Table 19

PFOS (potassium salt)

CAS. No. 2795-39-3

86.9%.

Bagley et al. (2017)

SD rats

Males and females.

12/sex/dose.

0 or 100 ppm in diet equivalent to 6 (males) and 6.6 (females).

Diet,

3 weeks,

Non-GL study,

GLP not stated.

NR

Males (mean ± SD):

↓ body weight gain: data only reported in figures.

↑ absolute liver weight (g): 9.3 ± 1.2 vs 16.4 ± 1.6.

↑ relative liver weight: 0.031 ± 0.003 vs 0.057 ± 0.003.

↓ AST (U/L): 69 ± 7.2 vs 58 ± 3.8 on day 2; 89 ± 20.0 vs 64 ± 5.2 on day 9.

↓ ALT (U/L):  29 ± 4.0 vs 26 ± 3.0 on day 2; 32 ± 6.3 vs 28 ± 3.7 on day 9; 63 ± 8.2 vs 62 ± 7.2 on day 16.

↓ TGs (mg/dL): 120 ± 36.6 vs 71 ± 19.3 on day 16; 57 ± 9.3 vs 28 ± 6.3 on day 23.

↓ total bilirubin (mg/dL): 0.1 ± 0.1 vs 0.02 ± 0.04 on day 9;

0.1 ± 0.1 vs 0.3 ± 0.1 on day 23.

↑ hepatic free FA: data only reported in figures.

↑ hepatic TGs: data only reported in figures.

↑ ground-glass cytoplasmic alterations:  0 vs 12.

↑ minimal to moderate microscopic hepatic necrosis: 0 vs 1.

↑ hepatocellular hypertrophy: 0 vs 9.

Females:

↓ body weight from day 11: data only reported in figures.

↓ body weight gain: data only reported in figures.

↑ absolute liver weight (g): 5.9 ± 0.6 vs 7.6 ± 0.6.

↑ relative liver weight: 0.032 ± 0.003 vs 0.047 ± 0.002.

↓ AST

↓ total cholesterol.

↓ LDH

↓ hepatic free FA: data only reported in figures.

↓ hepatic TGs: data only reported in figures.

↑ minimal to moderate microscopic hepatic necrosis: 0 vs 2.

↑ hepatocellular hypertrophy: 0 vs 7.

Males:

NA / 6*.

Females:

NA / 6*.

Dietary 100 ppm PFOS fed to male rats caused hepatic steatosis through an unknown mechanism.

Incidental statistically significant differences were noted in the liver (AST, ALT, ALP, bilirubin (total, indirect and direct), gamma-glutamyl transferase), in male and/or female rats across the evaluated timepoints, but

these values were within the historical reference ranges and

were not considered toxicologically relevant.

K1

This study tested whether

dietary choline supplementation attenuates PFOS-induced hepatic steatosis in rats.

Only two dose groups were used i.e., control and single treatment group.

Unrestricted funding was provided by 3M Company, St Paul, MN, USA, which is a current or former employer of the authors.

PFOS (potassium salt)

CAS. No. 2795-39-3

87.6%.

Bijland et al. (2011)

APOE*3-Leiden.CETP mice.

Male

6-8/dose.

0 or 0.003% in diet equivalent to 3

Diet (vehicle).

Diet,

4-6 weeks,

OECD 407,

GLP not stated.

At 6 mg/kg bw/day at 4-6 weeks (mean ± SD)

Serum: 85.6-124.7 ± 4.2-9.5.

Males:

↑ liver weight: data only reported in figures.

↓ plasma TG: data only reported in figures.

↓ free cholesterol: data only reported in figures.

↓ non HDL cholesterol: data only reported in figures.

↓ HDL cholesterol: data only reported in figures.

↑ hepatic TG: data only reported in figures.

↓ bile acid excretion: data only reported in figures

Altered gene expression related to transcription factors, lipolysis, FA uptake and transport, FA binding and activation, FA oxidation, FA/TG synthesis, VLDL assembly, cholesterol synthesis, storage, metabolism and excretion, HDL formation, maturation, remodeling and uptake.

Recovery not assessed.

Males:

NA / 3*

The potency of PFAS to affect lipoprotein metabolism increased with increasing alkyl chain length.

The data suggest that PFOS reduces plasma TG and total cholesterol mainly by impairing lipoprotein production.

K2

This study investigated the mechanism underlying the effect of PFAS on lipoprotein metabolism.

Only two dose groups were used i.e., control and single treatment group and only male animals were used.

The study was funded by the Nutrigenomics Consortium/Top Institute Food and Nutrition; the Netherlands Genomics Initiative; the Netherlands Organization for Health Care Research Medical Sciences); the Netherlands Organization for Scientific Research; the Netherlands Heart Foundation.

Authors are affiliated to 3M company.

PFOS (potassium salt)

CAS no. Not given

86.9%.

Butenhoff et al. (2012b)

Crl:CD®(SD)

IGS BR rats.

Male and

Female,

60-70/sex

/dose.

Recovery group: 40/dose.

0, 0.5, 2, 5 or 20 ppm in diet equivalent to 0, 0.024, 0.098, 0.242, 0.984 (males) and

0, 0.029, 0.120, 0.299, 1.251 (females).

Diet,

104 weeks,

Non-GL study,

GLP not stated.

Recovery:

20 ppm in diet equivalent to 1.144 (males) or 1.385 (females)

52 weeks treatment followed by control diet to 104 weeks.

At 0.024 mg/kg bw/day in males at week 105 (mean ± SD)

Serum: 1.31 ± 1.30

Liver: 7.83 ± 7.34.

At 0.098 mg/kg bw/day in males at week 105

Serum: 7.60 ± 8.60

Liver: 26.40 ± 20.40.

At 0.024 mg/kg bw/day in females at week 105

Serum: 4.35 ± 2.78

Liver: 12.9 ± 6.81.

At 0.098 mg/kg bw/day in females at week 102 (mean ± SD)

Serum: 20.20 ± 13030.

Liver: 55.10 ± 31.50.

Males:

↑ hepatocellular centrilobular hypertrophy: 0/65 vs 4/55^#.

↑ cystic hepatocellular

degeneration: 5/65 vs 19/55.

Females:

↑ hepatocellular periportal vacuolation: 15/65 vs 22/55.

↓ serum total cholesterol at week 27: data only reported in figures.

Recovery:

Data not presented as animals only treated with 1.144/1.385 mg/kg bw/day and not 0.098 mg/kg bw/day (LOAEL).

Males:

0.024 / 0.098.

Females: 0.024 / 0.098.

Increased liver tumour incidence BMDL10 (diet)

7.9 and 8.0 ppm in males and females respectively.

BMDL10 (serum)

62 and 92 µg/mL in males and females respectively.

Recovery

Males:

NA / 1.144.

Females: 1.385 / NA.

Liver was the principal target of dietary exposure. The liver effects, as evidenced by either serum clinical chemistry or microscopic observations, were largely limited to centrilobular findings of hypertrophy, eosinophilic hepatocytic granules, hepatocytic pigment, hepatocytic vacuolation, and an increase in hepatocellular adenoma in the highest dietary dose group.

There were relatively few statistically significant or otherwise notable differences between the control and treated groups for clinical chemistry results.

The lowering of serum cholesterol is consistent with data from other studies with PFOS and likely represents a treatment-related effect.

K1

This study examined the toxicity and carcinogenicity of chronic (two years) dietary exposure to PFOS in male and female SD rats.

PFOS was of low purity with impurities including 4.73% PFHxS, 0.71% perfluorinated carboxylic acids (C4, C5, and C8), 1.45% metals, 0.59% inorganic fluoride.

Clinical chemistry changes were only largely seen at higher doses.

Limited changes in clinical chemistry were observed at the LOAEL as effects were only seen at higher doses.

^# liver histopathology measured in 55-65males and females/dose.

Authors are employees of 3M Company.

PFOS

(potassium salt)

CAS No. 2795-39-3

98%.

Chen et al. (2022)

C57BL/6 mice.

Male

6/dose.

0 or 500 µg/l in drinking water equivalent to 109. 

Drinking water.

28 days,

OECD 407,

GLP not stated.

At 109 mg/kg bw/day (mean ± SE)

Liver: 10.73 ± 1.19.

Males:

↑ lipid droplets: data only reported in figures.

↑ inflammation and apoptosis: data only reported in figures.

↑ TG: data only reported in figures.

↑ CAT activities (data only reported in figures: 310 lipids changed.

Changes in hepatic lipidome.

Recovery not assessed.

Males:

NA / 109*

PFOS is easier to accumulate in mouse livers than its substitute PFBS, which could be the most important contributor to the difference in toxicity of strength at the same exposure concentration.

PFOS exposure induced toxicity mainly through increasing oxidative damage and accumulation of TG.

K2

This study examined the effects of PFOS on lipid homeostasis in the liver of male C57BL/6 mice.

Only two dose groups were used i.e., control and single treatment group and only male animals were used.

This study was supported by the Natural Science Foundation of Jiangsu Province, and the Fundamental Research Funds for the Central Universities, the Research Program of State Key Laboratory of Pollution Control and Resource Reuse, and the Excellent Research Program of Nanjing University.

PFOS (potassium salt)

CAS no. Not given

86.9%.

Elcombe et al. (2012)

Sprague-Dawley rats.

Male,

10/dose (total 40/dose, 10 sacrificed on days 1, 28, 56 and 84 days post-treatment).

Recovery group: 10/dose.

0, 20 or 100 ppm in diet equivalent to 1.93 or 9.65.

Diet,

7 days,

Non-GL study

GLP not stated.

Recovery:

0, 20 or 100 ppm in diet equivalent to 0, 1.93 or 9.65.

Sacrificed on days 1, 28, 56, and 84.

At 1.93 mg/kg bw/day on day 1 (mean ± SD)
Serum: 39.49 ± 7.76

Liver: 123.92 ± 23.95.

At 1.93 mg/kg bw/day on day 28.
Serum:15.49 ± 1.60
Liver: 44.17 ± 4.36.

At 1.93 mg/kg bw/day on day 56.
Serum:8.03 ± 1.14

Liver: 32.99 ± 4.19.

At 1.93 mg/kg bw/day on day 84.
Serum:4.38 ± 0.72.

Liver: 24.99 ± 1.30.

Males (mean ± SD):

↓ body weight (g): 412.2 ± 46.8 vs 384.8 ± 46.8 on day 21 and 428.2 ± 50.9 vs 397.0 ± 51.4 on day 28. Comparable to controls on day 84.

↑ relative liver weight (%): 4.53 ± 0.29 vs 5.06 ± 0.38 on day 1 and 3.63 ± 0.39 vs 4.09 ±0.51 on day 84.

↑ plasma cholesterol (nmol/L): 2.73 ± 0.44 vs 2.17 ± 0.37 on day 1 and 2.29 ± 0.24 vs 1.61 ± 0.33 on day 28. Comparable to controls on day 84.

↑ DNA in liver (mg DNA/whole liver): 39.10 ± 5.30 vs 3.71 ± 3.74 on day 28 and 43.45 ± 10.91 vs 33.14 ± 5.09 on day 56. Comparable to controls on day 84.

 ↑ CYP450 (nmol P450/mg protein): 0.86 ± 0.12 vs 1.07 ± 0.24 on day 1, 0.65 ± 0.05 vs 0.87 ± 0.17 on day 28 and 0.68 ± 0.14 vs 0.95 ± 0.16 on day 56 and 0.60 ± 0.15 vs 0.80 ± 0.12 on day 84.

↑ hepatocellular hypertrophy: (0/10 vs 8/10 on day 1, 0/10 vs 5/10 on day 28, 0/10 vs 4/10 on day 56 and 0/10 vs 5/10 on day 84.

Males:

NA / 1.93*

Liver-related effects were seen in male rats during an 84-day recovery period following a 7-day dietary exposure. Exposure was sufficient to result in increased relative liver weight and centrilobular hepatocellular hypertrophy. Although many of the hepatic responses observed on the first day of recovery attenuated over the course of the recovery period, minimal-to-mild centrilobular hepatocellular hypertrophy tended to persist.

There were no significant elevations in liver enzymes (ALT or AST) during this study, suggesting absence of overt hepatic toxicity.

K2

This study evaluated the hepatic responses for up to 84 days in male Sprague-Dawley rats following a 7-day exposure to PFOS.

Only three dose groups were used i.e., control and two treatment groups and only male animals were used.

Authors are employed by 3M Company. This study was funded by 3M Company.

PFOS (potassium salt)

CAS no. Not given

98%.

Han et al. (2018b)

Sprague-Dawley rats.

Male,

6/dose.

0, 1 or 10

DMSO (< 0.4%) in corn oil.

Gavage,

28 days,

OECD 407,

GLP not stated.

Data only reported in figures.

Males (mean ± SE):

↑ ALT (U/L): 38.83 ± 4.59 vs 49.86 ± 3.78.

↑ TBA (nmol/L): 10.57 ± 1.20 vs 16.23 ± 0.55.

↑ TNF-α (ng/mL): 3.87 ± 0.40 vs 5.809 ± 0.34.

↑ IL-6 (ng/mL): 2.72 ± 0.13 vs 3.85 ± 0.43.

↑ PCNA positive nuclei: data only reported in figures.

↑ gene expression (PCNA, c-Jun, c-MYC, CydD1): data only reported in figures

Centrilobular hepatocyte hypertrophy: data only reported in figures.

Recovery not assessed.

Males:

NA / 1

The data suggest that PFOS induces Kupffer cell activation, leading to hepatocyte proliferation by through the NF-kB/TNF-ɑ/IL-6-dependent pathway.

K2

This study explored the effect of PFOS on Kupffer cell activation and hepatocyte proliferation in male SD rats.

Only three dose groups were used i.e., control and two treatment groups and only male animals were used.

This work was supported in part by a grant from the National Science and Technology Ministry of China, the National Natural Science Foundation of China, and the Gong-Yi Program of China Ministry of Environmental Protection.

PFOS (potassium salt)

CAS no. Not given

98%.

Han et al. (2018a)

Sprague-Dawley rats.

Male,

6/dose.

0, 1 or 10

DMSO (<0.4%) in corn oil.

Gavage,

28 days,

OECD 407,

GLP not stated.

NR

Males:

↑ ALT: data only reported in figures.

Recovery not assessed.

Males:

NA / 1

The study demonstrated the mechanism of action of PFOS-induced hepatic injury through ROS generation.

K2

This study investigated the effect of PFOS on oxidative stress and apoptosis in the liver of male rats.

Only three dose groups were used i.e., control and two treatment group and only male animals were used.

This work was supported in part by a grant from the National Science and Technology Ministry of China, the National Natural Science Foundation of China, and the Gong-Yi Program of China Ministry of Environmental Protection.

PFOS

(potassium salt)

CAS no. Not given

Purity not given.

Huck et al. (2018)

C47BL6/J mice,

Male,

5/dose.

0 or 0.089,

Diet,

6 weeks,

Non-GL study,

GLP not stated.

NR

Males:

↑ relative liver weight: data only reported in figures.

↑ TG in liver: data only reported in figures.

↓ gene expression of APOA1, APOA2, PEPCK, G6PC: data only reported in figures.

↑ gene expression of SREBF1: data only reported in figures.

↑ expression of CD36 and PPARγ:  data only reported in figures.

Males:

NA / 0.089

PFOS treatment significantly affected expression of lipid trafficking genes to favour steatosis. CD36, the major hepatocyte lipid importer, and PPARγ were induced by PFOS.

K2

This study examined the effects of PFOS on nonalcoholic fatty

liver disease and nonalcoholic steatohepatitis pathogenesis in male C47BL6/J mice.

Only two dose groups were used i.e., control and single treatment group and only male animals were used.

The study was supported by NIH-COBRE, NIEHS Toxicology Training Grant.

PFOS (potassium salt)

CAS No. 2795-39-3

>98%.

Kim et al. (2011)

Sprague-Dawley rats,

Male and female,

12/sex/group.

0, 1.25, 5 or 10

<0.1% DMSO in saline.

Gavage,

28 days,

OECD 407,

GLP not stated.

NR

Males (mean ± SD or SE (not specified)):

↑ relative liver weight: data only reported in figures.

↑ AST (IU/L): 56.8 ± 16.4 vs 89.4 ± 7.7.

↓ TGs (mg/dL): 58.7 ± 34.8 vs 12.9 ± 3.4.

↑ apoptosis: data only reported in figures.

↑ mRNA and protein levels of Cyp4A1: data only reported in figures.

Females:

↓ body weight in females: data only reported in figures

↑ relative liver weight: data only reported in figures

↑ hepatocellular hypertrophy: 0 vs 12.

Recovery not assessed.

Males:

5 / 10*.

Females:

5 / 10*.

PFOS revealed a significant hepatotoxicity in Sprague-Dawley rats at the dose levels of 5 and 10 mg/kg bw/day. However, the response showed an apparent gender difference. PFOS primarily affected liver by inducing apoptotic signals and CYP4A1 expression which might be a potent cause of blood hypolipidemia.

K1

This study explored the effects of low dose PFOS toxicity in male and female rats.

Only male rats at 0 and 10 mg/kg bw/day were investigated for apoptosis in liver and gene expression.

This research was supported by a grant from National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration for the Korea National Toxicology Program.

PFOS (potassium salt)

CAS No. 1763-23-1

>96%.

NTP. (2022a)

Sprague-Dawley rats,

Male and female, 10/sex/dose.

0, 0.312, 0.625, 1.25, 2.5 or 5.

2% Tween® 80 in deionized water.

Gavage,

28 days,

OECD 407,

GLP study.

At 3.12 mg/kg bw/day in males (mean ± SE)

Plasma: 23.7 ± 1.1

Liver: 87.2 ± 3.04.

At 3.12 mg/kg bw/day in females.

Plasma: 30.5 ± 0.9

Liver: NR.

Males (mean ± SE):

↑ relative liver weight (mg/g body weight): 34.92 ± 0.22 vs 38.66 ±0.47.

↑ absolute liver weight (g): 11.79 ± 0.29 vs 13.14 ± 0.28.

↓ cholesterol in serum (mg/dL): 115 ± 2 vs 97 ± 3.

↑ gene expression of Cyp4a1: 1.04 ± 0.1 vs 2.09 ± 0.18. 

↑ gene expression of Cyp2b1: 1.17 ± 0.21 vs 5.87 ± 1.05.

↑ gene expression of Cyp2b2: 1.22 ± 0.23 vs 6.60 ± 1.01.

Females (mean ± SE):

↑ relative liver weight (mg/g body weight): 33.56 ± 0.66 vs 36.15 ± 0.54.

↑ absolute liver weight (g): 7.37 ± 0.18 vs 8.26 ± 0.22.

↑ gene expression of Acox1:  1.02 ± 0.06 vs 1.32 ± 0.05.

↑ gene expression of Cyp4a1: 1.03 ± 0.08 vs 1.75 ± 0.12.

↑ gene expression of Cyp2b1: 1.53 ± 0.44 vs 32.47 ± 4.28.

↑ gene expression of Cyp2b2: 1.56 ± 0.47 vs 34.78 ± 6.76.

Recovery not assessed.

Males:

NA / 0.312*

Females:

NA / 0.312*

A major target organ for PFOS was the liver.

PFOS females showed increased liver weights, Cyp2b1 expression, and hepatocellular hypertrophy in the presence of minimal increases in Cyp4a1 expression.

Hepatocyte hypertrophy observed with PFOS is likely due to the peroxisome proliferation. This is also supported by the elevated Acox1 and Cyp4a1 levels known to be inducible by PPARα agonists. Hepatocyte hypertrophy can also partially be mediated through CAR, because CAR-activated Cyp2b1 is also elevated.

K1

This study investigated toxicity of PFOS following a 28-day exposure.

Liver enzymes were elevated only at higher doses than the LOAEL.

This study was funded by NTP. The study was audited retrospectively by an independent QA contractor.

PFOS (potassium salt)

CAS No. 2795-39-3

86.9%.

Seacat et al. (2002)

Cynomolgus monkeys

Male and female

4-6/sex/dose.

Recovery group:

(2/sex/dose).

0, 0.03, 0.15 or 0.75,

Lactose,

Gavage,

182 days,

Non-GL study,

GLP not stated.

Recovery group:

0, 0.15 or 0.75,

1 year.

At 0.15 mg/kg bw/day in males (mean ± SD)

Serum: 86.2 ± 25.2 ppm

Liver: 58.8 ± 19.5 ppm.

At 0.75 mg/kg bw/day in males.

Serum: 173 ± 37 ppm

Liver: 395 ± 24 ppm.

At 0.15 mg/kg bw/day in males.

Serum: 66.8 ± 10.8 ppm

Liver: 69.5 ± 14.9 ppm.

At 0.75 mg/kg bw/day in females.

Serum: 171 ± 22 ppm

Liver: 273 ± 14 ppm.

Males (mean ± SD):

↓ body weight gain (%): 14 ± 11% vs -8 ± 8% on day 182.

↑ mortality (0 vs 2)

↓ total cholesterol from day 91 (mg/dL): 152 ± 28 vs 48 ± 19.

↑ HDL from day 153 (mg/dL): 63 ± 11 vs 13 ± 5.

↑ TG (mg/dL): 45 ± 9 vs 30 ± 12.

↓ total bilirubin from day 91 (mg/dL): 0.6 ± 0.2 vs 0.2 ±0.1

↑ SBA from day 153 (mg/dL): 6 ± 0.8 vs 18 ± 9.

↓ SDH from day 37 (IU/L): 6 ± 4 vs 3 ±1.

↑ centrilobular

vacuolation, hypertrophy, and mild bile stasis: sex and data NR.

↑ lipid-droplet accumulation (no. animals): 0/4 vs 2/2.

Females (mean ± SD):

↓ body weight gain (%): 5 ± 5% vs -4 ± 5% on day 182.

↑ absolute liver weight (g): 51.1 ± 9.4 vs 75.3 ± 0.3 on day 182.

↑ relative liver weight (%): 1.8 ± 0.2 vs 2.9 ± 0.3 on day 182.

↓ total cholesterol from day 91 (mg/dL): 160 ± 47 vs 82 ± 15.

↑ HDL from day 153 (mg/dL): 56 ± 16 vs 21 ± 7.

↓ SDH from day 37 (IU/L): 5 ± 3 vs 3 ± 2.

↓ ALT from day 37 (IU/L): 87 ± 86 vs 44 ± 10.

↑ ALP from day 37 (IU/L): 283 ± 137 vs 316 ± 172

↑ centrilobular.

vacuolation, hypertrophy, and mild bile stasis (sex and data NR).

↑ lipid-droplet accumulation: 0/4 vs 2/4. 

Recovery:

Males:

Cholesterol and HDL returned to control levels.

No data given for bilirubin, SBA, CK and SDH.

Lipid-droplet accumulation, hepatocellular hypertrophy and vacuolation comparable to controls.

Females:

No data given for liver weight

Lipid-droplet accumulation, hepatocellular hypertrophy and vacuolation comparable to controls.

Males:

0.15 / 0.75

Females: 0.15 / 0.75.

Recovery

Males:

0.75 / NA.

Females:

0.75 / NA.

The results of this study indicated lipid accumulation occurred in the liver, without peroxisome proliferation.

The decrease in serum total cholesterol observed in cynomolgus monkeys reported was the earliest reliable measure of clinical response to PFOS. In the case of the 0.03 mg/kg/day males it appeared to be a result of inherently lower cholesterol in these monkeys as compared to control and was not believed to be an effect of treatment.

The recovery group animals revealed that the effects of PFOS on clinical chemistry, hormones, and liver histology are reversible. This reversal was accompanied by significant decreases in serum and liver PFOS.

K1

This study was conducted to determine the earliest measurable

response of primates to low-level PFOS exposure.

PFOS was of low purity with impurities including 8.4% lower chain length homologues of PFOS, 1.4% sodium, 0.6% inorganic fluoride, 0.3% PFOA, 0.3%

PFPeA, 0.1% PFBA.

Authors are affiliated to 3M Company. No details of funding given.