PFAS/2023/04 - Annex A
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Skip the menu of subheadings on this page.Table 3 Acute toxicity studies for PFSAs - PFOS
*Derived by contractor; NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
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Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw) / vehicle / route of admin / duration / Guideline (GL) study / Good Laboratory Practice (GLP) status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw) |
Study author conclusions |
Comments |
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PFOS (potassium salt). CAS No. not given 86.9%. Chang et al. (2008) Study 1: effects of time and PFOS on serum thyroid hormones. |
Sprague-Dawley rats Female
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0 or 15. 0.5% Tween 20® in distilled water. Gavage Single dose, followed by sacrifice 2, 6 and 24 hr post-treatment Non-GL study GLP not stated.
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At 15 mg/kg bw 66.90 ± 8.00 at 6 hr, 61.58 ± 8.81 at 24 hr. |
Females (mean ± SE):
Liver (mean ± SE): ↑ ME mRNA (ME transcript per 18s rRNA copies) at 2 hr (7.14 ± 1.05 vs 11.30 ± 1.28), but not at 6 hr or 24 hr. Recovery assessed as reported above over 24 hr period. |
Females: NA / 15.
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PFOS caused transiently increased tissue availability of THs and turnover of T4 with a resulting reduction in serum TT4. Transient elevations of FT4 was hypothesised to be due to ability of PFOS to compete with T4 for binding proteins. A classic hypothyroid state was not induced under the conditions of this study.
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K1 Only female animals used. Only two dose groups, i.e. control and single treatment group. Low purity. No details of impurities given. No effect on FT3 and TT3 at LOAEL. mRNA transcripts for hepatic ME, respond to changes in THs. Study 2 is presented below.
Authors are affiliated to 3M Company. |
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PFOS (potassium salt) CAS No. not given 86.9%.
Chang et al. (2008) Study 2: effects of PFOS on 125I elimination. |
Sprague-Dawley rats Male and female 4/dose (male), 5/dose (female).
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0 or 15. 0.5% Tween 20® in distilled water. Gavage Single dose, followed by sacrifice 24 hr post-treatment. Non-GL study GLP not stated. |
NR. |
Males and females: ↓ TT4 at 24 hr (data only reported in figures). Recovery not assessed. |
Males: NA / 15*. Females: NA / 15*.
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The decrease in TT4 is due to increased turnover and elimination. |
K1 Only two dose groups, i.e., control and single treatment group. Low purity. No details of impurities given. Study investigated 125I elimination, therefore only TT4 measured. Study 1 is presented above. Authors are affiliated to 3M Company. |
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PFOS (potassium salt). CAS No. not given 88.9%. Chang et al. (2017). |
Cynomolgus monkeys Male and female 6/sex/dose.
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Group 1 and 2: 0 or 9 0.5% Tween 20® ± 5% EtoH. Gavage Single dose, animals not sacrificed Non-GL study GLP not stated. Recovery period: 294 days. |
At 9 mg/kg bw in males on day 113 (mean ± SD) Serum: 67.7 ± 7.5. At 9 mg/kg bw in females on day 113 (mean ± SD): Serum: 68.8 ± 2.5. |
Males and females: No effects seen on thyroid hormones (TSH, FT4, TT3, TT4) (data only reported in figures). Recovery: No effects seen on THs (TSH, FT4, TT3, TT4) (data only reported in figures). |
Males: 9* / NA. Females: 9* / NA.
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No toxicologically meaningful or clinically relevant changes in TH. |
K1 Only two dose groups, i.e., control and single treatment group. Low purity. Impurities include 3.2% PFHxS, 1.2% PFHpS, 1.1% PFPeS, 0.97% PFBS and 0.74% PFPS. Study funded by 3M Company. (See below for study group 3). |
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PFOS (potassium salt) CAS No. not given 88.9%. Chang et al. (2017). |
Cynomolgus monkeys Male and female 4-6/sex/dose. |
Group 1 and 3: 0, 14, 14.8 / 17.2 (male/female) or 11 0.5% Tween 20® ± 5% EtoH. Gavage Single doses on days 43, 288 and 358, animals not sacrificed Non-GL study. GLP not stated. Recovery period: 294 days.
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At 14 mg/kg bw in males on day 50 (mean ± SD) Serum: 104.8 ± 502. At 14 mg/kg bw in females on day 50 (mean ± SD): Serum: 96.5 ± 6.2. At 14.8 mg/kg bw in males on day 288 (mean ± SD) Serum: 141.0 ± 13.1.
At 17.2 mg/kg bw in females on day 288 (mean ± SD) Serum: 147.6 ± 17.5. At 11 mg/kg bw in males on day 365 (mean ± SD) Serum: 160.8 ± 14.2. At 11 mg/kg bw in females on day 365 (mean ± SD) Serum: 165.0 ± 6.7. |
Males and females: ↓ TT4 (data only reported in figures). Recovery: ↓ TT4 (data only reported in figures) TSH, FT4, TT3 comparable to controls.
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Males: NA / 13.3* (average dose). Females: Recovery Males: NA / 13.3* (average dose). Females:
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No toxicologically meaningful or clinically relevant changes in TH at serum PFOS concentrations up to 165 µg/ml. Measurement of TT4 reflected >99% of the biologically inactive thyroxine, and therefore is not considered a clinically relevant endpoint for interpreting thyroid function. Decrease in TT4 while remaining within the normal range, appeared to be associated with treatment. |
K1 Only two dose groups i.e. control and single treatment group, with variable dosing of 14, 14.8/17.2 or 11 mg/kg bw/day, varying across treatment days, and between sexes on study day 288 (aiming to achieve serum concentrations ~ 100 µg/ml (on Study Day 43), 150 µg/ml (on Study Day 288), and 170 µg/ml (on Study Day 358), Low purity. Low purity. Impurities include 3.2% PFHxS, 1.2% PFHpS, 1.1% PFPeS, 0.97% PFBS and 0.74% PFPS. THs (TSH, FT4, TT3, TT4) measured on days -7, 1, 8, 22, 43, 50, 64, 85, 106, 113, 127, 148, 169, 176, 190, 211, 232, 253, 274, 288, 295, 309, 330, 358, 365, 379 and 400. Study funded by 3M Company |
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PFOS (potassium salt) CAS No. not stated 86.9%. Elcombe et al. (2012a). |
Sprague-Dawley rats Male 10/dose (total 30/dose, sacrificed on days 2, 8 and 29). Recovery group: 10/dose.
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0, 20 or 100 ppm in diet equivalent to 0, 2.12 or 11.05. RMI powdered diet. Diet Single dose, followed by sacrifice 2 days post-treatment. Non-GL study GLP not stated. Recovery group: 0, 20 or 100 ppm in diet equivalent to 0, 2.12 or 11.05, 8 and 29 days. |
NR. |
Males: No effects seen. Recovery: Thyroid histopathology, cell apoptosis and cell proliferation comparable to controls. |
Males: 11.05* / NA. |
No specific comments on thyroid toxicity. |
K1 Only male animals used. Three dose groups, including control. Low purity. No details of impurities given. Principal objective to investigate the activation of the xenosensor nuclear receptors PPARα and CAR/PXR as aetiological factors in PFOS-induced hepatomegaly and hepatic tumorigenesis in rats. Thyroid histopathology, cell apoptosis or cell proliferation measured. Study funded by 3M Company |
Table 4 Acute toxicity studies for PFCAs - PFDA
*Derived by contractor; NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
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Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups)
Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw) |
Study author conclusions |
Comments |
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PFDA CAS No. 335-76-2 96%. Harris et al. (1989). |
C57BL/6N mice. Female 10/dose.
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0, 20, 40, 80, 160 or 320 Corn oil. Gavage Single dose, followed by sacrifice 30 days post-treatment. Non-GL study GLP not stated. |
NR. |
Females (mean ± SE) ↑ TT4 (3.6 ± 0.2 µg/dL vs 5.1 ± 0.4 µg/dL)#. Recovery not assessed (THs only measured 30 days post-treatment).
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Females: NA / 20*. |
All mice at 160 and 320 mg/kg bw died by 14-days post-exposure. PFDA appears to cause a rise in TT4. A similar rise was also seen in the congenic C57BL/6J strain (data NR).
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K1 Only females used. TSH, FT3 and FT4 not measured. No effect on TT3 at LOAEL. THs only measured once, 30 days post-treatment, therefore levels at other time points are unknown. #THs measured in 4-10 animals per dose. No details of funding or conflicts of interest given. |
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PFDA CAS No. not given. Purity not given. Langley and Pilcher (1985).
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Wistar rats Male 5/dose-time point (total 30/dose, 5 sacrificed on each of days 0.5, 1, 2, 4, 6 and 8 days post-treatment).
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0 or 75. Propylene glycol i.p. Single dose, followed by sacrifice 0.5 days post-treatment. Non-GL study GLP not stated. Recovery group: 0 or 75. 1, 2, 4, 6 and 8 days.
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NR. |
Males: ↓ TT4 (all time points, data only reported in figures).
Recovery: ↓ TT4 (days 1, 2, 4, 6 and 8, data only reported in figures). TT3 levels comparable to controls on days 4, 6 and 8. |
Males: NA / 75*. Recovery Males: NA / 75*.
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Effects on the thyroid axis may be an early primary response to PFDA, and some subsequent effects may be secondary to the change in TH levels. Decreased THs not solely a result of starvation. |
K1 i.p. method of administration. Only male animals used. Only two dose groups, i.e. control and single treatment group, however multiple recovery times used. Purity not given. TSH, FT3 and FT4 not measured. No details of funding or conflicts of interest given.
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PFDA CAS No. not given 96%.
Van Rafelghem et al. (1987). |
Sprague-Dawley rats Male 8 -16/dose.
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0, 20, 40 or 80 Propylene glycol-water i.p. Single dose, followed by sacrifice 7 days post-treatment. Non-GL study GLP not stated. |
NR. |
Males (mean ± SE): ↓ TT4 (4.41 ± 0.19 µg/dL vs 2.81 ± 0.19 µg/dL). Recovery not assessed. |
Males: NA / 20*. |
Despite alterations in plasma TH levels, no consistent effect on hypo / hyperthyroidism. |
K1 i.p. method of administration. Only male animals used. No effect on thyroid weight or histopathology at the LOAEL. TSH, FT3 and FT4 not measured. No effect on TT3 at LOAEL. Dose response for TT4. Study funded by the Air Force Office of Scientific Research. |
Table 5 Repeated dose toxicity studies for PFSAs – PFBS
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
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Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups)
Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author comments |
Comments |
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PFBS CAS No. 375-73-5 >97%. NTP (2022b). |
Sprague-Dawley rats Male and female 10/sex/dose.
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0, 62.6, 125, 250, 500 or 1000. 2% Tween® 80 in deionized water. Gavage 28 days NTP protocol GLP study (FDA GLP Regs).
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At 62.6 mg/kg bw/day in males on day 29 (mean ± SE) Plasma: 2.222 ± 0.477. At 62.6 mg/kg bw/day in females on day 29 (mean ± SE) Plasma: 0.154 ± 0.048.
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Males (mean ± SE): ↓ TT4 (3.34 ± 0.18 µg/dL vs 0.90 ± 0.009 µg/dL)#. ↓ FT4 (2.09 ± 0.09 ng/dL vs 0.64 ± 0.04 ng/dL) #. ↓ TT3 (117.76 ± 8.31 ng/dL vs 87.85 ± 5.00 ng/dL) #. Females (mean ± SE): ↓ TT4 (3.10 ± 0.15 µg/dL vs 1.48 ± 0.09 µg/dL) #. ↓ FT4 (1.54 ± 0.08 ng/dL vs 0.72 ± 0.05 ng/dL) #. ↓ TT3 (89.29 ± 5.57 ng/dL vs 61.81 ± 3.34 ng/dL) #. Recovery not assessed. |
Males: NA / 62.6*. Females: NA / 62.6*.
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The reason for a lack of TSH response in the face of substantially low TH concentrations is not clear and not consistent with a disruption in the HPT axis. |
K1 FT3 not measured. No effect on thyroid or parathyroid histopathology, or thyroid weight at LOAEL. TSH levels unaffected by treatment. Significant decreases in TT4, FT4 and TT3 at all doses but no clear dose response for males. THs not measured in surviving animals at 1000 mg/kg bw/day. #THs measured in 9 control males and 9 treated males at 500 mg/kg bw/day. THs measured in 9 female animals at 250 and 500 mg/kg bw/day. Government funded study. Study was audited retrospectively by an independent QA contractor. |
Table 6 Repeated dose toxicity studies for PFSAs – PFHxS
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
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Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups)
Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author comments |
Comments |
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PFHxS (potassium salt) CAS No. not given 99.98%. Butenhoff et al. (2009). |
Sprague-Dawley rat Male 15/dose.
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0, 0.3, 1, 3 or 10 0.5% Carboxymethylcellulo. Gavage Males: 42 days beginning 14 days prior mating to sacrifice on study day 44. Females: 14 days prior to mating to PND22 OECD 422 (with modifications) GLP not stated.
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At 1 mg/kg bw/day in F0 males on day 42 (mean ± SD) Serum: 89.12 ± 0.80. At 3 mg/kg bw/day in F0 males on day 42 (mean ± SD) Serum: 128.67 ± 10.30. |
Males: ↑ hyperplasia of thyroid follicular cells in F0 males (total incidence 2 vs 4). Recovery not assessed.
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Males: 1 / 3.
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THs not measured. Changes in thyroid consisted of hypertrophy and hyperplasia of follicular epithelial cells. Changes were consistent with known effects of compounds that cause microsomal enzyme induction where the hepatocellular hypertrophy results in a compensatory hyperplasia and hypertrophy of the thyroid due to increased plasma turnover of T4 and associated stimulation of TSH in rats. |
K1 Only male animals used for repeated dosing segment of the OECD 422 study. While this is a repeat dose with reproductive/developmental toxicity study, results are presented here as they relate to effects (in males only). Study funded by 3M Company. |
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PFHxS |
Sprague-Dawley rats Male and female 10/sex/dose.
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0, 0.625, 1.25, 2.5, 5 or 10 (males) 0, 3.12, 6.25, 12.5, 25 or 50 (females) 2% Tween® 80 in deionized water. Gavage 28 days. NTP protocol GLP study (FDA GLP Regs).
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At 0.625 mg/kg bw/day in males (mean ± SE) Plasma: 66.76 ± 3.518. At 3.12 mg/kg bw/day in females (mean ± SE) Plasma: 37.030 ± 1.651. At 6.25 mg/kg bw/day in females (mean ± SE): Plasma 50.410 ± 1.552.
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Males (mean ± SE): ↓ TT4 (4.24 ± 0.23 µg/dL vs 2.39 ± 0.08 µg/dL). ↓ FT4 (1.74 ± 0.10 ng/dL vs 0.82 ± 0.07 ng/dL). ↓ TT3 (85.18 ± 5.74 ng/dL vs 66.21 ± 4.20 ng/dL). Females (mean ± SE): ↓ TT4 (3.99 ± 0.19 µg/dL vs 3.37 ± 0.17 µg/dL). Recovery not assessed. |
Males: NA / 0.625*. Females: 3.12 / 6.25. |
The reason for a lack of TSH response (an increase) in the face of substantially low TH concentrations is not clear and not consistent with a disruption in the HPT axis. Female rats displayed much lower plasma PFAS concentrations than males. |
K1 FT3 not measured. No effect on thyroid or parathyroid histopathology, or thyroid weight, at LOAEL. Significant decreases in TT4, FT4 and TT3 at all doses but no clear dose response for males. Government funded study. Study was audited retrospectively by an independent QA contractor. |
Table 7 Repeated dose toxicity studies for PFSAs – PFOS
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
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Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups)
Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author comments |
Comments |
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PFOS (potassium salt) CAS No. not given 86.9%. Butenhoff et al. (2012b). |
Sprague-Dawley rats Male and female 60-70/dose. Recovery group: 40/dose.
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0, 0.5, 2, 5 or 20 ppm in diet equivalent to 0, 0.024, 0.098, 0.242 or 0.984 (males) and 0, 0.029, 0.120, 0.299 or 1.251 (females). Rodent Diet 5002 meal Diet 104 weeks Non-GL study GLP not stated. Recovery group: 20 ppm in diet equivalent to 1.144 (males) or 1.385 (females) 52 weeks treatment followed by control diet to 104 weeks. |
At 0.984 mg/kg bw/day in males at 105 weeks (mean ± SD) Serum: 69.3 ± 57.9. At 0.984 mg/kg bw/day in females at 105 weeks (mean ± SD) Serum: 233.0 ± 124.0. |
Males and females: No effects seen# (NOAEL is the highest dose tested for both sexes). Recovery: No effects seen during treatment or recovery. |
Males: 0.984* / NA. Females: 1.251* / NA. |
No anatomical indications of a response of the thyroid, including thyroid weight and microscopic histological changes. No treatment-related findings for thyroid tissue. In males, there was a significant increase in incidence of thyroid follicular cell adenoma, and incidence of combined thyroid follicular cell tumours (adenoma and carcinoma), at 1.144 mg/kg bw/day in the recovery group, compared with controls. Although the increased incidence of thyroid follicular cell tumours was outside the range of historical control values, there was no other microscopic evidence of thyroid abnormality. The increased incidence of thyroid follicular cell adenoma in the 1.144 mg/kg bw/day recovery group, without similar increases at 0.984 mg/kg bw/day in males and/or at 1.251 mg/kg bw/day in females during treatment, is contradictory and may represent a chance occurrence. In females, there was a significant increase in combined thyroid follicular cell adenoma and carcinoma at 0.299 mg/kg bw/day, compared with controls. The authors noted these tumours are known to occur in historical controls. |
K1 Low purity. Impurities include 4.73% PFHxS, 0.71% perfluorinated carboxylic acids (C4, C5, and C8), 1.45% metals, 0.59% inorganic fluoride. In the basic study, thyroids were only removed from top dose animals at scheduled necropsy at week 53. #Thyroid weight and histopathology measured in males at 11-25/dose, and in females at 12-24/dose. Recovery group had no comparable controls; animals were observed for reversibility, persistence, or delayed occurrence of toxic effects for 52 weeks post-treatment. Study funded by 3M Company. |
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PFOS (potassium salt) CAS No. not given 86.9%. Chang et al. (2008). |
Sprague-Dawley rats Male 6/dose.
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0 or 3, 0.5% Tween 20® in distilled water. Gavage 7 days Non-GL study GLP not stated. |
NR. |
Males: ↓ TT4 (data only reported in figures). ↓ TT3 (data only reported in figures). Recovery not assessed. |
Males: NA / 3*. |
PFOS did not appear to alter the function of the HPT hypothalamic axis.
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K1 Only male animals used. Only two dose groups. Low purity. No details of impurities given. Study aim to investigate pituitary function (Trh-mediated pituitary release of TSH). FT3 and FT4 not measured. No effect on TSH at LOAEL. Authors are affiliated to 3M Company. No details of funding given. |
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PFOS (potassium salt) CAS No. 2795-39-3 ≥98%. Curran et al. (2008). |
Sprague-Dawley rats Male and female 15/sex/dose
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0, 2, 20, 50 or 100 ppm in diet equivalent to 0, 0.14, 1.33, 3.21 or 6.3 (males) and 0, 0.15, 1.43, 3.73 or 7.58 (females.) AIN-93G purified diet. Diet 28 days Non-GL study GLP not stated. |
At 0.14 mg/kg bw/day in males (mean ± SD) Serum: 0.95 ± 0.13. At 1.33 mg/kg bw/day in males (mean ± SD) Serum: 13.45 ± 1. 48. At 0.15 mg/kg bw/day in females (mean ± SD) Serum: 1.50 ± 0.23. At 1.43 mg/kg bw/day in females (mean ± SD) Serum: 15.40 ± 0.56. |
Males (mean ± SD): ↓ TT4 (80.94 ± 11.83 nmol/L vs 14.36 ± 4.18 nmol/L). Females (mean ± SD): ↓ TT4 (37.71 ± 15.41 nmol/L vs 19.62 ± 2.49 nmol/L). Recovery not assessed. |
Males: Females: |
No specific comments on thyroid toxicity. Decreased TT4 and TT3 occurred concurrently with hepatic changes indicative of peroxisome proliferation. At doses above the LOAEL significant treatment-related changes in thyroid weight relative to body weight, were suggestive of altered endocrine functions. |
K1 Authors derived a LOEL (not LOAEL). No effect on TT3 levels at LOEL, absolute or relative thyroid weight, or thyroid:brain weight. No histopathological changes in thyroid tissue. Significant decrease in TT4 at all doses above the LOAEL but no clear dose response in either males or females. TSH, FT3 and FT4 not measured. There was a dose related increase in PFOS serum levels; PFOS in other tissues also showed a dose related response. No details of funding or conflicts of interest given. |
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PFOS (potassium salt). CAS No. not given 86.9%. Elcombe et al. (2012b). |
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.
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0, 20 or 100 ppm in diet equivalent to 0, 1.93 or 9.65. RMI powdered diet. Diet 7 days Non-GL study GLP not stated. Recovery groups: 0, 20 or 100 ppm in diet equivalent to 0, 1.93 or 9.65. Sacrificed on days 28, 56, and 84. |
At 1.93 mg/kg bw/day on days 1, 28, 56 and 84 (mean ± SD) |
Males: No effects seen (NOAEL is highest dose tested). ↓ body weight on recovery days 21 and 28 (mean ± SD): 412.2 ± 46.8 g vs 384.8 ± 46.8 g and 428.2 ± 50.9 g vs 397.0 ± 51.4g respectively). Recovery: Effects comparable to controls. |
Males: 9.65* / NA. |
Thyroid parameters (thyroid status (histology, follicular epithelial apoptosis, follicular epithelial cell proliferation) were unaffected at all time points. |
K1 Only male animals used. Only three dose groups. Low purity. No details of impurities given. Authors are affiliated to 3M Company. No details of funding given. |
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PFOS (potassium salt) CAS No. not stated 86.9%. Elcombe et al. (2012a). |
Sprague-Dawley rats Male 10/dose (total 30/dose, 10 sacrificed at three time points).
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0, 20 or 100 ppm in diet equivalent to 0, 1.66 or 7.90. RMI powdered diet Diet 7 or 28 days Non-GL study GLP not stated. |
NR. |
Males: No effects seen (NOAEL is highest dose tested) in both 7-day or 28-day studies. Recovery not assessed. |
Males: 7.90* / NA.
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No specific comments on thyroid toxicity. |
K1 Only male animals used. Only three dose groups. Low purity. No details of impurities given. Principal objective to investigate the activation of the xenosensor nuclear receptors PPARα and CAR/PXR as etiological factors in PFOS-induced hepatomegaly and hepatic tumorigenesis in rats. Thyroid histopathology, cell apoptosis and cell proliferation measured. Study funded by 3M Company. No details of funding given. |
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PFOS CAS No. 1763-23-1 >96%. NTP (2022b). |
Sprague-Dawley rats Male and female 10/sex/dose.
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0, 0.312, 0.625, 1.25, 2.5 or 5 2% Tween® 80 in deionized water. Gavage 28 days NTP protocol GLP study (FDA GLP Regs).
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At 0.312 mg/kg bw/day in males (mean ± SE) Plasma: 23.73 ± 1.114. At 0.312 mg/kg bw/day in females (mean ± SE) Plasma: 30.53 ± 0.918. |
Males (mean ± SE): ↓ TT4 (3.51 ± 0.30 µg/dL vs 1.33 ± 0.19 µg/dL). ↓ FT4 (2.53 ± 0.22 ng/dL vs 0.95 ± 0.10 ng/dL). Females (mean ± SE): ↓ TT4 (2.21 ± 0.24 µg/dL vs 1.11 ± 0.12 µg/dL) #. ↓ FT4 (1.74 ± 0.23 ng/dL vs 1.07 ± 0.09 ng/dL) #. Recovery not assessed. |
Males: NA / 0.312. Females: NA / 0.312.
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The reason for a lack of TSH response in the face of substantially low TH concentrations is not clear and not consistent with a disruption in the HPT axis. |
K1 No effect on TT3, thyroid weight, thyroid or parathyroid histopathology at LOAEL. Significant decreases in TT4 and FT4 at all doses but no clear dose response for TT4 for either males or females. #THs measured in 9 females at 5 mg/kg bw/day. Government funded study. Study was audited retrospectively by an independent QA contractor.
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PFOS (potassium salt). CAS No. 2795-39-3 86.9%. Seacat et al. (2002). |
Cynomolgus monkeys Male and female 4-6/dose. Recovery group: (2/group).
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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.
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At 0.15 mg/kg bw/day in males on day 183 (mean ± SD). At 0.15 mg/kg bw/day in females on day 183 (mean ± SD) 66.8 ± 10.8. At 0.75 mg/kg bw/day in males on day 183 (mean ± SD) At 0.75 mg/kg bw/day in females on day 183 (mean ± SD) Serum: |
Males on day 184 (mean ± SD): ↓ TT3 (146 ± 19.8 ng/dL vs 76 ± 22 ng/dL). ↓ FT3 (4.21 ± 0.85 pg/mL vs 2.45 ± 0.80 pg/mL). ↑ mortality (0 vs 2).
Females on day 184 (mean ± SD): ↓ TT3 (148 ± 21.6 ng/dL vs 99 ± 16.8 ng/dL). ↓ FT3 (4.05 ± 0.98 pg/ml vs 2.82 ± 0.29 pg/ml). Recovery: all TH levels returned to control levels between days 33 to 61 in both sexes (NOAEL is highest dose tested). |
Males: 0.15 / 0.75 Females: 0.15 / 0.75. Recovery Males: 0.75 / NA. Females: 0.75 / NA.
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Variations in TT4 levels were not consistent with respect to dose response or over time. No evidence of hypothyroidism. Clinical relevance of the decreased TT3 values was not apparent since there was no indication of a clinical hypothyroid response. Decrease in TT3 consistent with the slight (approximately 2-fold) compensatory increase in TSH. |
K1 Low purity. Impurities include 8.4% lower chain length homologues of PFOS, 1.4% sodium, 0.6% inorganic fluoride, 0.3% perfluorooctanoate, 0.3% nonafluoropentanoic acid, 0.1% heptafluorobutyric acid. No effect on FT4, TT4, or thyroid/parathyroid weight at LOAEL. No clear dose response for TSH in females. Serum PFOS levels similar in both sexes. Authors are affiliated to 3M Company. No details of funding given. |
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PFOS (potassium salt). CAS No. not given 91%. Thibodeaux et al. (2003). |
Sprague-Dawley rats Female 6-8 /dose.
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0, 3 or 5 0.5% Tween® 20. Gavage 20 days Non-GL study. GLP not stated. |
NR. |
Females: ↓ TT4 on day 3 – 20 (data only reported in figures). ↓ FT4 on day 3 – 20 (data only reported in figures). Recovery not assessed |
Females: NA / 3*. |
T3 and T4 results largely substantiated other findings in pregnant rats, discounting potential confounding effects of pregnancy. |
K1 Only female animals used. Only three dose groups. No details of impurities. FT3 not measured. Study funded primarily by US EPA, analytic chemistry support from 3M Company. See Table 15 for developmental studies also reported in this paper. |
|
PFOS (potassium salt). CAS No 2795-39-3 98%. Yu et al. (2011). |
Wistar rats Female 12-13/dose. |
0, 0.2, 1.0 or 3.0 0.5 % Tween 20®. Gavage 5 days Non-GL study. GLP not stated. |
At 0.2 mg/kg bw/day (mean ± SE) Serum: 1.09 ± 0.12. At 1.0 mg/kg bw/day (mean ± SE) Serum: 8.20 ± 0.13.
|
Females: ↓ TT4 (data only reported in figures)#. ↑ relative expression MRP2 mRNA. Recovery not assessed.
|
Females: 0.2 / 1. |
MRP2, a member of the ATP-binding cassette transporters, plays an important role in regulating T4 hepatic efflux. PFOS increased hepatic expression of OAPT2 (at higher doses), which could possibly enhance hepatic uptake and metabolism of T4 in rats. PFOS-induced TT4 deficiency is mainly due to the extrathyroidal metabolism of T4, which is probably different from the classic goitrogen, propylthiouracil. |
K1 Only female animals used. No effect on TT3 at LOAEL.TSH, FT3 and FT4 not measured. #THs measured in 6-7animals per dose. The aim of the study was to further identify the major factors contributing to a reduction in circulating TT4 in rats following PFOS exposure. Parameters examined were serum concentrations of TTR and TG as well as transcripts of transporters involved in hepatic T4 uptake and efflux. Study funded by the National Nature Science Foundation of China, Scientific Research Fund of Liaoning Provincial Education Department, and the Program for Changjiang Scholars and Innovative Research Team in University. |
|
PFOS (potassium salt). CAS No. 2795-39-3 >98%. Yu et al. (2009a).
|
Sprague-Dawley rats Male 8-10/dose. |
0, 1.7, 5 or 15 mg/L in drinking water equivalent to 0, 0.15, 0.45 or 1.35**. Drinking water 91 days. Non-GL study GLP not stated. |
At 0.15 mg/kg bw/day (mean ± SE) Serum:5.0 ± 0.3. At 0.45 mg/kg bw/day (mean ± SE) Serum: 33.6 ± 2.1.
|
Males (mean ± SE): ↓ TT4 (40.9 ± 1.8 µg/L vs 23.9 ± 1.3 µg/L) #. Upregulation of hepatic mRNA UGT1A1. Recovery not assessed.
|
Males: 0.15 / 0.45. |
No effect on thyroid weight or TSH levels at any dose. Consistent with previous reports, PFOS decreased serum TT4 levels in rats without significant alteration in TSH. Hepatic UGT1A1, but not UGT1A6, mRNA was up-regulated at 5.0 and 15.0 mg/L (i.e. 0.45 and 1.35 mg/kg bw/day). Treatment lowered hepatic DIO1 mRNA at 15.0 mg/L but increased thyroidal DIO1 mRNA dose dependently. The activity of TPO, NIS, and TSHR mRNA in thyroid were unaffected. These results indicate that increased hepatic T4 glucuronidation via UGT1A1 and increased thyroidal conversion of T4 to T3 via DIO1 were responsible in part for PFOS-induced hypothyroxinemia in rats. |
K1 Only male animals used. No effect on TSH, FT4 or TT3 at LOAEL. FT3 not measured. Significant decrease in TT4 at all doses, with a dose response. #THs measured in 5-6 animals per dose. EFSA. (2012) dose conversion factor of 0.09 for subchronic studies used. EFSA. (2018) present doses as equivalent to 0, 0.09, 0.25 or 0.75 mg/kg bw/day, assumed to be based on a drinking water conversion factor of 0.05 for chronic studies. UGT1A and UGT1A6 in liver used to determine the effect of PFOS on T4 metabolism. Study funded by the National Nature Science Foundation of China. |
Table 8 Repeated dose toxicity studies for PFCAs – PFBA
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFBA (ammonium salt). CAS No. not given 28.9% solution in distilled water. Butenhoff et al. (2012a).
|
Sprague-Dawley rats Male and female 10/sex/dose. Recovery group: Male and female 10/sex/dose.
|
0, 6, 30 or 150 (actual dose 0, 5.3, 25.4 or 130.2). Milli-Q or Milli-U water Gavage 28 days. Non-GL study. GLP not stated. Recovery group: 0, 6, 30 or 150 (actual dose 0, 5.3, 25.4 or 130.2) 3 weeks.
|
At 6 mg/kg bw/day in males at end of treatment (mean ± SD) Serum: 24.65 ± 17.63. At 6 mg/kg bw/day in males at end of recovery (mean ± SD) Serum: 0.06 ± 0.02. At 30 mg/kg bw/day in males at end of treatment (mean ± SD) Serum: 38.04 ± 23.15. At 30 mg/kg bw/day in males at end of recovery (mean ± SD) Serum: 0.20 ± 0.13. At 150 mg/kg bw/day in females at end of treatment (mean ± SD) Serum: 10.30 ± 4.50. At 150 mg/kg bw/day in females at end of recovery (mean ± SD) Serum: 0.234 ± 0.165. |
Males (mean ± SD): ↓ TT4 (3.09 ± 0.82 µg/dL vs 1.26 ± 0.26 µg/dL). ↓ FT4 (1.83 ± 0.53 ng/dL vs 0.98 ± 0.34 ng/dL). ↑ absolute thyroid weight (0.011g vs 0.023 g). Females: No effects seen (NOAEL is highest dose tested). Recovery: TT4, FT4, TSH and thyroid weight comparable to controls after a 3-week recovery period, at 6 mg/kg bw/day (but no recovery of TT4 at 150 mg/kg bw/day).
|
Males: NA / 6*. Females: 150 / NA. Recovery Males: 6 / 30. Females: 150 / NA.
|
NOAELs were 6 and 150 mg/kg bw/day for male and female rats respectively, based on reversibility of effects on THs (reported at 6 mg/kg bw/day in males following treatment) after 3 weeks. Male rats appeared more sensitive. Due to lack of dose-response, known difficulties in obtaining thyroid weights, and lack of consistent histological correlations, the thyroid weight increases observed in males at 6 and 30 mg/kg bw/day (but not observed at 150 mg/kg bw/day) were not considered toxicologically significant.
|
K1 No effect on TSH at LOAEL, TT3 and FT3 not measured. No dose response for thyroid weight. Recovery of TT4 and FT4 at 6 and 30 mg/kg bw/day occurred, but the decrease in TT4 seen at the end of treatment at the highest dose tested of 150 mg/kg bw/day did not show recovery. Study funded by US EPA. Authors are affiliated to 3M Company.
|
|
PFBA (ammonium salt). CAS No. not given 28.9% solution in distilled water. Butenhoff et al. (2012a). |
Sprague-Dawley rats Male and female 10/sex/dose. Recovery group: Male and female 10/sex/dose.
|
0, 1.2, 6 or 30 (actual dose 0, 1.4, 6.9 or 32.4) Milli-Q or Milli-U water. Gavage 90 days. Non-GL study. GLP not stated. Recovery group: 0 and 30 (actual doses 0 and 32.4) 3 weeks. |
At 6 mg/kg bw/day in males at end of treatment (mean ± SD) Serum: 13.63 ± 9.12 (no data for end of recovery period). At 30 mg/kg bw/day in males at end of treatment (mean ± SD) Serum: 52.22 ± 24.89. At 30 mg/kg bw/day in males at end of recovery (mean ± SD) Serum: 0.51 ± 0.31. At 30 mg/kg bw/day in females at end of treatment (mean ± SD) Serum: 5.15 ± 3.29. At 30 mg/kg bw/day in females at end of recovery (mean ± SD) Serum: 0.11 ± 0.0 |
Males (mean ± SD): ↓ TT4 (5.27 ± 0.71 µg/dL vs 3.23 ± 0.55 µg/dL) ↑ incidence thyroid follicular hypertrophy/ hyperplasia (40% vs 90%)
Females: No effects seen (NOAEL is highest dose tested Recovery: Males (mean ± SD): ↑ TT4 (5.14 ± 0.33 µg/dL vs 6.37 ± 0.76 µg/dL). FT4 and TSH comparable to controls Incidence of thyroid follicular hypertrophy/ hyperplasia comparable to controls (43% vs 50%)#. |
Males: 6 / 30
Females: 30 / NA
Recovery NA (effects seen in males). |
NOAELs were 6 and >30 mg/kg bw/day for male and female rats respectively. Male rats appeared more sensitive. Insufficient serum for measurement of FT4 not available for control males at the end of treatment. A decrease in mean FT4 was evident in 30 mg/kg bw/day males at the end of treatment, based on a statistically significant reduction when compared to the mean value for the 1.2 mg/kg bw/day group males. |
K1 No effect on TSH at LOAEL, TT3 and FT3 not measured. Thyroid weight not measured. No dose response for hypertrophy/hyperplasia incidence. Male (and female) treatment and recovery groups for 1.2 and 6 mg/kg bw/day not included in study design for PFAS serum concentrations. # Histological observations in 7 control animals and 6 treated animals. Study funded by US EPA. Authors are affiliated to 3M Company. |
Table 9 Repeated dose toxicity studies for PFCAs – PFHxA
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFHxA (sodium salt) CAS No. 2923-26-4 100%. Loveless et al. (2009). |
Crl:Cd Sprague-Dawley rats Male and female 10/sex/dose. Recovery group: 10/sex/dose for 30-day recovery period, and 5/sex/dose for 90-day recovery period.
|
0, 20, 100 or 500 NANOpure® water. Gavage 92/93 days (males/females) OECD 408 GLP not stated. Recovery groups: 0 or 500, followed by recovery for 30 days (to day 122/123). 0, 20 or 100, followed by recovery for 90 days (to day 182/183). |
NR. |
Males: ↓ body weight (transient on, days 42 to 105, data only reported in figures) ↑ thyroid follicular epithelial hypertrophy (day 92, 2/10 animals). Females: ↑ thyroid follicular epithelial hypertrophy (day 92, 4/10 animals). Recovery: Males: ↑ incidence thyroid follicular epithelial hypertrophy on recovery days 30 and 90 (3/10 and 2/10 animals respectively). Females: ↑ thyroid follicular epithelial hypertrophy on recovery day 30 (6/10 animals). Comparable to controls on recovery day 90 ↑ thyroid weight on recovery day 30. Comparable to controls on recovery day 90. Data NR. |
Males: 100 / 500. Females: 100 / 500. Recovery Males: 100 / 500. Females: 500 / NA.
|
Increased female thyroid weights in the 30-day recovery group may be adverse and treatment related. Thyroid follicular cell hypertrophy is potentially adverse (although may not be relevant to non-rodent species) albeit minimal and likely to be secondary and related to liver hypertrophy and induction of metabolic liver enzymes. Increase in thyroid weight in female rats at 500 mg/kg bw/day in the 30-day recovery group were not seen at the end of the dosing period, nor after 90 days recovery, or in male rats at any time point. |
K1 OECD 408 study. Authors affiliated to the DuPont Company. No details of funding given. |
|
PFHxA CAS No. 307-24-4 >99% NTP (2022a). |
Sprague-Dawley rats Male and female 10/sex/dose.
|
0, 62.6, 125, 250, 500 or 1000. 2% Tween® 80 in deionized water. Gavage 28 days NTP protocol GLP study (FDA GLP Regs). |
At 62.6 mg/kg bw/day in males (mean ± SE) Plasma: 0.378 ± 0.178. At 1000 mg/kg bw/day in females (mean ± SE) Plasma: 6.712 ± 0.841
|
Males (mean ± SE): ↓ TT4 (4.26 ± 0.15 µg/dL vs 3.40 ± 0.23 µg/dL) ↓ FT4 (2.88 ± 0.09 ng/dL vs 2.16 ± 0.17 ng/dL) ↓ TT3 (84.17 ± 5.25 ng/mL vs 68.88 ± 3.76 ng/mL) Females: No effects seen (NOAEL is highest dose tested). Recovery not assessed. |
Males: NA / 62.6
Females: 1000 / NA
|
In general, the effects in male and female rats administered PFHxA were of lower magnitude or not apparent compared with effects following exposure to PFNA or PFDA. The reason for a lack of TSH response (an increase) in the face of substantially low TH concentrations is not clear and not consistent with a disruption in the HPT axis. |
K1 No effect on thyroid weight, thyroid or parathyroid histopathology at LOAEL. Significant decreases in TT4, FT4 and TT3 at all doses, but no clear dose response for TT3. Government funded study. Study was audited retrospectively by an independent QA contractor. |
Table 10 Repeated dose toxicity studies for PFCAs – PFOA
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls bs treated groups)
Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFOA (ammonium salt). CAS No. not given 97.99%. Butenhoff et al. (2012a).
|
Sprague-Dawley rats Male and female 10/sex/dose. Recovery group: Male and female 10/sex/dose.
|
0 or 30 (actual dose 0 or 27.8). Milli-Q or Milli-U water. Gavage 28 days Non-GL study. GLP not stated. Recovery group: 0 or 30 (actual dose 0 or 27.8) 3 weeks.
|
At 30 mg/kg bw/day in males at end of treatment (mean ± SD) Serum: 145.60 ± 28.25. At 30 mg/kg bw/day in males at end of recovery (mean ± SD) Serum: 14.67 ± 5.30. At 30 mg/kg bw/day in females at end of treatment (mean ± SD) Serum: 7.98 ± 4.03. At 30 mg/kg bw/day in females at end of recovery (mean ± SD) Serum: 0.03 ± 0.02. |
Males (mean ± SD): ↓ body weight gain (data NR). ↓ food consumption (data NR). ↓ TSH (4.88 ± 3.30 ng/dL vs 2.59 ± 0.96 ng/dL). ↓ TT4 (3.09 ± 0.82 µg/dL vs 0.52 ± 0.15 µg/dL). ↓ FT4 (1.83 ± 0.53 ng/dL vs 0.94 ± 0.34 ng/dL). ↑ thyroid follicular epithelial cell height (10.6 ± 2.3 µm vs 14.8 ± 2.4 µm). ↑ incidence thyroid follicular hypertrophy/ hyperplasia (30% vs 100%). Females (mean ± SD): ↓ TT4 (2.06 ± 0.74 µg/dL vs 0.62 ± 0.42 µg/dL). ↓ FT4 (2.00 ± 0.68 ng/dL vs 1.14 ± 0.35 ng/dL). Recovery: Males (mean ± SD): ↓ body weight gain (data NR). ↓ TT4 (3.52 ± 0.56 µg/dL vs 1.40 ± 0.39 µg/dL). ↓ FT4 (1.98 ± 0.43 ng/dL vs 1.26 ± 0.29 ng/dL). ↑ incidence thyroid follicular hypertrophy/ hyperplasia (40% vs 80%). TSH comparable to recovery group controls Thyroid follicular epithelial cell height comparable to recovery group controls. Females: THs comparable to recovery group controls (NOAEL is highest dose tested). |
Males: NA / 30*. Females: NA / 30*. Recovery Males: NA / 30*. Females: 30* / NA.
|
PFOS was used as a comparator to PFBA. No specific discussion of thyroid toxicity.
|
K1 Only two dose groups. TT3 and FT3 not measured. TH effects, and thyroid follicular hypertrophy/ hyperplasia in males were not reversible. Study funded by US EPA. Authors are affiliated to 3M Company.
|
|
PFOA (ammonium salt) CAS No. 3825-26-1 95.2%. Butenhoff et al. (2002) |
Cynomolgus monkeys. Male 4-6/dose. Recovery group: 2/dose.
|
0, 3, 10 or 30 (highest dose suspended on day 12 and reduced to 20 from day 22). No vehicle. Gelatin capsules 26 weeks (182 days). Non-GL study. GLP not stated. Recovery group: 0, 3, 10 or 30 90 days. |
At 3 mg/kg bw/day at week 6 (mean ± SD) Serum: 77 ± 39. |
Males: At week 27 / 183 days (mean ± SD): ↓ TT4 (3.84 ± 0.77 µg/dL vs 2.58 ± 0.17 µg/dL). ↑ TSH (0.40 ± 0.23 µg/dL vs 0.65 ± 0.17 µg/dL). Recovery not assessed for THs.
|
Males: NA / 3*. |
No effects on thyroid histology. There were no clear changes in TH homeostasis. All TH values (TSH, FT3, TT3, FT4, TT4) were within normal range, and there did not appear to be any relevant histological changes nor relevant changes in TT4 or TSH. Serum concentrations of PFOA did not increase in a linear dose-dependent manner. |
K1 Only male animals used. TH levels not reported in the recovery groups. Significant decrease in TT4 at all doses, with no clear dose response. TSH increased at 3 and 10 mg/kg bw/day but not at highest dose. Study funded by 3M Company and member companies of the Association of Plastic Manufacturers of Europe. |
|
PFOA (ammonium salt) CAS No. 3825-26-1 97.2%. Butenhoff et al. (2012c). |
Sprague-Dawley rats Male and female 50-65/sex/dose. |
0, 30 or 300 ppm in diet equivalent to 0, 1.3 or 14.2 (males) and 0, 1.6 or 16.1 (females). Certified Purina Laboratory Chow Diet 2 years Non-GL study. GLP not stated |
NR. |
Males and females: No effects seen (NOAEL is highest dose tested). Recovery not assessed. |
Males: 14.2* / NA. Females: 16.1* / NA.
|
No specific comments on non-neoplastic microscopic findings in the thyroid.
|
K1 No effects on incidence of hyperplasia (C-cell or follicular cell) in males or females. Study funded by 3M Company.
|
|
PFOA (ammonium salt). CAS No. not given Purity not given. Griffith and Long (1980). |
ChR-CD albino rats Male and female 5/sex/dose. |
0, 10, 30, 100, 300 or 1000 ppm in diet equivalent to 0, 0.9, 2.7, 9, 27 or 90**. Purina laboratory chow Diet 90 days Non-GL study GLP not stated. |
NR. |
Males and females: No effects seen (NOAEL is highest dose tested). Recovery not assessed. |
Males: 90* / NA. Females: 90* / NA. |
No specific comments on thyroid toxicity. |
K2 Purity not given. No methodology for histopathology. Thyroid and parathyroid weight and histopathology assessed. EFSA. (2012) dose conversion factor of 0.09 for subchronic studies used. Study funded by 3M Company. |
|
PFOA CAS No. 335-67-1 >98%. NTP (2022a). |
Sprague-Dawley rats Male and female 10/dose.
|
0, 0.625, 1.25, 2.5, 5 or 10 (males) or 0, 6.25, 12.5, 25, 50, or 100 (females) 2% Tween® 80 in deionized water. Gavage 28 days NTP protocol GLP study (FDA GLP Regs).
|
At 0.625 mg/kg bw/day in males (mean ± SE) Plasma: 50.690 ± 2.207. At 6.25 mg/kg bw/day in females (mean ± SE) Plasma: 0.491 ± 0.072. |
Males (mean ± SE): ↓ TT4 (2.34 ± 0.24 µg/dL vs 0.21 ± 0.05 µg/dL). ↓ FT4 (2.14 ± 0.13 ng/dL vs 0.44 ± 0.04 ng/dL). ↓ TT3 (88.55 ± 5.58 ng/mL vs 53.52 ± 1.45 ng/mL). Females (mean ± SE): ↑ TSH (10.05 ± 0.81 ng/mL vs 14.08 ± 1.17 ng/mL)#. Recovery not assessed. |
Males: NA / 0.625. Females: NA / 6.25.
|
The reason for a lack of TSH response in the face of substantially low TH concentrations is not clear and not consistent with a disruption in the HPT axis. |
K1 No effect on thyroid weight or thyroid histopathology at LOAEL. FT3 not measured. Significant decrease in TT4, FT4 and TT3 at all doses in males, but no clear dose response. Significant increase in TSH in females at all doses, but no clear dose response. #THs measured in 9 female animals at 100 mg/kg bw/day. Government funded study. Study was audited retrospectively by an independent QA contractor. |
Table 11 Repeated dose toxicity studies for PFCAs – PFNA
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups) Recovery (controls vs treated groups) |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFNA |
Sprague-Dawley rats Male and female 10/dose.
|
0, 0.625, 1.25, 2.5, 5 or 10 (males) 0, 1.56, 3.12, 6.25, 12.5 or 25 (females) 2% Tween® 80 in deionized water. Gavage 28 days NTP protocol GLP study (FDA GLP Regs).
|
At 0.625 mg/kg bw/day in males (mean ± SE) Plasma: 56.730 ± 1.878. At 1.56 mg/kg bw/day in females (mean ± SE) Plasma: 26.400 ± 1.085. At 3.12 mg/kg bw/day in females (mean ± SE) Plasma: 54.360 ± 2.486.
|
Males (mean ± SE): ↓ TT4 (2.36 ± 0.27 µg/dL vs 0.21 ± 0.07 µg/dL). ↓ FT4 (2.16 ± 0.15 ng/dL vs 0.55 ± 0.02 ng/dL). Females (mean ± SE): ↓ TT4 (4.37 ± 0.41 µg/dL vs 2.81 ± 0.17 µg/dL). ↓ FT4 1.70 ± 0.20 ng/dL vs 1.10 ± 0.10 ng/dL). Recovery not assessed. |
Males: NA / 0.625. Females: 1.56 / 3.12. |
The reason for a lack of TSH response in the face of substantially low TH concentrations is not clear and not consistent with a disruption in the HPT axis. |
K1 No effect on thyroid weight, thyroid or parathyroid histopathology at LOAEL. FT3 not measured. Significant decrease in TT4 and FT4 at all doses in males, but no clear dose response for TT4. THs not measured in any animals at the top two doses due to mortality. Government funded study. Study was audited retrospectively by an independent QA contractor. |
Table 12 Repeated dose toxicity studies for PFCAs – PFDA
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups). |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFDA |
Sprague-Dawley rats / Male and female 10/dose.
|
0, 0.156, 0.312, 0.625, 1.25, or 2.5 2% Tween® 80 in deionized water. Gavage 28 days NTP protocol GLP study (FDA GLP Regs).
|
At 0.156 mg/kg bw/day in males (mean ± SE) Plasma: 8.51 ± 0.59. At 0.156 mg/kg bw/day in females (mean ± SE) Plasma: 11.21 ± 0.43. At 0.312 mg/kg bw/day in males (mean ± SE) Plasma: 23.03 ± 1.77. At 0.312 mg/kg bw/day in females (mean ± SE) Plasma: 25.70 ± 1.05. |
Males (mean ± SE): ↓ TT4 (4.36 ± 0.32 µg/dL vs 3.24 ± 0.18 µg/dL). ↓ FT4 (2.02 ± 0.21 ng/dL vs 1.17 ± 0.11 ng/dL). Females (mean ± SE): ↑ absolute thyroid weight (0.0253 ± 0.0010 g vs 0.0336 ± 0.0016 g) ↑ relative thyroid weight (0.11 ± 0.00 g vs 0.14 ± 0.01 g). Recovery not assessed. |
Males: 0.156 / 0.312. Females: 0.156 / 0.312.
|
The reason for a lack of TSH response in the face of substantially low TH concentrations is not clear and not consistent with a disruption in the HPT axis. |
K1 No effect on thyroid histopathology at LOAEL. FT3 not measured. Decrease in TT4 only seen at 0.312 mg/kg bw/day in males with no clear dose response. Government funded study. Study was audited retrospectively by an independent QA contractor. |
Table 13 Repeated dose toxicity studies for PFCAs - PFTeDA
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups). |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFTeDA CAS No. not given 96.5%. Hirata-Koizumi (2015).
|
Crl:CD (SD) rats Males and females 7-12/sex/dose. Recovery group: Males and females 5/sex/dose.
|
0, 1, 3 or 10 0.5% water solution of carboxymethylcellulose sodium. Gavage Males: 42 days beginning 14 days prior mating, females: 14 days prior to mating, gestation and to PND5 OECD 422 GLP. Recovery group: 0 or 10 14 days. |
NR. |
Males: No effects seen# (NOAEL is highest dose tested). Females: No effects seen# (NOAEL is highest dose tested). Recovery:Effects on thyroid weight and histopathology comparable to controls.
|
Males: 10* / NA. Females: 10* / NA.
|
Increased incidence of thyroid follicular cell hypertrophy was observed in males at 3 and 10 mg/kg bw/day during treatment and in males at 10 mg/kg bw/day following recovery, but this was not significantly different to controls. THs not measured because no change in thyroid weight.
|
K2 Only 7 males/dose in the main group. OECD 422 recommends that each group be started with at least 10 males and 12-13 females. Results of repeated dose part of OECD 422. Thyroid weight and histopathology assessed. #Thyroid weight measured in 7/sex/ dose. Funded by the Ministry of Health, Labour and Welfare, Japan, and supported by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan. |
Table 14 Repeated dose toxicity studies for PFCAs - PFHxDA
*Derived by contractor; **calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups). |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFHxDA CAS No. not given 95.3%. Hirata-Koizumi (2015).
|
Crl:CD (SD) rats Males and females 7-12/sex/dose. Recovery group: Males and unmated females 5/sex/dose.
|
0, 4, 20 or 100 0.5% water solution of carboxymethylcellulose sodium. Gavage Males: 42 days beginning 14 days prior mating. Females: 14 days prior to mating, gestation and to PND5 OECD 422 GLP. Recovery group: 0 or 100. Males: 14 days Females: 14 days (recovery group females were not mated). |
NR. |
Males: ↑ relative thyroid weight (mean ± SD): 18.94 ± 1.6 mg vs 24.26 ± 4.28 mg). No effect at 100 mg/kg bw/day (see recovery)#. Females: ↓ TT3 (mean ± SD: 0.734 ± 0.023 ng/mL vs 0.606 ± 0.036 ng/mL)#. Recovery: Males at 100 mg/kg bw/day (mean ± SD): ↓ TT4 (117.50 ± 15.00 ng/mL vs 89.25 ± 11.87 ng/mL). Thyroid weight comparable to controls. Females: THs and thyroid weight comparable to controls. |
Males: 4 / 20. Females: NA / 4*. Recovery Males: 20 / 100*. Females: 100* / NA.
|
Effects on the thyroid (THs TT3, FT4 and TT4, histopathology and weight) were not consistent between sexes and lacked clear dose-dependency. Results indicate that PFHxDA may slightly affect the thyroid system through a similar mechanism to PFTeDA and PFDA based on other studies. NOAEL concluded to be 4 mg/kg bw/day for repeated dose toxicity (sex not specified). |
K2 Only 7 males/dose in the main group. OECD 422 recommends that each group be started with at least 10 males and 12-13 females. Results of repeated dose part of OECD 422. No effects on TSH in treatment or recovery groups. No effect on thyroid histopathology. FT3 not measured. Increase in thyroid weight in males shows no dose response. #THs and thyroid weight measured in 7/sex/ dose. Effects on TT4 seen in males at 100 mg/kg bw/day following the recovery period, but not during treatment. Effects on TT3 seen in females reported at 4 mg/kg bw/day during treatment, but no effect following the recovery period. Recovery group females were administered PFHxDA for 42 days without mating. Funded by the Ministry of Health, Labour and Welfare, Japan, and supported by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan. |
Table 15 Developmental toxicity studies for PFSAs – PFBS
*Derived by contractor; ** calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups). |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFBS (potassium salt) CAS No. 9420-49-3 98%. Feng et al. (2017). |
ICR mice Female (pregnant) 10/dose.
|
0, 50, 200 or 500 0.1% carboxymethyl cellulose. Gavage GD1-GD20 Non-GL study GLP not stated. |
At 50 mg/kg bw/day in dams at GD20 (mean ± SE). At 200 mg/kg bw/day in dams at GD20 (mean ± SE). At 50 / 200 mg/kg bw/day in F1 pups Serum: NR. |
Maternal effects (mean ± SE): ↓ TT3 (90.63 ± 3.22 ng/dL vs 75.55 ± 3.99 ng/dL). ↓ FT4 (16.81 ± 0.70 pg/ml vs 14.74 ± 0.51 pg/ml). Offspring effects: (female) (mean ± SE): ↓ TT4 and TT3 on PND1, PND30 and PND60 (data only reported in figures). Recovery not assessed. |
Maternal: F1 pups: |
Prenatal exposure causes permanent hypothyroxinemia in female mice.
|
K1 FT3 not measured in dams or offspring. Trh mRNA in hypothalmus not measured in dams. Decreases in TT4, TT3 and FT4 in dams and decreases in TT4 and TT3 in pups do not show a clear dose response. Increases in TSH in dams and pups do not show a clear dose response. Increase in Trh mRNA does not show a clear dose response. THs and mRNA measured in 30, 10 and 10 offspring at PND1, PND30 and PND60, respectively. Funded by the National 973 Program and the National Natural Science Foundation. |
Table 16 Developmental toxicity studies for PFSAs – PFHxS
*Derived by contractor; ** calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups). |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFHxS (potassium salt) CAS No. 3871-99-6 ≥98%. Gilbert et al. (2021). |
Long-Evans rats Female (pregnant) 6-9/group.
|
0 or 50 2% Tween-20® and deiodinized Water. Gavage GD6-PND21 Non-GL study GLP not stated |
NR |
Maternal effects: ↓ TT3 in serum (data only reported in figures) ↓ FT4 in serum (data only reported in figures) Offspring effects: ↓ TT3 in serum (data only reported in figures) ↓ FT4 in serum (data only reported in figures) Recovery not assessed. |
Maternal: NA / 50*. F1 pups: NA / 50*. |
No effect on expression of TH-response genes in offspring cortex. Reliance on serum THs as prescriptive of specific neurodevelopmental outcomes may be too simplistic. Mapping the relationships between serum and brain tissue THs may more accurately identify xenobiotics of neurotoxicological concern. Thyroid gland transcripts involved in hormone synthesis (Tpo) and responsive to thyroid stimulating hormone (Nis) were not significantly altered in thyroid glands collected from dams on PND22 or pups on PND0, PND6, or PND14. Despite significant reductions in serum and brain T4 in the early neonatal period, the few effects observed were not consistent with what would be expected based on serum THs. |
K2 Only two dose groups. Some basic methodology is not given, but the study is well reported. No effect on serum TSH at LOAEL. No effect on brain TT3 at LOAEL. FT3 not measured. THs measured in 8 or 10 offspring at 0 or 50 mg/kg bw/day, respectively. Authors declared no conflicts of interest. No details of funding given. |
|
PFHxS (potassium salt) CAS No. 3871-99-6 >98%. Ramhøj et al. (2018). |
Wistar rats Female (pregnant) 8/dose.
|
0, 25 or 45 Corn oil. Gavage GD7-PND22 Non-GL study (range finding study for main study -see below) GLP not stated. |
At 25 mg/kg bw/day in dams (mean ± SD) |
Maternal effects: Offspring effects: ↓ TT4 (data only reported in figures). Recovery not assessed. |
Maternal: NA / 25. F1 pups: NA / 25. |
No author conclusions for the range finding study and thyroid effects. |
K1 Only three dose groups. Range finding study. Only TT4 measured. No specific discussion of thyroid toxicity. Funded by the Danish Centre on Endocrine Disruptors and the Environmental Protection Agency, Ministry of Environment and Food of Denmark. |
|
PFHxS (potassium salt) CAS No. 3871-99-6 >98%. Ramhøj et al. (2018). |
Wistar rats Female (pregnant) 16-20/dose.
|
0, 0.05, 5 or 25 Corn oil. Gavage GD7-PND22 Non-GL study GLP not stated |
NR |
Maternal effects: Offspring effects: ↓ TT4 (data only reported in figures). Recovery not assessed. |
Maternal: 0.05 / 5. F1 pups: 0.05 / 5.
|
A marked effect on TT4 levels was seen in both dams and offspring. PFHxS is an effective TH disruptor in rats. The observed postnatal TT4 decreases in offspring, seen at PND16/17, were likely due to lactational transfer of PFHxS. |
K1 Only TT4 reported. #THs measured in 13-20 animals /dose in dams, and in one male and one female per litter (where the litter comprises both sexes), from 14-18 litters/ dose. Funded by the Danish Centre on Endocrine Disruptors and the Environmental Protection Agency, Ministry of Environment and Food of Denmark. |
|
PFHxS (potassium salt) CAS No. 3871-99-6 >98%. Ramhøj et al. (2020). |
Wistar rats Female (pregnant) 16-20/dose.
|
0, 0.05, 5 or 25 Corn oil. Gavage GD7-PND22 Non-GL study GLP not stated |
NR |
Maternal effects: ↓ TT3 (data only reported in figures) #. Offspring effects: Recovery not assessed. |
Maternal: 5* / 25*. F1 pups: 0.05* / 5*. |
TH levels decreased in a dose dependent manner, with no effect on TSH levels. HPT axis not activated. No evidence of TH-mediated neurobehavioral disruption in offspring, but current rodent models are not sufficiently sensitive to detect adverse neurodevelopmental effects of maternal and perinatal hypothyroxinemia. |
K1 TT4 levels reported in Ramhøj et al. (2018). No effect on TSH or thyroid histopathology in dams or offspring at the LOAEL. #THs measured in 15-20 animals/dose in dams. TT3 and TT4 measured in up to one male and one female per litter, from 14-18 litters/dose. Thyroid weight measured in 11-16 offspring/dose. Funded by the Danish Centre on Endocrine Disruptors and the Environmental Protection Agency, Ministry of Environment and Food of Denmark. |
Table 17 Developmental toxicity studies for PFSAs – PFOS
*Derived by contractor; ** calculated according to EFSA. (2012); NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/mL) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups). |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author comments |
Comments |
|
PFOS (potassium salt) CAS No. 2795-39-3 ≥98%. Conley et al. (2022). |
Sprague-Dawley rats Female (pregnant) 5/dose.
|
0, 0.1, 0.3, 1, 2 or 5 0.5 % Tween-80®. Gavage GD8-PND 2 Non-GL study GLP not stated.
|
At 0.1 mg/kg bw/day in dams on PND2 (mean ± SE). Serum: 2.2 ± 0.1. At 0.3 mg/kg bw/day in pups (mean ± SE) Serum: NR. |
Maternal effects (mean ± SE): ↓ TT4 on PND2 (32.5 ± 2.5 ng/mL vs 25.8 ± 2.3 ng/mL). Offspring effects (mean ± SE): ↓ TT4 on PND2 (6.38 ± 2.8 ng/mL vs 4.92 ± 0.59 ng/mL). Recovery not assessed. |
Maternal: NA / 0.1*. F1 pups: 0.1/ 0.3*. |
PFOS did not decrease maternal FT3 at any dose. Decreases in serum THs are potentially involved in the observed reductions in pup body weights and growth (at higher doses), which requires additional investigation.
|
K1 No effect on TT3 at LOAEL.TSH not measured. #THs measured in 4-5 animals /dose in dams. THs measured in 4-5 animals /dose in offspring. No measurements at 5 mg/kg bw/day due to complete litter loss. Study funded by the US EPA Research and Development and Office of Water.
|
|
PFOS (potassium salt) CAS No. 2795-39-3 86.9%. Chang et al. (2009). Butenhoff et al. (2009b) for maternal body weight data and test guidelines.
|
Sprague-Dawley rats Female (pregnant) 25/dose.
|
0, 0.1, 0.3 or 1.0 0.5% Tween-20® in water. Gavage GD0-PND20 EPA OPPTS 870.6300 and OECD 426 GLP not stated.
|
At 1.0 mg/kg bw/day in dams on GD20, PND4 and PND21 (mean ± SE). Serum: 26.63 ± 3.94, 34.32 ± 31.15 and 30.48 ± 1.29. At 1.0 mg/kg bw/day in female fetuses or pups on GD20 (fetus), PND4, PND21 and PND72 (mean ± SE) Serum: 31.463 ± 1.032, 22.440 ± 0.723, 18.010 ± 0.744 and 1.993 ± 0.293. |
Maternal effects: Offspring effects (mean ± SE): Recovery not assessed. |
Maternal: F1 fetus: |
Interpretation of the toxicological significance of fetal cell proliferation is problematic without further studies. No clear adverse effect on thyroid status (TSH, morphology, hormone homeostasis, proliferation, and liver gene expression). In PND21 male offspring, follicular epithelial cell height was significantly higher than controls, although this difference was considered spurious by the authors because of the low result in the male control group as compared to the female control group. For the significant increase in number of Ki-67-positive thyroid follicular epithelial cells seen in fetus at 1.0 mg/kg bw/day. Due to the range in corresponding control values, the authors were unable to determine the toxicological significance of this finding. |
K1 OECD 426 study. Low purity. No details of impurities given. TSH is the only TH measured. Thyroid follicular epithelial cell counts based on positive staining for Ki-67 as evidence of cell proliferation only measured at 0 and 1 mg/kg bw/day. Thyroid histopathology in 6-10/ dose in offspring. NOAEL (maternal) is highest dose tested. Study funded by 3M Company.
|
|
PFOS (potassium salt) CAS No. not given Purity not given. Fuentes et al. (2006). |
CD-1 mice Female (pregnant) 10-11/dose.
|
0, 1.5, 3 or 6 0.5% Tween-20®. Gavage GD6-GD18 Non-GL study GLP not stated.
|
NR. |
Maternal effects: No effects seen (NOAEL is highest dose tested). Offspring effects: NR. Recovery not assessed. |
Maternal: 6 / NA.
|
Serum THs in pregnant mice at term tended to reduce circulating TT3, FT3, TT4 or FT4 levels. However, no significant differences between dams exposed and non-exposed to PFOS could be noted. |
K2 Purity not given. Information on housing and feeding conditions not given. TT3, FT3, TT4 and FT4 measured. TSH not measured. No details of funding or conflicts of interest given. |
|
PFOS (potassium salt) CAS No. not given 91%. Lau et al. (2003). |
Sprague-Dawley rats Female (pregnant) 17-28/dose.
|
0, 1, 2, 3, 5 or 10 0.5% Tween-20®. Gavage GD2-GD21 Non-GL study GLP not stated.
|
Data only reported in figures. |
Maternal effects: NR. Offspring effects: ↓ FT4 (data only reported in figures). Recovery not assessed. |
Maternal: NR. Offspring NA / 1*.
|
Hypothyroxinemia was detected in treated neonates as early as PND2. Rats are more sensitive than the mouse to PFOS (see entry below). |
K1 No details of impurities given. No effect on TSH or TT3 at LOAEL. FT3 not measured. Dose response in TT4 and TT3 in pups unclear in figures. THs measured in 1 animal/sex/litter (3-8 measurements) in offspring. Maternal and prenatal data reported in Thibodeaux et al. (2003). Study funded primarily by US EPA, analytic chemistry support from 3M Company. |
|
PFOS (potassium salt) CAS No. not given 91%. Lau et al. (2003). |
CD-1 mice Female (pregnant) 21-22/dose.
|
0, 1, 5, 10, 15 or 20 0.5% Tween-20®. Gavage GD1-GD17 Non-GL study GLP not stated.
|
NR. |
Maternal effects: NR. Offspring effects:
Recovery not assessed. |
Maternal: NR. Offspring: 10 / NA.
|
No specific comments on thyroid toxicity. Most offspring exposed to 15 or 20 mg/kg bw/day did not survive for 24 h after birth. 100% mortality from PND3 at both doses. |
K1 No details of impurities given. TT4, FT4, TT3, TSH measured. FT3 not measured. THs measured in 1/sex/litter (3-7 measurements) in offspring. Maternal and prenatal data reported in Thibodeaux et al. (2003). Study funded primarily by US EPA, analytic chemistry support from 3M Company. |
|
PFOS (potassium salt) CAS No. not given 86.9%. Luebker et al. (2005). |
Sprague-Dawley rats Female 8-20/dose.
|
0, 0.4, 0.8, 1.0, 1.2, 1.6 or 2. 0.5% Tween-80®. Gavage 42 days prior to and throughout mating, lactation to GD20 or LD4. Non-GL study. GLP not stated.
|
At 0.4 mg/kg bw/day in dams on GD21, GD7, GD15 and GD21 (mean ± SD). Serum: 40.7 ± 4.46, 40.9 ± 5.89, 41.4 ± 4.80 and 26.2 ± 16.1. At 0.4 mg/kg bw/day in pups. Serum: NR. |
Maternal effects (mean ± SD). Offspring effects (mean ± SD): Recovery not assessed. |
Maternal:
F1 pups: |
Results did not suggest a hypothyroid state in pups. The lack of a major increase in TSH, and that liver malic enzyme (a marker for TH response) concentrations were comparable to controls, suggest that pups were in a normal (euthyroid) state. No histopathological changes in pup thyroids. |
K3 Low purity. Impurities include 8.4% lesser homologues of PFOS (C4-C7), 1.9% unspecified impurities, 1.5% metals, 0.6% inorganic fluoride, 0.3% perfluorooctanoic acid, 0.3% nonafluoropentanoic acid and 0.1% heptafluorobutyric acid. No histopathology methodology and number animals/endpoint either low or not given. No effect on TSH, FT3 or TT3 at LOAEL. Decrease in TT4 shows a dose response in dams, but no clear dose response in pups. #THs measured in 6-20 animals/dose in dams, and in 1-13 animals /dose in offspring. Authors affiliated to 3M Company. No details of funding given. |
|
PFOS (potassium salt) CAS No. not given 91%. Thibodeaux et al. (2003). |
Sprague-Dawley rats Female (pregnant) 25-50/dose.
|
0, 1, 2, 3, 5 or 10 0.5% Tween-20®. Gavage GD2-GD20 Non-GL study. GLP not stated.
|
NR. |
Maternal effects: ↓ TT4 on GD7, GD14 and GD21 (data only reported in figures) #. ↓ FT4 on GD7, GD14 and GD21 (data only reported in figures) #. Offspring effects: NR in this paper. Recovery not assessed. |
Maternal: NA NA / 1*. BMDL5/BMD5 (based on maternal serum TT4 on GD7) 0.046 / 0.234. F1 pups: NR. |
Despite a decrease in THs, a feedback elevation of TSH through activation of the HPT axis was not apparent.
|
K1 No details of impurities given. No effect on TSH at LOAEL. Offspring data reported in Lau et al. (2003). #THs measured in 9-14/dose. Study authors do not specify why a 5% response was selected for BMD modelling. Study funded primarily by US EPA, analytic chemistry support from 3M Company. |
|
PFOS (potassium salt) CAS No. not given 91%. Thibodeaux et al. (2003).
|
CD mice Female (pregnant) 60-80/dose.
|
0, 1, 5, 10, 15 or 20 0.5% Tween-20®. Gavage GD1-GD17 Non-GL study. GLP not stated.
|
Data primarily only reported in figures. No data reported at LOAEL. At 10 mg/kg bw/day in dams on GD18 (mean ± SE) Serum: 179 ± 7. |
Maternal effects: ↓ TT4 on GD6 (data only reported in figures). Offspring effects: NR in this paper. Recovery not assessed. |
Maternal: 15 / 20. BMDL5/BMD5 (based on maternal serum TT4 on GD7) 0.352 / 0.513. F1 pups: NR. |
Similar pattern of decreased TT4 to rats. Reductions of TT3 and TT4 without a compensatory elevation of TSH, though puzzling, is not unique. Generally, the mouse appeared to be a less sensitive species than the rat. |
K1 No details of impurities given. Number of animals for TH analysis not given. No effect on TSH, TT3 or FT4 at LOAEL. Dose response for decrease in TT4 unclear from figures. Study authors do not specify why a 5% response was selected for BMD modelling. Offspring data reported in Lau et al. (2003) Study funded primarily by US EPA, analytic chemistry support from 3M Company. |
|
PFOS (potassium salt) CAS No. 2795-39-3 >98%. Wang et al. (2011). |
Wistar rats Female (pregnant) 4-9/dose.
|
0, 3.2 and 32 ppm in diet equivalent to 0.38 or 3.8**. 2% Tween-20® in deionized water mixed with diet power. Diet GD1-PND14 Non-GL study GLP not stated.
|
At 0.38 mg/kg bw/day in dams on PND1, PND7 and PND14 (mean ± SE). At 0.38 mg/kg bw/day in pups on PND1, PND7 and PND14 (mean ± SE). Serum: 5.85 ± 0.33, At 3.8 mg/kg bw/day in pups on PND1, PND7 and PND14 (mean ± SE). Serum: 32.9 ± 0.81, 21.3 ± 1.06 and 25.2 ± 1.27. |
Maternal effects (mean ± SE): ↓ TT4 on PND1 (43.2 ± 1.6 ng/mL vs 29.5 ± 0.8 ng/mL) and PND7 (42.9 ± 1.8 ng/mL vs 30.9 ± 1.0 ng/mL#. Offspring effects (mean ± SE): ↓ TT4 on PND7 (40.3 ± 0.5 ng/mL vs 24.8 ± 1.2 ng/mL) and PND14 (73.7 ± 2.9 ng/mL vs 53.5 ± 1.4 ng/mL). Recovery not assessed. |
Maternal: NA / 0.38*. F1 pups: NA / 0.38*.
|
Exposure- and time-dependent alterations in TH concentrations. Results suggest a complex TH-mediated gene and protein response to PFOS exposure that seems little related to TH homeostasis. |
K1 Only three dose groups. TSH, FT4 and FT3 not measured. Decrease in TT4 in dams and pups does not show a clear dose response. #THs measured in 3-9 animals /dose in dams, and in 4-12 animals /dose in offspring. EFSA. (2012) dose conversion factor of 0.12 for subacute studies used. Funded by National Natural Science Foundation of China. |
|
PFOS (potassium salt) CAS No. 2795-39-3 98%. Yu et al. (2009b).
|
Wistar rats Female (pregnant) 20/dose. CF study: Wistar rats Male and female pups 5/dose.
|
0 or 3.2 mg/kg diet equivalent to 0.29** 0.5 %. Tween-20® mixed with diet powder Diet. Through gestation and lactation. Non-GL study. GLP not stated. CF study: 0 or 0.29 / diet / GD0 to weaning at PND21 or to PND35. Pups exposed prenatally only (TC) postnatally only (CT) prenatally and postnatally (TT). |
At 0.29 mg/kg bw/day in TC male pups on PND21 and PND35 (mean ± SE). Serum: 2.41 ± 0.17 and 0.41 ± 0.02. At 0.29 mg/kg bw/day in TC female pups on PND21 and PND35 (mean ± SE). Serum: 2.40 ± 0.08 and 1.02 ± 0.08. At 0.29 mg/kg bw/day in CT male pups on PND21 and PND35 (mean ± SE). Serum: 4.80 ± 0.22 and 6.64 ± 0.35. At 0.29 mg/kg bw/day in CT female pups on PND35 (mean ± SE) Serum: 7.04 ± 0.59. At 0.29 mg/kg bw/day in TT male pups on PND21 and PND35 (mean ± SE). Serum: 8.95 ± 0.16 and 10.60 ± 0.53. At 0.29 mg/kg bw/day in TT female pups on PND21 and PND35 (mean ± SE) Serum: 8.89 ± 0.07 and 11.53 ± 0.28. |
Maternal effects: NR. Offspring effects (mean ± SE): ↓ TT4 in TC group on PND21 (58.1 ± 3.1 ng/mL vs 46.3 ± 2.7 ng/mL) and PND35 (67.5 ± 3.5 ng/mL vs 54.4 ± 3.3 ng/mL). ↓ TT4 in CT group on PND21 (58.1 ± 3.1 ng/mL vs 41.5 ± 2.6 ng/mL). and PND35 (67.5 ± 3.5 ng/mL vs 43.3 ± 3.0 ng/mL). ↓ TT4 in TT group on PND14 (67.8 ± 3.5 ng/mL vs 42.9 ± 1.7 ng/mL), PND21 (58.1 ± 3.1 ng/mL vs 43.8 ± 2.4 ng/mL) and PND35 (67.5 ± 3.5 ng/mL vs 42.3 ± 2.2 ng/mL). ↑ TTR (TT, PND21, male and female combined; data only reported in figures). Recovery not assessed. |
Maternal: NR. F1 pups (TC, CC, TT): NA / 0.29*. |
Prenatal and postnatal exposure induced hypothyroxinemia in rat pups. No alteration of mRNA expression observed for selected genes important for TT4 deiodination, glucuronidation and TH receptors. |
K1 Only two dose groups. No effect on TT3 or rT3 at LOAEL. TSH not measured. THs measured in 1 male and 1 female (where possible) per nursing dam. EFSA. (2012) dose conversion factor of 0.09 for subchronic studies used. Funded by the National Nature Science Foundation of China and Scientific Research Fund of Liaoning Provincial Education Department. |
Table 18 Developmental toxicity studies for PFCAs - PFOA
*Derived by contractor; ** calculated according to EFSA. (2012): NR – not reported; NA – not applicable; # - no. of animals studied per endpoint differs to the no. of animals treated.
|
Substance / CAS no. / purity / reference |
Strain & species / sex / no. of animals |
Dose (mg/kg bw/day) / vehicle / route of admin / duration / GL study / GLP status |
PFAS concentration (µg/ml) |
Observed effects at LOAEL (controls vs treated groups). Recovery (controls vs treated groups). |
Published NOAEL / LOAEL (mg/kg bw/day) |
Study author conclusions |
Comments |
|
PFOA (ammonia salt) CAS No. 3825–26-1 ≥98%. Conley et al. (2022). |
Sprague-Dawley rats Female (pregnant) 5/dose.
|
0, 10, 30, 62.5, 125 or 250. 0.5 % Tween-80®. Gavage GD8-PND2 Non-GL study GLP not stated.
|
At 10 mg/kg bw/day in dams on PND2 (mean ± SE). Serum: 31.8 ± 1.1. At 10 mg/kg bw/day in pups (mean ± SE). Serum: NR. |
Maternal effects on PND2 (mean ± SE): ↓ TT4 (29.10 ± 0.96 ng/mL vs 16.18 ± 0.90 ng/mL). ↓ TT3 (0.56 ± 0.04 ng/mL vs 0.44 ± 0.02 ng/mL). ↓ FT4 (42.18 ± 7.71 pg/mL vs 25.88 ± 1.99 pg/mL). ↓ FT3 (0.82 ± 0.11 pg/mL vs 0.47 ± 0.13 pg/mL). Offspring effects on PND2 (mean ± SE): ↓ birth weight (7.05 ± 0.32 g vs 6.20 ± 0.15 g) ↓ TT3 (0.12 ± 0.01 ng/mL vs 0.09 ± 0.01 ng/mL). ↓ TT4 (5.87 ± 0.49 ng/mL vs 3.69 ± 0.35 ng/mL). ↓ rT3 on PND2 (0.07 ± 0.1 ng/mL vs 0.04 ± 0.004 ng/mL). Recovery not assessed. |
Maternal: NA / 10*. F1 pups: NA / 10*. |
Decreases in serum THs were potentially involved in the observed reductions in pup body weights and growth, which requires additional investigation, Pup birth weight was reduced in all dose groups, however after adjusting with ANCOVA for birthtime and litter size, significantly reduced only at ≥62.5 mg/kg bw/day (17% and 26% reductions at 62.5 and 125 mg/kg bw/day respectively). |
K1 TSH not measured. Decrease in TT4 and TT3 in dams show a dose response. No dose response in dams for FT4 and FT3. Decrease in TT3, TT4 and rT3 in pups shows no dose response, THs measured in 2-5 animals /dose in offspring. Funded by the US EPA Office of Research and Development and Office of Water. |