National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/764686

Abstract for TR-589

ABSTRACT

Toxicology Studies of a Pentabromodiphenyl Ether Mixture [DE-71 (Technical Grade)] (CAS No. 32534-81-9) in F344/N Rats and B6C3F1/N Mice and Toxicology and Carcinogenesis Studies of a Pentabromodiphenyl Ether Mixture [DE-71 (Technical Grade)] in Wistar Han [Crl:WI(Han)] Rats and B6C3F1/N Mice (Gavage Studies)

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Abstract

DE-71, a pentabromodiphenyl ether mixture, was used in the past as an additive flame retardant, often in furniture materials. Additive flame retardants are mixed into products, but they are not covalently bound to the polymers in the commercial products, and thus can leach out into the environment. Though use and sale of polybrominated diphenyl ethers (PBDEs) was banned in the European Union and production was voluntarily phased out in the United States around 2004, they remain in the environment as products produced before use was discontinued or as discarded products. PBDEs can be found in water, wildlife, and in humans, as well as in various food products including meat, poultry, and fish. The California Office of Environmental Health Hazard Assessment nominated individual PBDE congeners for study because they were considered a health risk and have been found in human and animal tissue in the United States. Because of limited availability of the individual PBDE congeners, DE-71, the flame retardant used in furniture, was evaluated in rats and mice to characterize the toxic and carcinogenic potential of PBDEs. Male and female F344/N rats and B6C3F1/N mice were administered DE-71 in corn oil by gavage for 3 months. Wistar Han [Crl:WI(Han)] dams (referred to as Wistar Han rats) were administered DE-71 in corn oil by gavage from gestational day (GD) 6 through postnatal day (PND) 20. Their pups were administered the same doses in corn oil by gavage from PND 12 through 2 years. Male and female B6C3F1/N mice were administered DE-71 in corn oil by gavage for 2 years. Genetic toxicology studies of DE-71 as well as three individual PBDEs were conducted in Salmonella typhimurium and Escherichia coli, mouse bone marrow cells, and mouse peripheral blood erythrocytes.

3-MONTH STUDY IN F344/N RATS

Groups of 10 male and 10 female rats were administered 0, 0.01, 5, 50, 100, or 500 mg DE-71/kg body weight in corn oil by gavage 5 days per week for 14 weeks. Groups of 10 male and 10 female special study rats were administered the same doses for 25 days. All rats survived to the end of the study. Mean body weights of 500 mg/kg males and females and 100 mg/kg females were significantly less than those of the vehicle controls.

Dose-related decreases in serum thyroxine (T4) concentration occurred on days 4, 25, and 93 in males and females administered 5 mg/kg or greater. The decreases in T4 were accompanied by increases in serum thyroid stimulating hormone concentrations, which occurred most consistently in the 100 and 500 mg/kg groups at 14 weeks. Serum cholesterol concentrations demonstrated dose-related increases at all time points in males and females administered 50 mg/kg or greater; the 0.01 and 5 mg/kg groups demonstrated an increase in cholesterol concentration at one or more time points.

At week 14, a small decrease in the circulating red cell mass, evidenced by decreases in hematocrit values and hemoglobin concentrations, occurred in 100 and 500 mg/kg males and females.

Absolute and relative liver weights of males and females administered 5 mg/kg or greater were significantly increased. Absolute and relative kidney weights were significantly greater than those of the vehicle controls in the 50, 100, and 500 mg/kg male groups. In females, absolute kidney weights were significantly increased in the groups administered 5 mg/kg or greater. Relative kidney weights were significantly greater than those of the vehicle control in all dosed groups of females. The absolute thymus weight in 500 mg/kg males and absolute and relative thymus weights in females administered 50 mg/kg or greater were significantly decreased.

In the liver, uridine diphosphate glucuronosyl transferase (UDPGT) activities were significantly increased in male rats administered 0.01 mg/kg on day 25 and in male and female rats administered 5 mg/kg or greater on day 25 and at week 14. 7-Ethoxyresorufin-O-deethylase (EROD) activities on day 25 displayed generally dose-related increases and significant increases were observed in males and females administered 5 mg/kg or greater. By week 14, EROD activity in 500 mg/kg males was induced approximately 105-fold, while in 500 mg/kg females, it was induced approximately 209-fold. Significant but smaller increases were observed in 50 and 100 mg/kg males and females administered 5 mg/kg or greater. On day 25, acetanilide-4-hydroxylase (A4H) activities were significantly increased in male rats administered 50 mg/kg or greater and in female rats administered 5 mg/kg or greater. At week 14, significant dose-related increases were observed in both male and female rats administered 5 mg/kg or greater. 7-Pentoxyresorufin-O-dealkylase (PROD) activities were increased in male and female rats administered 5 mg/kg or greater on day 25 and at week 14.

In the liver, there were significantly increased incidences of hepatocyte hypertrophy in males and females administered 5 mg/kg or greater. The incidences of cytoplasmic vacuolization of the hepatocytes were significantly increased in 50 mg/kg males and 100 and 500 mg/kg males and females. There were significantly increased incidences of thyroid gland follicle hypertrophy in females administered 50 mg/kg or greater and in 500 mg/kg males. In the 500 mg/kg groups, there were significantly increased incidences of epididymis hypospermia and glandular stomach erosion in males and thymus atrophy in females.

Epididymis and cauda epididymis weights were significantly decreased in 500 mg/kg males. The 500 mg/kg group also exhibited significantly decreased sperm per cauda and sperm per gram of cauda. In general, dosed males exhibited fewer total spermatids per testis and sperm per gram of testis were significantly decreased in the 100 and 500 mg/kg groups. Sperm motility was significantly decreased in the 500 mg/kg group. All 500 mg/kg females failed to cycle and remained in persistent diestrus throughout the examination period. Based on these findings, DE-71 exhibits the potential to be a reproductive toxicant in both male and female rats.

In males and females administered 5 mg/kg or greater, the concentrations of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99), and 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE-153) in adipose and liver increased with increasing dose on day 25 and at week 14. The concentrations in adipose were higher than in liver suggesting preferential accumulation in the adipose. BDE-47 and BDE-99 concentrations in adipose were similar and were higher than the BDE-153 concentrations in both sexes; however, BDE-47, BDE-99, and BDE-153 concentrations were similar in the liver. Although there were no differences in BDE-153 concentrations on day 25 or at week 14 in the liver, BDE-47 and BDE-99 concentrations at week 14 were lower than on day 25, suggesting that BDE-47 and BDE-99 induce their own metabolism.

3-MONTH STUDY IN MICE

Groups of 10 male and 10 female mice were administered 0, 0.01, 5, 50, 100, or 500 mg DE-71/kg body weight in corn oil by gavage 5 days per week for 14 weeks. Survival of the 500 mg/kg groups was decreased. Mean body weights were significantly decreased in 100 and 500 mg/kg males and 500 mg/kg females.

For the surviving 500 mg/kg male and female mice, a small decrease in the circulating red cell mass, evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, was observed.

The absolute and relative liver weights of 50 mg/kg males and 100 and 500 mg/kg males and females were significantly greater than those of the vehicle controls. The absolute kidney weight of 500 mg/kg males was significantly less (26%) than that of the vehicle controls. The absolute heart weights of 500 mg/kg males and females were significantly less (15% and 17%, respectively) than those of the vehicle controls. The absolute testis weight of 500 mg/kg males was significantly less than that of the vehicle controls. Males administered 100 mg/kg displayed significantly decreased left cauda epididymis weight and sperm motility, indicating that DE-71 exhibits the potential to be a reproductive toxicant in male mice.

UDPGT activities in the liver were significantly increased in all dosed groups of females. EROD activities were significantly increased in females administered 5 mg/kg or greater. A4H activities were significantly increased in males administered 50 mg/kg or greater, and in females administered 5 mg/kg or greater. PROD activities were significantly increased in male and female mice administered 5 mg/kg or greater.

In the liver, there were significantly increased incidences of hepatocyte hypertrophy in males administered 50 mg/kg or greater and in 100 and 500 mg/kg females. There were also significantly increased incidences of hepatocyte necrosis in 500 mg/kg males and females and hepatocyte cytoplasmic vacuolization in 500 mg/kg males. In the adrenal cortex, there were significantly increased incidences of fatty degeneration and hypertrophy of the zona fasciculata in males administered 500 mg/kg. There was a significantly increased incidence of atrophy of the thymus in 500 mg/kg males. In the testis, the incidence of abnormal residual bodies was significantly increased in males administered 500 mg/kg.

In male mice, concentrations of BDE-47, BDE-99, and BDE-153 in adipose increased linearly with dose up to 100 mg/kg, above which the increase in concentrations was more than proportional to the dose, indicating saturation of metabolism at or above 500 mg/kg. In females, the concentrations of all congeners increased proportionally with the dose. In general, the concentrations of BDE-99 were higher than those of the other two congeners; the concentrations of BDE-47 and BDE-153 were similar (except in 500 mg/kg males) suggesting a higher rate of accumulation of BDE-153 regardless of the lower percentage of BDE-153 in DE-71.

2-YEAR STUDY IN WISTAR HAN RATS

Groups of 62 time-mated F0 female rats were administered 0 or 50 mg DE-71/kg body weight in corn oil by gavage and groups of 52 time-mated F0 female rats were administered 3 or 15 mg/kg daily from GD 6 until PND 20. F1 offspring were administered the same doses as their dams by gavage starting on PND 12 until 105 weeks after weaning. Weaning occurred on the day the last litter reached PND 21. At weaning, litters were randomly standardized to two male and two female offspring, and groups of 60 males and 60 females (0 and 50 mg/kg) or 50 males and 50 females (3 and 15 mg/kg) were assigned to the 2-year study and dosed 5 days per week for the remainder of the study. Ten vehicle control and 10 50 mg/kg rats of each sex were evaluated at 3 months to allow comparison to 3-month endpoints in F344/N rats.

Administration of DE-71 had no biologically relevant effect on survival or body weights of pups or dams and no effects on the percentage of mated females producing pups, litter size, pup sex distribution, or weights of dams or male or female pups.

In the 2-year study, survival of 50 mg/kg males was significantly less than that of the vehicle controls. Mean body weights of dosed males were similar to those of the vehicle controls throughout the study. In 50 mg/kg females, there were increased incidences of thinness and the mean body weights were at least 10% less than those of the vehicle controls after week 37.

At the 3-month interim evaluation, organ weights were measured in vehicle control and 50 mg/kg rats. The absolute and relative liver weights of 50 mg/kg males and females were significantly greater than those of the vehicle controls. The absolute and relative kidney and absolute testis weights of 50 mg/kg males were significantly increased. The absolute thymus weight of 50 mg/kg females was significantly decreased.

In the liver at the 3-month interim evaluation, the incidences of hepatocyte hypertrophy were significantly increased in 50 mg/kg males and females. The incidence of fatty change was significantly increased in 50 mg/kg males. In the 2-year study, the incidences of liver neoplasms occurred with positive trends in males and females. The incidences of hepatocellular adenoma or carcinoma (combined) and hepatocholangioma, hepatocellular adenoma, or hepatocellular carcinoma (combined) were significantly increased in males and females administered 50 mg/kg. The incidences of hepatocholangioma, hepatocellular adenoma, and hepatocellular carcinoma were significantly increased in 50 mg/kg females. Cholangiocarcinoma occurred in two 50 mg/kg females. There was a significantly increased incidence of nodular hyperplasia in 50 mg/kg females. There were significantly increased incidences of eosinophilic focus and fatty change in 15 and 50 mg/kg male and female rats. There were significantly increased incidences of hepatocyte hypertrophy in all dosed groups of male and female rats. In 50 mg/kg females, there was a significantly increased incidence of oval cell hyperplasia.

In the thyroid gland at the 3-month interim evaluation, there were significantly increased incidences of follicle hypertrophy in 50 mg/kg males and females. At 2 years, there were increased incidences of follicular cell adenoma in 50 mg/kg males. Follicular cell carcinoma occurred in two 3 mg/kg males and one 15 mg/kg male. The incidence of follicular cell hyperplasia was significantly increased in 50 mg/kg females. There were significantly increased incidences of follicle hypertrophy in all dosed groups of males and in 15 and 50 mg/kg females.

At 2 years, there was a significantly increased incidence of adenoma in the pars distalis of the pituitary gland in 50 mg/kg males.

Uteri from the 2-year groups were examined both in an original cross sectional evaluation and in an additional residual longitudinal section evaluation. There were significantly increased incidences of stromal polyp or stromal sarcoma combined in 3 and 15 mg/kg females when both evaluations were combined. The occurrence of two polyps (multiple) in the vagina of 50 mg/kg females supported the findings for the uterus. There were also significantly increased incidences of squamous metaplasia of the uterus in the 15 and 50 mg/kg groups and of squamous hyperplasia of the cervix in the 50 mg/kg group when both evaluations were combined.

In the kidney, there were significantly increased incidences of hydronephrosis in 15 mg/kg males and 50 mg/kg males and females at 2 years. In the 2year study, there were significantly increased incidences of atrophy and cytoplasmic vacuolization of the parotid salivary gland in 50 mg/kg male rats. In the 2year study, there were significantly increased incidences of chronic active inflammation of the prostate gland in the 15 and 50 mg/kg males and ectasia of the preputial gland duct in 50 mg/kg males. In the 2-year study, there were significantly increased incidences of thymic atrophy and epithelial hyperplasia of the forestomach in 50 mg/kg males and adrenal cortex focal hyperplasia in 50 mg/kg females.

In adipose, liver, and plasma, at the end of the study, the concentrations of BDE-47, BDE-99 and BDE-153 increased with increasing dose and were higher than the corresponding vehicle control values. The concentrations were lowest in plasma and highest in adipose. In a given matrix, the concentrations of BDE-47, BDE-99, and BDE-153 were similar, suggesting a higher rate of accumulation of BDE-153 regardless of the lower percent of BDE-153 in DE-71.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were administered 0, 3, 30, or 100 mg DE-71/kg body weight in corn oil by gavage, 5 days per week for up to 105 weeks. Survival of 100 mg/kg males and females was significantly less than that of the vehicle controls, leading to these groups being removed from the study at 18 months. Mean body weights of 100 mg/kg males and females were at least 10% less than those of the vehicle control groups after weeks 17 and 21, respectively. The mean body weights of 30 mg/kg males were at least 10% less than those of the vehicle controls after week 87. Clinical findings included increased occurrences of distended abdomen, which correlated with liver neoplasms.

The incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepatocellular adenoma or carcinoma (combined) were significantly increased in 30 and 100 mg/kg males and females (except carcinoma in 30 mg/kg females). There were also significantly increased incidences of hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) in 30 and 100 mg/kg males. The incidence of hepatocellular adenoma was significantly increased in 3 mg/kg males, and the incidences of hepatoblastoma were significantly increased in 30 and 100 mg/kg males.

There were significantly increased incidences of centrilobular hepatocyte hypertrophy in all dosed groups of male and female mice. There were significantly increased incidences of eosinophilic focus in 30 and 100 mg/kg female mice. In 30 mg/kg males, there was a significantly increased incidence of clear cell focus. There were significantly increased incidences of fatty change in 30 and 100 mg/kg females. There were significantly increased incidences of focal necrosis in 30 mg/kg males and Kupffer cell pigmentation in all dosed groups of males and females.

There were significantly increased incidences of follicle hypertrophy of the thyroid gland in all dosed groups of male mice and in 30 and 100 mg/kg female mice. In the forestomach, there were significantly increased incidences of epithelial hyperplasia in 30 and 100 mg/kg males and in 100 mg/kg females and inflammation in 30 and 100 mg/kg males. In 100 mg/kg males and females, there were significantly increased incidences of diffuse hypertrophy of the adrenal cortex. The incidence of germinal epithelium atrophy was significantly increased in the testes of 100 mg/kg males.

Concentrations of BDE-47, BDE-99, and BDE-153 were determined in the adipose and liver of male and female mice at the end of the 2-year study, except for 30 mg/kg males. In both males and females, the tissue concentrations of all three congeners in adipose and liver increased with increasing dose and were higher in adipose than in liver, suggesting preferential accumulation in adipose. Regardless of the lower percentage of BDE-153 in DE-71 compared to the other two congeners, concentrations of BDE-153 were relatively higher in both adipose and liver, suggesting a higher rate of accumulation of BDE-153.

GENETIC TOXICOLOGY

DE-71 was tested for mutagenic activity in bacteria in three independent studies in three laboratories using a S. typhimurium strains TA98, TA100, TA102, TA1535, and TA1537, and E. coli strain WP2 uvrA/pKM101 with and without rat or hamster liver metabolic activation enzymes (S9), and no evidence of mutagenicity was observed in any of the tests.

Three related test BDE-47, BDE-99, and BDE-153 were tested for mutagenic activity in S. typhimurium strains TA98, TA100, and TA102 with and without rat liver S9 mix, and no evidence of mutagenicity was observed with any of the three test articles in any of the tests that were conducted.

In vivo, no increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood samples from male or female B6C3F1/N mice following administration of DE-71 for 3 months by corn oil gavage. In addition, no increases in micronucleated immature or mature erythrocytes were seen in peripheral blood samples from male B6C3F1/N mice administered DE-71 by gavage once daily for 3 days and evaluated using flow cytometric methods. In these same mice, bone marrow smears were also scored for frequency of micronucleated polychromatic erythrocytes, and no increases were observed. In none of the micronucleus tests were significant alterations in the percentage of immature erythrocytes (polychromatic erythrocytes or reticulocytes) seen over the dose range tested, suggesting no chemical-associated toxicity to the bone marrow.

CONCLUSIONS

Under the conditions of these 2-year oral gavage studies, there was clear evidence of carcinogenic activity of DE-71 in male Wistar Han rats based on increased incidences of hepatocholangioma, hepatocellular adenoma, or hepatocellular carcinoma (combined). Increased incidences of thyroid gland follicular cell adenoma or carcinoma and increased incidences of pituitary gland (pars distalis) adenoma were also considered to be related to exposure. There was clear evidence of carcinogenic activity of DE-71 in female Wistar Han rats based on increased incidences of hepatocholangioma, hepatocellular adenoma, and hepatocellular carcinoma. The occurrence of cholangiocarcinoma of the liver was also considered related to treatment. The incidences of stromal polyp or stromal sarcoma (combined) of the uterus may have been related to treatment. There was clear evidence of carcinogenic activity of DE-71 in male B6C3F1/N mice based on increased incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma. There was clear evidence of carcinogenic activity of DE-71 in female B6C3F1/N mice based on increased incidences of hepatocellular adenoma and hepatocellular carcinoma.

Administration of DE-71 resulted in increased incidences of nonneoplastic lesions in the liver, thyroid gland, kidney, parotid salivary gland, prostate gland, preputial gland, thymus, and forestomach of male rats; liver, thyroid gland, uterus, cervix, kidney, and adrenal cortex of female rats; liver, thyroid gland, forestomach, adrenal cortex, and testes of male mice; and liver, thyroid gland, forestomach, and adrenal cortex of female mice.



Summary of the 2-Year Carcinogenesis and Genetic Toxicology Gavage and Perinatal and Postnatal Gavage Studies of DE-71
  Male
Wistar Han Rats
Female
Wistar Han Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Doses in corn oil by gavage 0, 3, 15, or 50 mg/kg 0, 3, 15, or 50 mg/kg 0, 3, 30, or 100 mg/kg 0, 3, 30, or 100 mg/kg
Survival rates 36/50, 35/50, 38/50, 25/50 37/50, 39/50, 33/50, 28/50 29/50, 33/50, 31/50, 0/50 33/50, 35/50, 37/50, 0/50
Body weights Dosed groups similar to the vehicle control group 50 mg/kg group at least 10% less than the vehicle control group after week 37 30 and 100 mg/kg group at least 10% less than the vehicle control group after weeks 87 and 17, respectively 100 mg/kg group at least 10% less than the vehicle control group after week 21
Nonneoplastic effects Liver: eosinophilic focus (3/49, 3/50, 12/50, 15/50); hepatocyte, hypertrophy (1/49, 44/50, 50/50, 50/50); fatty change (32/49, 37/50, 48/50, 48/50)
Thyroid gland: follicle, hypertrophy (1/45, 26/45, 34/48, 23/46)
Kidney: hydronephrosis (1/49, 5/46, 8/50, 10/50)
Parotid salivary gland: atrophy (2/46, 2/48, 4/50, 13/50); cytoplasmic vacuolization (4/46, 4/48, 7/50, 17/50)
Prostate gland: inflammation, chronic active (17/49, 20/50, 28/50, 27/50)
Preputial gland: duct, ectasia (2/49, 2/49, 5/50, 15/50)
Thymus: atrophy (14/45, 11/49, 15/49, 26/50)
Forestomach: epithelium hyperplasia (8/49, 6/50, 5/50, 17/50)
 
Liver: hyperplasia, nodular (0/50, 0/49, 2/50, 7/47); eosinophilic focus (5/50, 7/49, 21/50, 31/47); hepatocyte, hypertrophy (0/50, 48/49, 49/50, 45/47); fatty change (15/50, 12/49, 28/50, 39/47); oval cell, hyperplasia (1/50, 3/49, 3/50, 10/47)
Thyroid gland: follicle, hypertrophy (8/45, 17/49, 22/47, 35/42); follicular cell hyperplasia (1/45, 5/49, 4/47, 6/42)
Uterus: squamous metaplasia (original and residual evaluations, combined – 0/50, 2/50, 5/50, 6/49)
Cervix: squamous hyperplasia (original and residual evaluations, combined – 2/50, 3/50, 4/50, 8/49)
Kidney: hydronephrosis (1/50, 1/50, 1/49, 6/47)
Adrenal cortex: focal hyperplasia (8/50, 6/49, 12/50, 19/46)
 
Liver: centrilobular, hepatocyte, hypertrophy (0/50, 28/50, 46/50, 48/50); clear cell focus (10/50, 13/50, 20/50, 7/50); necrosis, focal (2/50, 2/50, 16/50, 2/50); Kupffer cell, pigmentation (5/50, 15/50, 33/50, 25/50)
Thyroid gland: follicle, hypertrophy (25/50, 35/49, 41/50, 45/49)
Forestomach: epithelium, hyperplasia (26/50, 19/50, 40/50, 29/50); inflammation (18/50, 18/50, 34/50, 19/50)
Adrenal cortex: hypertrophy, diffuse (1/50, 0/50, 3/49, 20/48)
Testes: germinal epithelium, atrophy (11/50, 8/50, 20/50, 13/49)
 
Liver: centrilobular, hepatocyte, hypertrophy (0/50, 7/49, 45/50, 47/49); eosinophilic focus (3/50, 2/49, 16/50, 15/49); fatty change (18/50, 18/49, 39/50, 20/49); Kupffer cell, pigmentation (3/50, 10/49, 24/50, 27/49)
Thyroid gland: follicle, hypertrophy (24/50, 31/49, 37/48, 42/47)
Forestomach: epithelium, hyperplasia (9/50, 5/50, 6/50, 16/49)
Adrenal cortex: hypertrophy, diffuse (0/50, 0/50, 4/49, 8/47)
 
Neoplastic effects Liver: hepatocellular adenoma or carcinoma (3/49, 2/50, 4/50, 9/50); hepatocholangioma, hepatocellular adenoma, or hepatocellular carcinoma (3/49, 2/50, 4/50, 11/50)
Thyroid gland: follicular cell adenoma (1/45, 3/45, 2/48, 6/46)
Pituitary gland: adenoma (19/49, 12/49, 22/50, 35/50)
Liver: cholangiocarcinoma (0/50, 0/49, 0/50, 2/47); hepatocholangioma (0/50, 0/49, 0/50, 8/47); hepatocellular adenoma (3/50, 2/49, 8/50, 16/47); hepatocellular carcinoma (0/50, 0/49, 1/50, 6/47); hepatocellular adenoma or carcinoma (3/50, 2/49, 8/50, 17/47); hepatocholangioma, hepatocellular adenoma, or hepatocellular carcinoma (3/50, 2/49, 8/50, 21/47) Liver: hepatocellular adenoma (23/50, 35/50, 49/50, 40/50); hepatocellular carcinoma (18/50, 15/50, 30/50, 45/50); hepatocellular adenoma or carcinoma (31/50, 40/50, 49/50, 47/50); hepatoblastoma (1/50, 1/50, 16/50, 5/50); hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (31/50, 40/50, 49/50, 47/50) Liver: hepatocellular adenoma (5/50, 7/49, 32/50, 46/49); hepatocellular carcinoma (4/50, 2/49, 6/50, 27/49); hepatocellular adenoma or carcinoma (8/50, 8/49, 33/50, 47/49)
Equivocal findings   Uterus: stromal polyp or stromal sarcoma (original and residual evaluations, combined – 4/50, 12/50, 12/50, 9/49)    
Level of evidence of carcinogenic activity Clear evidence Clear evidence Clear evidence Clear evidence
Genetic toxicology
Bacterial gene mutations:
DE-71:

BDE-47:
BDE-99:
BDE-153:

Negative in S. typhimurium strains TA98, TA100, TA102, TA1535, and TA1537 and E. coli with or without S9
Negative in S. typhimurium strains TA98, TA100, and TA102
Negative in S. typhimurium strains TA98, TA100, and TA102
Negative in S. typhimurium strains TA98, TA100, and TA102
Micronucleated erythrocytes
Mouse 3-month study peripheral blood in vivo:
Mouse 3-day study peripheral blood and bone marrow in vivo:

Negative in males and females
Negative in males

Date: February 2016 

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies 

Target Organs & Incidences from 2-year Studies

 

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