Table 10

PFNA

CAS No. 375-95-1

>97%.

Fang et al. (2012)

Sprague-Dawley rats,

Male

6/dose.

0, 0.2, 1 or 5.

Water,

Gavage,

14 days,

Non-GL study,

GLP not stated.

NR

↑ glycogen: data only presented in figures.

↑ MDA: data only presented in figures.

↑ H2O2: data only presented in figures.

Recovery not assessed.

Males:

1 / 5

PFNA administration increased the levels of rat serum glucose and hepatic glycogen via altering the expression of the genes related to glucose metabolism and suppressing the hepatic insulin pathway, which suggested that PFNA may be able to induce diabetes in rat. However, exposure of PFNA caused hepatic oxidative stress, which may contribute to the suppression of the insulin pathway and the disruption of hepatic glucose metabolism.

K2

The objective of this investigation was to characterize the specific effects of PFNA on rat hepatic carbohydrate metabolism.

Limited endpoints were measured. Only male animals were used. Data were only presented in figures.

This research was supported by the National Natural Science Foundation of China, Anhui provincial natural science foundation and the Scientific Research Foundation of Suzhou University for Doctor.

PFNA

CAS No. 375-95-1

>97%.

Hadrup et al. (2016)

Wister rats, Male

10/dose.

0, 0.0125, 0.25 or 5.

Corn oil,

Gavage,

14 days,

Non-GL study,

GLP not stated.

At 0.25 mg/kg bw/day

Serum: 29.95.

At 5 mg/kg bw/day

Serum: 602.

Males (mean ± SD):

↓ mRNA of AKR1C1, Ugt 2B15, Cyp2C11, Cyp1A2 and Cyp2B6.

Recovery not assessed.

Males:

0.25 / 5

At high PFNA concentrations, macroscopical and microscopical pathology of the liver as well as decreased body and organ weights showed that this dose is highly toxic to the animals. It is not surprising that the mRNA levels of several enzymes are down-regulated as seen for liver. Hepatotoxicity was noted with various PFAS chemicals. Notably, when these toxic effects occur, CYP1A2, CYP2B6 and CYP2C11 were down-regulated by PFNA, whereas CYP3A23/3A1 corresponding to the human CYP3A4 was up-regulated suggesting that this CYP is upregulated to increase elimination of multiple toxic metabolites and confirming the broad substrate specificity of this enzyme.

K1

The objective of the study was to investigate the effects of PFNA in combination with a mixture of 14 other chemicals.

Only data for PFNA alone are presented.  Limited endpoints were measured.

There were no significant effects caused by PFNA alone.

Study was financially supported by the Ministry of Food, Agriculture and Fisheries of Denmark and the Danish Veterinary and Food Administration.

PFNA

CAS No. 375-95-1

>97%.

NTP. (2022b)

Sprague-Dawley rats.

Male and female. 10/sex/dose.

0, 0.625, 1.25, 2.5, 5 or 10 (males) or 0, 1.56, 3.12, 6.25, 12.5 or 25 (females).

Tween® 80 in deionized water.

Gavage,

28 days,

NTP protocol,

GLP study.

At 0 mg/kg bw/day in males (mean ± SE).

Plasma: 0.055 ± 0.012

Liver: 0.762 ± 0.033.

At 0.625 mg/kg bw/day in males.

Plasma: 56.73 ± 1.88

Liver: 145.50 ± 2.68.

At 0 mg/kg bw/day in females (mean ± SE).

Plasma: 0.098 ± 0.011

Liver: not measured.

At 0.156 mg/kg bw/day in females.

Plasma:26.40 ± 1.09.

Males (mean ± SE):

↑ absolute liver weight (g): 11.73 ± 0.23 vs 13.99 ± 0.33.

↑ relative liver weight (mg/g body weight): 34.14 ± 0.30 vs 42.12 ± 0.58.

↓ TP (g/dL): 6.6 ± 0.0 vs 6.0 ± 0.1.

↓ globulin (g/dL): 2.2 ± 0.0 vs 1.5 ± 0.0.

↑ albumin/globulin ratio: 2.0 ± 0.0 vs 2.9 ± 0.1.

↓ cholesterol (mg/dL): 117 ± 5 vs 86 ± 2.

↓ TGs (mg/dL): 120 ± 9 vs 59 ± 9.

↑ total bile acids (µmol/L): 13.1 ± 2.4 vs 27.6 ± 3.1.

↑ hepatocytic cytoplasmic alterations: 0 vs 10 (minimal).

↑ hepatocyte hypertrophy: 0 vs 7.

↑ gene expression of Acox1: 1.06 ± 0.13 vs 4.33 ± 0.67.

↑ gene expression of Cyp4a1: 1.11 ± 0.16 vs 22.08 ± 4.87.

↑ gene expression of Cyp2b1: 1.40 ± 0.32 vs 9.01 ± 2.13.

↑ gene expression of Cyp2b2: 1.22 ± 0.27 vs 3.85 ± 0.48.

Females (mean ± SE):

↑ absolute liver weight (g): 7.67 ± 0.29 vs 9.30 ± 0.30.

↑ relative liver weight (g): 33.29 ± 0.70 vs 40.30 ± 0.91.

↓ TP (g/dL): 6.3 ± 0.1 vs 6.6 ± 0.1.

↑ albumin (g/dL): 4.4 ± 0.1 vs 4.9 ± 0.1.

↓ globulin (g/dL): 1.9 ± 0.1 vs 1.6 ± 0.1.

↑ albumin/globulin ratio: 2.4 ± 0.1 vs 3.0 ± 0.1.

↑ hepatocytic cytoplasmic alterations: 0 vs 5 (minimal).

↑ gene expression of Acox1: 1.02 ± 0.06 vs 3.12 ± 0.57.

↑ gene expression of Cyp4a1

1.05 ± 0.10 vs 8.08 ± 3.36.

↑ gene expression of Cyp2b1:

2.68 ± 1.37 vs 29.83 ± 9.57.

↑ gene expression of Cyp2b2:

2.06 ± 0.85 vs 14.42 ± 1.50.

Recovery not assessed.

Males:

NA / 0.625.

Females:

NA / 1.56.

A major target organ of toxicity for PFNA was the liver.

Cyp2b1/Cyp2b2 activation indicated CAR-mediated activity, and Acox1/Cyp4a1 activation suggests PPAR-α activity.

PFAS administration increased the levels of serum biomarkers associated with hepatobiliary injury.

K1

This study investigated toxicity of a number of PFAS, including PFHxA, following a 28-day exposure.

No treatment-related clinical observations were reported.

Normalized plasma concentrations were generally five- to ninefold higher in males compared to females (adjusting for the 2.5-fold higher dose compared to males). Liver concentrations (measured in males only) increased with dose, and when normalized to the dose administered, liver concentrations decreased with dose.

Government funded study. Study was audited retrospectively by an independent QA contractor.

PFNA (ammonium salt)

CAS No. 4149-60-4

99%.

Kennedy Jr (1987)

Crl:CD-1 mice.

Male and female. 5/sex/dose.

0, 3, 10, 30, 300 and 3000 ppm in diet equivalent to 0.27, 0.9, 2.7, 9, 27 or 270 **

Diet.

14 days,

Non-GL study,

GLP not stated.

NR

Males (mean):

↑ absolute liver weight (g): 1.77/2.08 vs 3.01.

↑ relative liver weight (g/100g): 5.4/6.0 vs 8.4.

Females (mean):

↑ absolute liver weight (g): 1.37/1.61 vs 2.29.

↑ relative liver weight (g/100g): 5.7/5.7 vs 7.7.

Recovery not assessed.

Males:

NA / 3*.

Females:

NA / 3*.

Ammonium perfluorononanoate led to death of mice at feeding concentrations of 300 ppm and liver weight increases at the lowest level tested, 3 ppm. This material appears to be more toxic than ammonium perfluorooctanoate and the liver weight response, in terms of both dose required to produce the change and the magnitude of the liver weight increase, is similar.

K2

This was a comparative study with PFOA and other fluorochemicals using liver weight as a means to compare the toxicological response between chemicals.

Only liver weight was measured.

Authors are affiliated to Central Research and Development Department, E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine. Study funding was not reported.