Incidences of selected non-neoplastic lesions of F344 rats in the NTP 13-week study.a in VS .NET

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Incidences of selected non-neoplastic lesions of F344 rats in the NTP 13-week study.a
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Dose, mg/kg
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Liver Biliary tract Cholangio brosis Hyperplasia Hepatocytes Cytomegaly Degeneration Necrosis Hyperplasia, nodular Kupffer cells Pigmentation
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Kidney Renal tubule Dilation Necrosis 0 0 ND ND ND ND ND ND ND ND
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Reference 4. ND = not determined.
124 2 4 8 15 30 60 10 0 10 10 10 10 10 10 10 10 0 10 ND ND ND ND ND ND 0 ND 0 0 0 0 0 ND ND ND 0 0 1 0 0 0 0 1 1 0 ND 0 ND ND ND 0 0 0 ND 0 0 0 0 3 0 0 ND 2 10 10 8 3 4 8 10 10 9 9 10 10 10 10 10 10
TABLE 2.4.3
Incidences of selected non-neoplastic lesions of B6C3F1 mice in the NTP 13-week study.a
Dose, mg/kg
Male Female Male Female Male Female Male Female Male Female Male Female Male Female
Number of animals examined
ND 0
Liver Biliary tract Cholangio brosis Hyperplasia Hepatocytes Cytomegaly Degeneration Necrosis Kupffer cells Pigmentation
0 0 0
0 0 0
Reference 4. ND = not determined.
TABLE 2.4.4 0 Male 50 50 50 50 50 50 50 Male Male Male Female Female Female 2 4 8 0 2 4
Incidences of selected non-neoplastic lesions of F344 rats in the NTP 2-year study.a 8 Female 50
Dose, mg/kg
Number of animals examined
0 0 0 0 0 0 2 0 0 0 0 1.56 2.38 3.16 88 96 98 3.16 0 0.48 70 78 66 60 64 92 90 92 92 92 98 98 98 98 98 0 0 0 0 0 88 86 70 64 36 98 1.84
88 88 88 88 88
96 94 96 96 96
98 98 98 98 98
0 0 0 0 0
98 98 98 98 98
100 100 100 100 100 100 98 98 94 92 100 2.54
98 92 96 98 98 98 94 94 92 94 96 3.10
Liver Biliary tract, % Chronic focal in ammation Cyst Focal brosis Focal hyperplasia Metaplasia Hepatocytes, % Cytomegaly Cytoplasmic vacuolization Focal degeneration Focal hyperplasia Focal necrosis Kupffer cells, % Focal pigmentation
Kidney Nephropathy, mean severity grade
Reference 4.
HAZARDS OF DIETARY FURAN
TABLE 2.4.5 Incidences of selected non-neoplastic liver lesions of B6C3F1 mice in the NTP 2-year study.a Dose, mg/kg Sex Number of animals examined Cytoplasmic vacuolization, % Focal hyperplasia, % Mixed cell cellular in ltration, % Biliary tract, % Chronic in ammation Fibrosis Hyperplasia Hepatocytes, % Cytomegaly Degeneration Necrosis Kupffer cells, % Focal pigmentation Parenchyma, % Focal atrophy
0 Male 50 16 2 4 0 0 0 16 0 4 4 2
8 Male 50 48 88 46 88 90 92 90 86 78 86 90
15 Male 50 72 98 58 98 98 98 100 86 82 100 100
0 Female 50 12 0 16 4 0 0 0 0 0 10 0
8 Female 50 58 96 46 96 94 94 96 94 88 96 96
15 Female 50 72 96 64 100 100 100 100 96 94 100 100
Reference 4.
whether or not it causes carcinogenic effects like those seen in the rodent bioassays. The National Toxicology Program (NTP) 2-year bioassay (1993) showed that there was clear evidence of carcinogenic activity of furan in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasm of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasm of the liver and benign pheochromocytomas of the adrenal gland. In these bioassays, it is clear that rats are more sensitive than mice to furaninduced neoplasms. Rats were dosed with 0, 2, 4, or 8 mg/kg for 5 days/week for 2 years. Mice were dosed with 0, 8, or 15 mg/kg bw for 5 days/week for 2 years. The results are summarized as follows: 1. Cholangiocarcinomas: The incidence was found high in rats receiving 2 mg/kg for 9 months (40 50%) or 15 months (70 90%). Rats receiving 2 mg/kg bw of furan for 2 years showed 86 98% incidence (Table 2.4.7). While no incidence was found at week 13, a 100% incidence was found at the 9- and 15-month interim evaluations or after in male rats exposed to 30 mg/kg for 13 weeks in a stop-exposure experiment.
TOXICOLOGY
TABLE 2.4.6 Genotoxicity studies of furan. Reference no. Negative results Nonmammalian systems Salmonella typhimurium ( rat and hamster liver S9): In strains TA100, TA1535, TA1537, and TA98 Drosophila melanogaster, sex-linked recessive lethal mutation Mammalian systems In vitro Unscheduled DNA synthesis (UDS) in rat and mouse hepatocytes Chromosomal aberrations ( rat S9 only) in Chinese hamster ovary cells In vivo UDS in mouse or rat hepatocytes after a single oral dose of 200 (mouse) or 100 (rat) mg/kg bw. Sister chromatid exchanges (SCE) in mouse bone marrow cells of male B6C3F1 mice (350 mg/kg bw, ip)
4 4, 13
14 15
4, 14 4
Positive results Nonmammalian systems Salmonella typhimurium ( rat and hamster liver S9): In strain TA100 (weakly positive) Mammalian systems In vitro Mouse L5178Y lymphoma cells ( rat S9) Mouse L5178Y lymphoma cells ( rat S9) Chinese hamster ovary cells (CHO): Sister chromatid exchanges and chromosomal aberrations ( rat S9) Chromosomal aberrations (+rat S9 only) DNA double-strand breaks in isolated rat hepatocytes In vivo Chromosome aberrations in mice bone marrow cells of male B6C3F1 mice (250 mg/kg bw, ip) Mutation in H-ras oncogene in mouse liver
17 4 4 15 18, 19 4 20
TABLE 2.4.7 Incidence of cholangiocarcinomas of the liver of F344 rats by furan (NTP 2-year gavage study). 9 months Dose , mg/kg 0 2 4 8
15 months Male 0/10 7/10 9/10 6/10 Female 0/10 9/10 9/10 7/10 Male 0/50 43/50 48/50 49/50
24 months Female 0/50 49/50 50/50 48/50 (0%) (98%) (100%) (100%)
Male 0/10 5/10 7/10 10/10
Female 0/10 4/10 9/10 10/10
(0%) (86%) (96%) (98%)
By gavage, 5 days a week (4).