Table F.7.
Perfluorooctanoic acid (PFOA) reproductive and developmental toxicity studies with pre‐ and perinatal exposure
| Substance/ (Purity) | Species/Experimental design and doses | Most sensitive endpoints | Highest dose with no effect (mg/kg bw per day) | Significant effect level (mg/kg bw per day) | Serum/tissue levels of compound | Reference | ||
|---|---|---|---|---|---|---|---|---|
| Mother | offspring | Mother | offspring | |||||
| PFOA ammonium salt, 98% pure | CD1 mice, GD1‐birth, 0, 1, 3, 5, 10, 20, 40 mg/kg per day |
Liver weight resorption of litters, reduced percentage of live fetuses, reduced weight of fetuses, reduced postnatal survival and growth deficits (ossification) |
n.d. | 1 | 1 | 3 |
Maternal serum levels (ng/mL) at term (estimated from figure). 0: n.d. 1: 20,000 3: 40,000 5: 70,000 10: 110,000 20: 170,000 40: 260,000 |
Lau et al. (2006) |
| PFOA ammonium salt, 97,99% pure | 129S1/SvlmJ wild‐type and PPARα knockout mice, 0.1, 0.3, 0.6, 1, 3, 5, 10, 20 mg/kg per day, GD 1–17. Results for WT |
Relative liver weight Relative liver weight Litter loss Postnatal survival |
0.6 |
n.d. 0.3 0.3 |
1 |
0.1 0.6 0.3 |
P0 with no pups, PND22 serum at 0, 0.1, 0.3, 0.6 and 1 mg/kg per day: 131, 4,400, 10,400, 17400 and 26,300 ng/mL P0 with pups, PND22 serum at 0, 0.1, 0.3, 0.6 and 1 mg/kg per day: 33.2, 1,600, 2,840, 5,170, 9,290 ng/mL Pups at PND22 serum at 0, 0.1, 0.3, 0.6 and 1 mg/kg per day: 17.3, 798, 2,150, 3,810, 9,860 ng/mL |
Abbott et al. (2007) |
| PFOA ammonium salt, 98% pure |
CD1 mice GD1–17, GD8–17, GD12–17: 0 and 5 ng/kg bw/day |
Reduced bw Decreased weaning‐induced mammary involution (P0) Mammary gland development retardation irrespective of the timing of exposure |
5 |
5 5 |
White et al. (2007) | |||
| PFOA ammonium salt, 98% pure |
CD1 mice Full gestational study (GD 1–17): 0 (n = 48), 3 (n = 28), 5 (n = 36) mg/kg bw (pregnant dams) cross‐fostering during lactational exposure leading to 7 groups. GD 8–17: 0 (n = 56), 5 (n = 56) ng/kg bw (pregnant dams). Cross‐fostering during lactational exposure. Early life effects restricted gestational (GD 7,10,13,15–17) exposure study at 5 mg/kg per day |
Mammary gland development retardation irrespective of the timing of exposure | n.d. |
3 5 5 |
Serum levels (ng/mL). Exposure GD 8‐17, dams on lactation day 1,3,5,10: Control dams nursing control pups: 11, 6, 4, 0. Control dams nursing treated pups: 26, 1,300, 6,510, 5,000. Treated dam nursing control pups: 47,900, 39,300, 34,000, 16,400. Treated dam nursing treated pups: 42,200, 43,000, 38,800, 24,400. Pups on PND 1, 3, 5, 10 (exposure GD 8–17) and PND 22, 42, 63 (exposure GD 1–17). Control pup nursed by control dam: 23, 16, 10, 8, nd, nd, nd. Treated pup nursed by control dam: 66,200, 43,900, 33,100, 20,500, 8,300, 646, nd. Control pups nursed by treated dam: 1,560, 10,500, 15,000, 15,700, 12,100, 894, nd. Treated pups nursed by treated dam: 70,000, 54,400, 52,200, 31,300, 21,900, 4,050, 500. |
White et al. (2009)1 | ||
| PFOA, ammonium salt > 98% pure |
CD‐1 mice Exp. 1: 0,1, 3, or 5 mg/kg; n = 5, 5, 8, 7 dams Exp. 2: 0, 0.01, 0.1, 0.3, 1 or 5 mg/kg; n = 14 dams except for 5 mg/kg n = 10 Exposure GD1–17 |
Transient body weight gain at mid age observation group of the pups (21–33 weeks) Increase of insulin and leptin 0.01–0.1 mg/kg. |
n.d. n.d. |
0.01– 0.3 0.01 |
Hines et al. (2009) | |||
| PFOA, purity 90%, salt unknown | ICR mice, 15–19 dams/group, 1, 5, 10 mg/kg per day, exposure GD1–17/18 |
Dose dependent liver weight gain, Significant change of 12 out of 20 metabolic parameters with phosphorus and urea levels being most sensitive Decreased neonatal survival |
1 n.d. |
1 |
5 1 |
5 | Yahia et al. (2010) | |
| PFOA, ammonium salt > 98% pure |
CD1 mice Full gestational study (GD 1–17): 0, 0.3, 1, 3 mg/kg per day, dams (n = 13) Late gestational study (GD 10–17): 0, 0.01, 0.1, 1.0 mg/kg per day, dams (n = 7–13) Offspring: 7–9 animals per litter |
Full gestational exposure: Transient (until PND7) increase in liver weight Decreased mammary gland developmental score Late gestational exposure: decreased mammary gland developmental score number of terminal end buds |
n.d n.d. n.d. 0.01 |
0.3 0.3 0.01 0.1 |
Full gest. exposure, female serum at 0.3 mg/kg per day: 4,980 (PND7)–16 ng/mL (PND84) Liver at 0.3 mg/kg per day: 2,078 (PND7)–43 ng/g (PND84) Late gest. exposure: Control 22.6 (PND1)–4.1 ng/mL (PND21) Female serum at 0.01 mg/kg per day: 284.5 (PND1)–16.5 ng/mL (PND21) Serum at 0.1 mg/kg per day: 2,303.5 ng/mL (PND1)–131.7 ng/mL (PND21) More concentration data in supplementary |
Macon et al. (2011) | ||
| PFOA, ammonium salt, purity not stated |
CD‐1 mice, 10 dams per group, 2, 10, 25 mg/kg bw/day, GD 11–16. Sacrificed on GD 16 |
No of resorptions and dead fetuses Decrease of placental weight Decrease in trophoblast cells in the placenta Decrease of mPL‐II, mPLP‐Cα and mPLP‐K expression levels and serum concentrations |
10 |
2 2 25 2 |
Suh et al. (2011) | |||
| PFOA, ammonium salt 98% pure |
Pregnant CD‐1 mice receiving 0, 1, 5 mg/kg bw per day PFOA by oral gavage from GD1–17. Pregnant CD‐1 mice receiving 0 and 1 mg/kg bw per day PFOA by gavage from GD1–17 and additional drinking water containing 5 μg/L (0.00045 mg/kg bw per day) of PFOA from GD7 until termination of the experiment for P0, F1 and F2 generations Dams: n = 5–12 Litter size neonates F1: 12–13 pups Litter size neonates F2: 10 pups |
Prenatal loss (P0) Decreased weaning‐induced mammary involution (P0) Postnatal survival (F1) |
1 | 1 |
5 0.00045 (5 μg/L in water) |
5 |
P0 dams at weaning (PND 22) Control: 4.0 ng/mL Control + 5 μg/L in water: 74.8 ng/mL 1 mg/kg bw per day: 6,658 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 4,772 ng/mL 5 mg/kg/ bw per day: 26,980 ng/mL |
White et al. (2011) |
| F1 developmental indices mammary gland without PFOA in drinking water (PND 22, 42, 63) | n.d. | 1 |
F1 pups PND 22 Control 0.6 ng/mL Control + 5 μg/L in water: 21.3 ng/mL 1 mg/kg bw per day: 2,444 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 2,744 ng/mL 5 mg/kg bw per day: 10,045 ng/mL |
|||||
| F1 developmental indices mammary gland with PFOA in drinking water (PND 22, 42, 63) | n.d. | 0.00045 5 μg/L in water |
F1 pups PND 42 Control: 1.4 ng/mL Control + 5 μg/L in water: 48.9 ng/mL 1 mg/kg bw per day: 610 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 558 ng/mL 5 mg/kg bw per day: 1,581 ng/mL |
|||||
| F1 maternal indices mammary gland without PFOA in drinking water (PND 10) | n.d. | 1 |
F1 pups PND 63 Control 3.1 ng/mL Control + 5 μg/L in water: 66.2 ng/mL 1 mg/kg bw per day: 211 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 187 ng/mL 5 mg/kg bw per day: 760 ng/mL |
|||||
| F1 maternal indices mammary gland with PFOA in drinking water (PND 10) | n.d. | 0.00045 5 μg/L in water |
F1 dams at weaning (PND 22) Control 2.0 ng/mL Control + 5 μg/L in water: 86.9 ng/mL 1 mg/kg bw per day: 9.3 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 173 ng/mL 5 mg/kg bw per day: 18.7 ng/mL |
|||||
| F2 developmental indices mammary gland without PFOA in drinking water (PND 63) | n.d. | 1 |
F2 pups PND 22 Control 0.4 ng/mL Control + 5 μg/L in water: 26.6 ng/mL 1 mg/kg bw per day: 4.6 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 28.5 ng/mL 5 mg/kg bw per day: 7.8 ng/mL |
|||||
| F1 developmental indices mammary gland with PFOA in drinking water (PND 42) | n.d. | 0.00045 5 μg/L in water |
F2 pups PND 42 Control 0.7 ng/mL Control + 5 μg/L in water: 57.4 ng/mL 1 mg/kg bw per day: 0.4 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 72.8 ng/mL 5 mg/kg bw per day: 0.4 ng/mL |
|||||
|
F1 pups PND 63 Control: 1.1 ng/mL Control + 5 μg/L in water: 68.5 ng/mL 1 mg/kg bw per day: 1.1 ng/mL 1 mg/kg bw per day + 5 μg/L in water: 69.2 ng/mL 5 mg/kg bw per day: 1.2 ng/mL |
||||||||
| PFOA ammonium salt, 98% pure | CD‐1 mice, 5 dams/group, 5 mg/kg bw per day, exposure GD 1–17 | Decreased neonatal survival | n.d. | 5 | Abbott et al. (2012) | |||
| PFOA, purity not stated |
Sv/129 Mice WT, mPPARα KO and expressing hPPARα GD 1–17 3 mg/kg bw per day. Results for WT (5–6 dams per group) |
Decrease postnatal survival Decrease mammary development |
3 | 3 | 19,000 ng/mL | Albrecht et al. (2013) | ||
| PFOA ammonium salt, 98% pure |
C57BL/6J‐Apc+/+ female mated with C67BL6J‐Min/+ males 10–24 dams/group 0.1 and 3 mg/kg bw per day (study 1) and 0.01 and 0.1 mg/kg bw per day (study 2) Exposure: GD 1 – 14–18 |
Decreased neonatal survival (not detectable for PFOS) Small increase of liver weight at 0.01 mg/kg per day, but not at 0.1 mg/kg per day |
0.1 n.d. |
3 0.01 (not detectable at 0.1) |
Serum levels in pups at 0, 0.01/0.1/3 mg/kg bw per day: < 0.05, 12–26, 213–216/n.d. ng/mL | Ngo et al. (2014) | ||
| PFOA ammonium salt, 98% pure |
CD‐1 mice, 12, 12, 14, 13, 12, and 6 pregnant dams resulting in 29, 29, 37, 26, 31, and 21 female offspring, exposure 0.01, 0.1, 0.3, 1, 5 mg/kg bw per day, GD 1 –17 129/Sv WT mice, 7, 7, 5, 3, and 5 pregnant dams resulting in 10, 10, 8, 6, and 8 female offspring, exposure 0, 0.1, 0.3, 0.6, 1 mg/kg bw per day, GD 1–17 129/Sv PPARα ko mice, 5, 9, 8, 7, and 9 pregnant dams resulting in 6, 10, 10,9 and 9 female offspring, exposure 0.1, 0.3, 1, 3 mg/kg bw per day, GD1–17 Investigation at 18 months |
CD1 mice: Several non‐neoplastic alterations in livers 129/Sv mice: bile duct hyperplasia in 129/Sv PPARα knockout, but not wild‐type mice liver lesions can occur independent of PPARα |
1 1 |
5 5 |
Filgo et al. (2014) | |||
| PFOA, ammonium salt 98% pure |
CD‐1 mice, 163 dams equally distributed to treatment groups, 6–7 females and 3–4 males per litter after birth C57Bl/6 mice, 41 dams divided to 5 groups, litter sizes > 5 were maintained Exposure 0, 0.01, 0.1, 0.3 1.0 mg/kg bw per day, GD1–17 |
CD‐1 mice: Decrease of mammary gland development score C57Bl/6 mice: Decrease of mammary gland development score |
0.01 (PND21) n.d. (PND 35, PND 56) 0.1 (all time points) |
0.1 (PND21) 0.01 (PND 35, PND 56) 0.3 (all time points) |
CD‐1: Female pups, PND 21 serum at 0, 0.01, 0.1, 0.3 and 1 mg/kg bw per day: < 5, 74.8, 457.3, 904.8, 3,119 ng/mL. C57Bl/6: Female pups, PND 21 serum at 0, 0.01, 0.1, 0.3 and 1 mg/kg bw per day: < 10, 26.1, 247.1, 891.3, 2,141.7 Concentrations in CD‐1 at PND 35 and 56 and in B6 at PND 61 available |
Tucker et al. (2015) | ||
| PFOA Na+ Salt > 99% |
Female C57BL/6J mice mated with male FVB mice. Supplemented through feed: 0, 0.017, 0.056, 0.17, 0.56, 1.7, 5.6 and 17 mg/kg bw per day. Corresponding exposure: 0, 3, 10, 30, 100, 300, 1,000 and 3,000 μg/kg bw per day. Feeding to females was started 2 weeks prior to mating and maintained through mating, gestation and lactation (6 F0 females) Follow up of 9 offspring animals per sex into juvenile and adult stages Switch to high fat diet at 21 weeks |
Decreased litter size Decreased Body weight Decreased perirenal fat pads weight Decreased cholesterol (female) Triglycerides (female offspring) |
BMDL 0.299 |
BMDL5 (week 25) 0.85 BMDL5 0.65 BMDL5 0.40 BMDL5 0.006 (BMDU/BMDL = 100) |
1 | Van Esterik et al. (2016) | ||
| PFOA salt not specified, 96% pure |
C57BL/6/Bkl female mice Exposure 0, 0.3 mg/kg per day, during gestation, n = 6 dams per group |
Periostal areas and medullary areas of the femur were increased at 17 months of age, the bone mineral density of the femur unaffected. Tibial bone mass was decreased both at 13 and 17 months. Biomechanical properties unaffected | n.d. | 0.3 |
Bone levels: 13 months: control 0.73 ng/g, PFOA 3 ng/g 17 months: control 0.64 ng/g, PFOA 3.7 ng/g |
Koskela et al. (2016) | ||
| PFOA, 99.2% pure |
Kunming mice Gavage, 0, 1, 5, 10, 20, 40 mg/kg bw per day, GD 1–17, 10 dams per group. Terminated on GD 18 |
Decreased bw gain Increased relative liver weight Decreased relative uterus weight Decreased embryo weight Decreased embryo survival |
10 n.d. 1 1 5 |
5 1 5 5 10 |
Li et al. (2018b) | |||
| PFOA > 98% pure |
Kunming mice, Gavage, 1, 2.5, 5 mg/kg bw per day from GD 1 to 17, 10 dams per group. Follow up on male offspring PND 21 and 70 |
Decreased postnatal survival Decreased bw PND 21 Decreased testosterone Decreased number of Leydig cells |
2.5 1 n.d. 1 |
5 2.5 1 2.5 |
Mice serum 0.17 μg/mL. At which dose or age of mice was not explained, and method not given | Song et al. (2018a) | ||
| PFOA, 99.2% pure |
Kunming mice Gavage 0, 1, 2.5, 5, 10 mg/kg bw per day, GD 1 to 17, 10 dams per group. Follow up on female offspring on PND21 |
Decreased postnatal survival Decreased weight gain Increased liver weight |
2.5 1 n.d. |
5 2.5 1 |
Li et al. (2019b) | |||
n.d.: not determined from the study; bw: body weight; BMDL: benchmark dose limit; BMDU: benchmark dose upper confidence limit; GD: gestation day; PND: postnatal day.
1Concentrations in serum quantified based on figure.