

PFOA
Male Rats

PFOA
Female Rats

PFNA
Male Rats

PFNA
Female Rats

PFDA
Male Rats

PFDA
Female Rats

Doses in Deionized Water with Tween® 80 (mg/kg/day)

0–1,000 [#]

0–1,000 [#]

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

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

R. Kidney

Absolute

No effect

Relative

Liver

Absolute

Relative

Spleen

Absolute

No effect

No effect

No effect

Relative

No effect

No effect

No effect

No effect

R. Testis

Absolute

No effect

-

No effect

-

-

-

Thymus

Absolute

No effect

No effect

No effect

Relative

No effect

No effect

No effect

No effect

No effect

Thyroid Gland

Absolute

No effect

No effect

No effect

No effect

No effect

Relative

No effect

No effect

No effect

No effect

Hematology

Hematocrit

No effect

No effect

No effect

↑ [a]

Hemoglobin

No effect

No effect

No effect

↑ [a]

Erythrocytes

No effect

No effect

↑ [a]

↑ [a]

Mean corpuscular hemoglobin concentration

No effect

No effect

No effect

Mean corpuscular volume

No effect

No effect

Reticulocytes

No effect

No effect

Platelets

No effect

No effect

No effect

No effect

No effect

Clinical Chemistry

Total Protein

No effect

↑ [a]

No effect

Albumin

No effect

No effect

↑ [a]

↑ [a]

No effect

Globulin

Albumin/Globulin Ratio

T Bilirubin

↓ [a]

↓ [a]

↓ [a]

No effect

No effect

Direct Bilirubin

No effect

No effect

No effect

Indirect Bilirubin

↓ [a]

No effect

↓ [a]

No effect

No effect

Cholesterol

No effect

No effect

Triglycerides

No effect

No effect

No effect

No effect

Alanine Aminotransferase

Alkaline Phosphatase

Aspartate Aminotransferase

No effect

No effect

Sorbitol Dehydrogenase

No effect

No effect

No effect

No effect

No effect

Creatinine Kinase

No effect

No effect

↓ [a]

No effect

No effect

No effect

No effect

Bile Acid

No effect

Thyroid Stimulating Hormone

No effect

No effect

No effect

No effect

No effect

Total Thyroxine

No effect

No effect

No effect

Free Thyroxine

No effect

Total Triiodothyronine

No effect

No effect

No effect

No effect

Testosterone

No effect

No effect

No effect

No effect

No effect

Gene Expression

Acox1

Cyp4a1

Cyp2b1

Cyp2b2

Acyl-CoA Oxidase

NA

NA

NA

NA

Reproductive Toxicity

Altered Estrous Cyclicity

-

No call

-

Yes

-

No call

-

Yes

Altered Sperm Parameters

Yes

-

Yes

-

Yes

-

Yes

-

Nonneoplastic Effects

Liver:

Hepatocyte, Cytoplasmic Alteration

Hepatocyte, Hypertrophy

Hepatocyte, Vacuolization Cytoplasmic

No effect

No effect

No effect

No effect

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

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

Respiratory Epithelium, Hyperplasia

No effect

No effect

No effect

No effect

No effect

No effect

Respiratory Epithelium, Inflammation, Chronic Active

No effect

No effect

No effect

No effect

No effect

No effect

Bone Marrow:

Hypocellularity

No effect

No effect

No effect

Spleen:

Extramedullary Hematopoiesis, Increased

No effect

No effect

No effect

No effect

No effect

No effect

Atrophy

No effect

No effect

No effect

No effect

No effect

No effect

Kidney:

Nephropathy, Chronic Progressive

No effect

No effect

No effect

No effect

No effect

No effect

No effect

Thymus:

Atrophy

No effect

No effect

No effect

No effect

Lymphocyte, Apoptosis

No effect

No effect

No effect

No effect

No effect

No effect

No effect

Thyroid Gland:

Follicular Cell Hypertrophy

No effect

No effect

No effect

No effect

No effect

No effect

Lymph Nodes:

Mandibular, Atrophy

No effect

No effect

No effect

No effect

No effect

No effect

Mesenteric, Atrophy

No effect

No effect

No effect

No effect

No effect

No effect

Forestomach:

Epithelium, Hyperplasia

No effect

No effect

No effect

No effect

No effect

No effect

Inflammation, Chronic Active

No effect

No effect

No effect

No effect

-

No effect

No effect

Testes:

Germinal Epithelium, Degeneration

No effect

-

No effect

-

-

-

Interstitial Cell, Atrophy

No effect

-

No effect

-

-

-

Seminiferous Tubule, Spermatid Retention

No effect

-

No effect

-

-

-

Epididymis:

Hypospermia

No effect

-

No effect

-

-

No effect

-

Duct, Exfoliated Germ Cell

No effect

-

No effect

-

-

-

Epithelium, Apoptosis

No effect

-

No effect

-

-

No effect

-

Genetic Toxicology

Bacterial Gene Mutations

Negative in TA98, TA100, and E. coli with or without S9

Negative in TA98, TA100, and E. coli with or without S9

Negative in TA98, TA100, and E. coli with or without S9

Negative in TA98, TA100, and E. coli with or without S9

Micronucleated Erythrocytes

Rat Peripheral Blood In Vivo

Negative

Negative

Positive

Negative

Negative

Negative

Negative

Negative


PFHxA = perfluorohexanoic acid.

PFOA = perfluorooctanoic acid.

PFNA = perfluorononanoic acid.

PFDA = perfluorodecanoic acid.

# One-half the dose was administered twice daily.

[a] Treatment-related effect not considered toxicologically relevant.

Summary of Findings Considered to Be Toxicologically Relevant in Sprague Dawley (Hsd:Sprague Dawley SD) Rats Administered Wyeth-14,643 by Gavage for 28 Days

WY 
Male Rats

WY
Female Rats

Doses in Deionized Water with Tween® 80 (mg/kg/day)

0–25

0–25

Survival Rates

No effect

No effect

Body Weights

No effect

Organ Weights

R. Adrenal Gland

Absolute

No effect

No effect

Relative

No effect

No effect

R. Kidney

Absolute

Relative

Liver

Absolute

Relative

Spleen

Absolute

No effect

Relative

No effect

No effect

R. Testis

Absolute

No effect

-

Thymus

Absolute

No effect

No effect

Relative

No effect

No effect

Thyroid Gland

Absolute

No effect

No effect

Relative

No effect

Hematology

Hematocrit

No effect

No effect

Hemoglobin

No effect

No effect

Erythrocytes

No effect

No effect

Mean corpuscular hemoglobin concentration

No effect

No effect

Mean corpuscular volume

No effect

No effect

Reticulocytes

No effect

No effect

Platelets

No effect

No effect

Clinical Chemistry

Total Protein

[a]

Albumin

[a]

[a]

Globulin

Albumin/Globulin Ratio

T Bilirubin

No effect No effect

Direct Bilirubin

No effect

Indirect Bilirubin

No effect No effect

Cholesterol

No effect

Triglycerides

No effect No effect

Alanine Aminotransferase

Alkaline Phosphatase

Aspartate Aminotransferase

Sorbitol Dehydrogenase

Creatinine Kinase

No effect No effect

Bile Acid

Thyroid Stimulating Hormone

Total Thyroxine

No effect

Free Thyroxine

No effect

Total Triiodothyronine

No effect

Testosterone

NA

 Gene Expression

Acox1

Cyp4a1

Cyp2b1

Cyp2b2

Acyl-CoA Oxidase

Not tested

Reproductive Toxicity

Altered Estrous Cyclicity

-

Yes

Altered Sperm Parameters

Yes

-

Nonneoplastic Effects

Liver:

Hepatocyte, Cytoplasmic Alteration

Hepatocyte, Hypertrophy

Hepatocyte, Vacuolization Cytoplasmic

No effect

No effect

Necrosis

No effect

No effect

Nose:

Olfactory Epithelium, Degeneration

No effect

No effect

Olfactory Epithelium, Hyperplasia

No effect

No effect

Olfactory Epithelium, Inflammation, Suppurative

No effect

No effect

Respiratory Epithelium, Hyperplasia

No effect

No effect

Respiratory Epithelium, Inflammation, Chronic Active

No effect

No effect

Bone Marrow:

Hypocellularity

No effect

No effect

Spleen:

Extramedullary Hematopoiesis, Increased

No effect

No effect

Atrophy

No effect

No effect

Kidney:

Nephropathy, Chronic Progressive

No effect

No effect

Thymus:

Atrophy

No effect

No effect

Lymphocyte, Apoptosis

No effect

No effect

Thyroid Gland:

Follicular Cell Hypertrophy

No effect

No effect

Lymph Nodes:

Mandibular, Atrophy

No effect

No effect

Mesenteric, Atrophy

No effect

No effect

Forestomach:

Epithelium, Hyperplasia

No effect

No effect

Inflammation, Chronic Active

No effect

No effect

Testes:

Germinal Epithelium, Degeneration

No effect

-

Interstitial Cell, Atrophy

No effect

-

Seminiferous Tubule, Spermatid Retention

No effect

-

Epididymis:

Hypospermia

No effect

-

Duct, Exfoliated Germ Cell

No effect

-

Epithelium, Apoptosis

No effect

-

Genetic Toxicology

Bacterial Gene Mutations

-

-

Micronucleated Erythrocytes Rat Peripheral Blood In Vivo

Negative

Negative


WY = Wyeth-14,643.

[a] Treatment-related effect not considered toxicologically relevant.