Table E.1.
Repeated dose toxicity studies for PFCAs
| Substance (purity) | Species/Experimental design and doses | Observed effect | Highest dose with no effects (mg/kg bw per day) | Lowest dose with effect (mg/kg bw per day) | Serum/tissue level of compound | Reference | |
|---|---|---|---|---|---|---|---|
| Perfluorobutanoic acid (PFBA) | |||||||
| PFBA (purity not specified) |
SV/129 wt mice (m) No/sex/group: 10 Duration: 28 days Gavage: 0, 35, 175 or 350 mg/kg bw per day |
Incr rel liver weight Incr hepatic replicative DNA synthesis Incr mRNA of Cyp4A10/ACO Hepatocellular necrosis |
35 |
35 35 35 175 |
At 35 mg/kg bw per day Serum: ~ 80 μg/mL Liver: ~ 27 μg/g |
Foreman et al. (2009) | |
| PFBA (ammonium salt, 3M, purity not specified) |
SD rats (m/f) No/sex/group: 10 Duration: 28 days Gavage: 0, 6, 30 or 150 mg/kg bw per day |
Incr abs liver weight (m) Decr serum cholesterol (m) Decr serum total T4 (m) Decr free T4 in serum (m) Incr mRNA of Acox, Cyp4A1 (m) |
6 6 6 |
30 30 6(a) 6(a) 30 |
At 6 mg/kg bw per day in males(f) Serum: 24.7 +/– 17.6 μg/mL Liver: 7.5 +/– 4.5 μg/g At 30 mg/kg bw per day in males(f) Serum: 38.04 +/– 23.2 μg/mL Liver: 17.4 +/– 8.2 μg/g |
Butenhoff et al. (2012) | |
| PFBA (ammonium salt, 3M, purity not specified) |
SD rats (m/f) No/sex/group: 10 Duration: 90 days Gavage: 0, 1.2, 6, or 30 mg/kg bw per day |
Incr abs liver weight (m) Incr mRNA of Cyp4A1 (m) Decr serum total T4 (m) |
6 6 6 |
30 30 30 |
At 6 mg/kg bw per day in males(f) Serum: 13.6 +/– 9.1 μg/mL Liver: 3.1 +/– 2 μg/g At 30 mg/kg bw per day in males(f) Serum: 52.2 +/– 25 μg/mL Liver: 16.1 +/– 9.1 μg/g |
Butenhoff et al. (2012) | |
| Perfluorohexanoic acid (PFHxA) | |||||||
| PFHxA (Sigma‐Aldrich) |
ddY mice (m/f) No/sex/group: 3–5 Duration: 5 days i.p.: 50, 100, 150 mg/kg bw per day |
Incr abs & rel liver weight a | 50 | 100 | Kudo et al. (2006) | ||
| PFHxA (98.5% purity) |
SD rats (m) No/sex/group: 10–15 Duration: 28 days Gavage: 0, 50, 150, 450/300* mg/kg bw per day (*reduced on day 4 from 450 to 300 mg/kg bw per day due to lethality in 5/15 males) |
Lethality, reduced body weight Decr mean corpuscular haemoglobin Incr abs and rel liver weight Decr serum cholesterol |
150 150 50 50 |
450/300 450/300 150 150 |
WIL Research Laboratories (2005) | ||
| PFHxA (98.5% purity) |
SD rats (m, f) no/sex/group: 10 Duration: 90 days Gavage: 0, 10, 50 or 200 mg/kg bw per day |
Incr rel liver weight, (m) Incr rel kidney weight, (m) Decr serum cholesterol, (m) Incr serum ALT and ALP, (m) |
50 10 50 |
200 10 50 200 |
Chengelis et al. (2009) | ||
| PFHxA (sodium salt, 100% purity) |
Crl:CD(SD) rats (m/f) No/sex/group: 10 Duration: 92 days Gavage: 0, 20, 100, or 500 mg/kg bw per day |
Decr body weight (m) Incr perox ß‐oxidation (m/f) Incr rel & abs liver weight (m/f) Incr ALT (m) Incr rel kidney weight (m/f) Incr urine volume (m/f) Degeneration/atrophy in nasal cavity (m,f) |
100 20/100 m/f: 100/100 100 100 20 |
500 100/500 m/f: 500/500 20 500 500 100 |
Loveless et al. (2009) | ||
| PFHxA (sodium salt, 100% purity) |
Crl:CD(SD) rats (m) No/sex/group: 10 Duration: ~ 110 days Gavage: 0, 20, 100 or 500 mg/kg bw per day |
Decr body weight (m, day 105) | 20 | 100 | Loveless et al. (2009) | ||
| PFHxA (> 99% purity) |
SD rats (m, f) No/sex/group: 10 Duration: 28 days Gavage: 0, 62.6, 125, 250, 500 or 1,000 mg/kg per day |
Incr rel liver weight (m) Incr abs liver weight (m) Incr rel+abs liver weight a Incr. acyl‐CoA oxidase activity (m) Decr haematocrit, haemoglobin, erys (m) Decr blood cholesterol (m) Decr T3 and free+total T4 (m) Incr ALT and AST (m+f) and ALP (m) Degeneration and hyperplasia of olfactory epithelium (m+f) |
125 250 250 125 250 125 |
250 500 500 250 62.6 62.6 62.6 500 250 |
Plasma conc. (ng/ml) at 62.6 mg/kg bw per day: 378 ± 178 (m) 129 ± 16 a at 250 mg/kg bw per day: 1,297± 265 (m) Liver conc (ng/g) at 250 mg/kg bw per day 655 ± 148 (m) |
NTP (2019a) | |
| Perfluoroheptanoic acid (PFHpA) | |||||||
| PFHpA (analytical grade) |
Wistar rats (m/f) No/sex/group: 4 Duration: 5 days i.p.: 0–160 mg/kg bw per day |
Incr hep peroxisomal ß‐oxidation (m) Incr hep peroxisomal ß‐oxidation a |
30(b) 160(b) |
160(b) | Kudo et al. (2000) | ||
| PFHpA (Sigma‐Aldrich) |
ddY mice (m/f) No/sex/group: 3–5 Duration: 5 days i.p.: 0, 20, 50, 100 mg/kg bw per day |
Incr abs & rel liver weight (m) Incr abs & rel liver weight a Incr hep peroxisomal ß‐oxidation (m) Incr hep peroxisomal ß‐oxidation a |
20 50 20 |
50 100 20 50 |
Kudo et al. (2006) | ||
| PFHpA (Sigma, purity not specified) |
C57BL/6 mice (sex) No/sex/group: 4 Duration: 3 days i.p. 0 or 20 mg/kg bw per day |
Incr rel liver weight | 20 | Abe et al. (2017) | |||
| Perfluoroctanoic acid PFOA | |||||||
| PFOA (> 96% purity) |
Balb/c mice (m) No/sex/group: not reported Duration: 7 days Via distilled water: 0, 1 or 5 mg/kg bw per day |
Incr ALT Necrosis and vacuolation of hepatocytes Incr abs liver weight Incr triglycerides in liver Decr body weight Decr free fatty acids in serum Decr triglycerides in serum |
1 1 |
1 1 5 1 1 5 1 |
Hui et al. (2017) | ||
| PFOA (96% purity) |
Balb/c mice (m) No/sex/group: 3–10 Duration: 28 days Orally: 0 or 1.25 mg/kg bw per day |
Incr rel liver weight Incr fasting blood glucose levels Decr glycogen and glucose content in the liver Incr blood glucagon |
1.25 1.25 1.25 1.25 |
Zheng et al. (2017) | |||
| PFOA |
SD rats (m) No/sex/group: 7 Duration: 14 days Gavage: 0, 1, 5, 25 mg/kg bw per day |
Incr abs & rel liver weight Incr activity of superoxide dismutase and glutathione peroxidase in the liver Incr MDA content in liver |
1 1 |
5 1 5 |
Wang et al. (2017b) | ||
| PFOA (commercial source, purity not specified) |
C57BL/6 mice (sex) No/sex/group: 4 Duration: 3 days i.p. 0 or 20 mg/kg bw per day |
Incr rel liver weight | 20 | Abe et al (2017) | |||
| PFOA (98% purity) |
Kunming mice (m) No/sex/group: 8 Duration: 21 days Gavage: 0, 1 or 5 mg/kg bw per day |
Incr abs & rel liver weight Incr ALT and AST Decr serum triglycerides Incr hepatic triglycerides Decr hepatic FGF21 protein |
1 1 1 1 1 |
5 5 5 5 5 |
Wu et al. (2018) | ||
| PFOA (ammonium salt, > 98% purity) |
C57BlL/6 mice (m) No/sex/group: 5 Duration: 2, 8 or 16 weeks Gavage: 1 mg/kg bw per day |
Decr body weight (week 8+16) Incr liver weight (week 8) Incr rel liver weight (week 2–16) Incr replication of hepatocytes (week 2+8) Incr hepatic peroxisomal ß‐oxidation activity (week 2–16) |
1 1 1 1 1 1 |
Li et al. (2019a) | |||
| PFOA (> 98% purity) |
SD rats (m, f) No/sex/group: 10 Duration: 28 days Gavage: males: 0, 0.625, 1.25, 2.5, 5, or 10 mg/kg bw per day; females: 0, 6.25, 12.5, 25, 50, or 100 mg/kg bw per day |
Incr rel+abs liver weight (m) Incr acyl‐CoA‐oxidase activity (m) Incr rel kidney weight (m) Incr rel+abs liver weight a Incr rel kidney weight a Incr rel thyroid weight (m) Decr serum cholesterin & triglyceride (m) Incr ALT, ALP, albumin/globulin ratio (m) Decr T3, free+total T4 (m) Decr haematocrit a Incr TSH, ALP a Incr serum cholesterin+triglycerides a Degeneration and inflammation of olfactory epithelium (m) |
25 25 0.625 25 |
0.625 0.625 0.625 50 50 1.25 0.625 0.625 0.625 6.25 6.25 50 0.625 |
Plasma conc. (ug/ml) at 0.625 mg/kg bw per day: 50.7 ± 2.2 (m) at 5 mg/kg bw per day: 110.7 ± 3.8 (m) at 6.25 mg/kg bw per day: 491 ± 72.1a Liver conc (ug/g) at 0.625 mg/kg bw per day 54.6 ± 2.2 (m) |
NTP (2019a) | |
| Perfluorononanoic acid (PFNA) | |||||||
| PFNA (analytical grade) |
Wistar rats (m/f) No/sex/group: 4 Duration: 5 days i.p.: 0, 2.5, 5, 10,15,20 mg/kg bw per day |
Incr hep peroxisomal ß‐oxidation (m) Incr hep peroxisomal ß‐oxidation a |
5(b) |
2.5(b) 10(b) |
Liver conc (ug/g) 20 mg/kg bw: 358 +/−19 (m) 102 +/−11 a |
Kudo et al. (2000) | |
| PFNA (commercial source; purity not specified) |
ddY mice(m/f) No/sex/group: 3–5 Duration: 5 days i.p.: 0, 2.5, 5, 10, 20 mg/kg bw per day |
Incr abs & rel liver weight a Incr abs liver weight (m) Incr rel liver weight (m) Incr perox ß‐oxidation (m/f) |
2.5 |
2.5 5 2.5 2.5 |
Kudo et al. (2006) | ||
| PFNA (97% purity) |
SD rats (m) No/sex/group: 6 Duration: 14 days Gavage: 0, 0.2, 1 or 5 mg/kg bw per day |
Incr abs & rel liver weight Decr total serum cholesterol Incr mRNA of SREBP‐1c, ACOT1/2 Incr hepatic levels of Il1ß,Il10,TNFa Incr serum levels of ALT, AST, ALP, LDH |
0.2 0.2 1 |
1 0.2 1 0.2 5 |
Liver conc. (ug/g) 0.2 mg/kg bw per day: 12.2 5 mg/kg bw per day: 135 |
Fang et al. (2012a) | |
| PFNA (97% purity) |
SD rats (m) No/sex/group: 6 Duration: 14 days Gavage: 0, 0.2, 1 or 5 mg/kg bw per day |
Incr serum glucose Decr serum HDL Incr liver glycogen Incr liver MDA Incr mRNA of G6PC/GLUT2 |
0.2 1 1 1 |
1 0.2 5 5 5 |
Fang et al. (2012b) | ||
| PFNA (97% purity) |
Balb/c mice (m) No/sex/group: 8 Duration: 14 days Gavage: 0, 0.2, 1 or 5 mg/kg bw per day |
Incr rel liver weight Incr total hepatic cholesterol/triglycer. Incr mRNA of Cyp4A1/ACOX1 Incr serum levels of AST, ALT |
1 |
0.2 0.2 0.2 5 |
Wang et al. (2015a) | ||
| PFNA (97% purity) |
SD rats (m)(c) No/sex/group: 10 Duration: 7 days Gavage: 0, 0.2, 1, 5 mg/kg bw per day |
Incr hepatic cholesterol Incr activity of glucose‐6‐P‐dehydrogenase Incr serum ALT |
0.2 0.2 0.2 |
1 1 1 |
Fang et al. (2015) | ||
| PFNA (purity not specified) |
Wistar rat (m) No/sex/group: 10 Duration: 14 days Gavage: 0, 0.0125, 0.25 or 5 mg/kg bw per day |
Incr plasma corticosterone Decr hepatic OATP4C1 protein |
0.0125(b) 0.0125(b) |
Serum levels (ug/ml): at 0.0125 mg/kg bw per day: 0.396 at 0.25 mg/kg bw per day: 30 at 5 mg/kg bw per day: 602 |
Hadrup et al. (2016) | ||
| PFNA (Sigma purity not specified) |
SV129 mice (m) No/sex/group: 4 Duration: 7 days Gavage: 0, 1 or 3 mg/kg bw per day |
Incr abs & rel liver weight | 1 | Rosen et al. (2017) | |||
| PFNA (97% purity) |
SV129 mice (m) No/sex/group: 4 Duration: 7 days Gavage: 0 or 10 mg/kg bw per day |
Incr abs & rel liver weight Incr hepatic lipid and triglyceride content |
10 10 |
Das et al. (2017) | |||
| PFNA (Sigma, purity not specified) |
C57BL/6 mice (sex) No/sex/group: 4 Duration: 3 days i.p. 0 or 20 mg/kg bw per day |
Incr rel liver weight | 20 | Abe et al. (2017) | |||
| PFNA (> 98% purity) |
SD rats (m, f) No/sex/group: 10 Duration: 28 days Gavage: males: 0, 0.625, 1.25, 2.5, 5, or 10 mg/kg bw per day; females: 0, 1.56, 3.12, 6.25, 12.5, or 25 mg/kg bw per day |
Decr body weight (m) Decr body weight a Incr rel + abs liver weight (m) Incr acyl‐CoA oxidase activity (m) Incr rel kidney weight (m) Incr rel + abs liver weight a Incr rel kidney weight a Decr serum cholesterol+triglyceride (m) Decr free + total T4 (m) Incr serum bile salts (m) Incr urea, albumin/globulin ratio (m) Incr total+direct bilirubin, ALP/ALT/AST (m) Incr albumin/globulin ratio a Incr urea and serum bile salts a Decr total+free T4 a |
0.625 0.156 0.625 0.625 1.56 1.56 |
1.25 3.12 0.625 0.625 0.625 1.56 1.56 0.625 0.625 0.625 1.25 1.25 1.56 3.12 3.12 |
Plasma conc. (ug/ml) at 0.625 mg/kg bw per day: 56.7 ± 1.9 (m) at 1.56 mg/kg bw per day: 26.4 ± 1.1 a Liver conc (u g/g) at 0.625 mg/kg bw per day 145.5 ± 2.7 (m) |
NTP (2019a) | |
| Perfluorodecanoic acid (PFDA) | |||||||
| PFDA (Aldrich) |
Wistar rats (m) No/sex/group: 4 Duration: 1 week Diet: 0, 0.00125, 0.0025, 0.005 or 0.01%; equivalent to 0, 1.5, 3, 6, or 12 mg/kg bw per day(e) |
Incr rel liver weight Incr abs liver weight Incr peroxisomal ß‐oxidation Incr acyltransferase activity Incr intrahepatic triacylglycerol |
1.5 1.5 |
1.5 3 3 1.5 1.5 |
Kawashima et al. (1995) | ||
| PFDA (analytical grade) |
Wistar rats (m/f) No/sex/group: 4 Duration: 5 days. i.p.: 0, 2.5, 5, 10, 15, 20 mg/kg bw per day |
Incr hep peroxisomal ß‐oxidation (m) Incr hep peroxisomal ß‐oxidation a |
2.5(d) 2.5(d) |
5(d) 5(d) |
Liver conc (ug/g) 20 mg/kg bw: 453 +/−19 (m) 412 +/−33 a |
Kudo et al. (2000) | |
| PFDA (Sigma, purity not specified) |
C57BL/6 mice (sex not reported) No/sex/group: 4 Duration: 3 days i.p. 0 or 20 mg/kg bw per day |
Incr rel liver weight | 20 | Abe et al. (2017) | |||
| PFDA (97.8% purity) |
SD rats a No/sex/group: 8 Gavage at 0, 0.125, 0.25, 0.5, 1, or 2 mg/kg bw per day Duration: 28 days |
Incr rel liver weight Incr abs liver and rel kidney weight Incr abs kidney weight |
0.125 0.25 |
0.125 0.25 0.5 |
Frawley et al. (2018) | ||
| PFDA (97.8% purity) |
B6C3F1 mice a No/sex/group: 8 Gavage at 0, 0.31, 0.625, 1.125, 2.5, or 5 mg/ kg bw per day Duration: 28 days |
Incr abs & rel liver weight Incr rel spleen weight |
0.31 0.625 |
0.625 1.125 |
Frawley et al. (2018) | ||
| PFDA (> 97% purity) |
SD rats (m, f) No/sex/group: 10 Duration: 28 days Gavage: 0, 0.156, 0.312, 0.625, 1.25, or 2.5 mg/kg bw per day |
Incr abs+rel liver weight (m, f) Incr acyl‐CoA‐oxidase activity (m) Decr abs weight of adrenal gland (m) Incr abs+rel weight of thyroid a Incr albumin/globulin ratio (m, f) Decr cholesterol in blood (m) Incr AST (m/f) Incr ALT (m/f) Incr ALP (m, f) |
0.156 −/0.625 0.156/0.625 0.156 |
0.156 0.156 0.156 0.312 0.156 0.156 0.156/1.25 0.312/1.25 0.312 |
Plasma conc. (ug/ml) at 0.156 mg/kg bw/day: 8.5 ± .6 (m) 11.2 ± 0.4 a Liver conc (ug/g) at 0.156 mg/kg bw/day 44.7 ± 1.5 (m) |
NTP (2019a) | |
| Perfluoroundecanoic acid (PFUnDA) | |||||||
| PFUnDA (98.5% purity) |
Crl:CD (SD) rats (m/f) No/sex/group: 12 Duration: 42 days Gavage: 0, 0.1, 0.3, 1 mg/kg bw per day |
Incr abs liver weight (m, f) Incr rel liver weight (m/f) Decr abs & rel spleen weight (m) Incr serum ALP, AST (m) Incr serum BUN (m/f) Decr serum albumin (m) |
0.3 0.1/0.3 0.3 0.3 0.3 0.3 |
1 0.3/1 1 1 1 1 |
Takahashi et al. (2014) | ||
| Perfluorododecanoic acid (PFDoDA) | |||||||
| PFDoDA (> 99% purity) |
SD Rats (m) No/sex/group: 6 Duration: 14 days Gavage: 0, 1, 5, or 10 mg/kg bw per day |
Incr abs & rel liver weight Incr serum triglyceride Incr hepatic triglyceride Incr hepatic SOD activity Incr hepatic mRNA of PPARα/g, ACOX, CypA4 Incr hepatic content of cholesterol |
1 5 5 5 |
5 10 10 1 1 10 |
Zhang et al. (2008) | ||
| PFDoDA (95% purity) |
SD Rats (m) No/sex/group: 10 Duration: 110 days Gavage: 0, 0.02, 0.05, 0.2, or 0.5 mg/kg bw per day |
Incr serum glucose Incr serum albumin Incr hepatic mRNA of PPARα, Cyp4A1, ACOX, cd36 |
0.05 |
0.02 0.02 0.2 |
Ding et al. (2009) | ||
| PFDoDA (95% purity) |
SD Rats (m) No/sex/group: 6 Duration: 110 days Gavage: 0, 0.05, 0.2, or 0.5 mg/kg bw per day |
Incr protein level of pyruvate carboxylase in kidney Incr protein level of isovaleryl coenzyme A dehydrogenase, malate dehydrogenase 1 and dihydrolipoamide S‐acetyltransferase in kidney |
0.05 |
0.05 0.2 |
Zhang et al. (2011) | ||
| PFDoDA (Sigma, purity not specified) |
SD rats (m) No/sex/group: 6 Duration: 110 days Gavage: 0, 0.2, or 0.5 mg/kg bw per day |
Incr hepatic cholesterol Incr hepatic triglycerides Altered hepatic levels of signal transduction proteins (e.g. glycogen synthase kinase, insulin receptor substrate) |
0.2 0.2 0.2 |
Zhang et al. (2013e) | |||
| PFDoDA (97% purity) |
SD Rats (m/f) No/sex/group: 7 Duration: 42 days Gavage: 0, 0.1, 0.5, or 2.5 mg/kg bw per day |
Incr rel liver weight (m/f) Decr weight of spleen/heart a Decr in reticulocytes (m) Incr serum ALP (m) Decr serum total cholesterol (m) Liver hypertrophy (m) Hepatic necrosis a Pancreas: decr zymogen granules (m) Decr serum glucose (m) |
0.1 0.1 0.5 0.1 0.5 0.5 0.5 0.5 |
0.5 0.5 2.5 0.5 0.1 2.5 2.5 2.5 2.5 |
Kato et al. (2015b) | ||
| PFDoDA (> 95% purity) |
SD Rats (m) No/sex/group: 4‐10 Duration: 110 days Gavage: 0, 0.05, 0.2, or 0.5 mg/kg bw per day |
Incr hepatic SOD activity Incr TBARS in liver Decr hepatic GPX activity Incr mRNA of PPARα/Cyp4A1 Incr mRNA of mitochondrial acyl‐CoA‐thioesterase 1 and hydroxyacyl‐CoA‐dehydrogenase |
0.2 0.2 0.2 0.05 |
0.5 0.5 0.5 0.2 0.05 |
Liu et al. (2016) | ||
| Perfluorotetradecanoic acid (PFTeDA) | |||||||
| PFTeDA (96.5% purity) |
Crl:CD (SD) rats (m) No/sex/group: 12 Duration: 42 days Gavage: 0, 1, 3, or 10 mg/kg bw per day |
Decr body weight Decr hindlimb strength Incr serum ALP and BUN Incr abs & rel liver weight Centrolob. liver hypertrophy & steatosis Decr abs & rel pituitary gland weight Decr abs weight of semin. vesicles Hypertrophy of thyroid follicular cells |
3 1 3 1 1 1 0 1 |
10 3 10 3 3 3 1 3 |
Hirata‐Koizumi et al. (2015) | ||
| Perfluorohexadecanoic acid (PFHxDA) | |||||||
| PFHxDA (95.3% purity) |
Crl:CD (SD) rats (m) No/sex/group: 12 Duration: 42 days Gavage: 0, 4, 20, or 100 mg/kg bw per day |
Decr body weight Incr abs & rel liver weight Centrolob. liver hypertrophy & steatosis Incr rel thyroid weight |
20 20 20 20 |
100 100 100 100 |
Hirata‐Koizumi et al. (2015) | ||
| Perfluorooctadecanoic acid (PFODA) | |||||||
| PFODA (98.9% purity) |
Crl:CD (SD) rats (m) No/sex/group: 12 Duration: 42 days Gavage: 0, 40, 200, or 1,000 mg/kg bw per day |
Decr body weight/food consumption Decr red blood cells/haemoglobin/haematocrit Decr serum gamma‐GTP Incr abs & rel liver weight Liver hypertrophy Incr serum ALP, ALT |
200 40 40 40 40 200 |
1,000 200 200 200 200 1,000 |
Hirata‐Koizumi et al. (2012) | ||
ALP: alanine phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; bw: body weight; f: female; m: male; i.p.: intraperitoneal; SOD: superoxide dismutase; T3: triiodothyronine; T4: thyroxine; TBARS: Thiobarbituric acid reactive substances.
Please note that the effect was not evident at the 90‐day time point of investigation.
Adequate statistical evaluation is missing.
Rats were treated with streptozotocin to induce diabetes.
Derived from figure 2D of Kudo et al. (2000). No statistical evaluation is given and significance of data is unclear.
Applying default values, provided by EFSA.
More data on serum and tissue concentrations are given in Butenhoff et al. (2012). The table is confined to serum/tissue concentration at doses with sensitive endpoints in males of the highest dose group.