SUPPLEMENTAL FILE 4:

REPORT OF THE CANCER ASSESSMENT REVIEW COMMITTEE 

(CARC) 

Supplemental File 4: Report of the Cancer Assessment Review Committee (CARC)
1

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DATE: September 17, 2014

SUBJECT: Tetrabromobisphenol-A: Report of the Cancer Assessment Review Committee

PC Code: 999999 DP Barcode: N/A

Decision No.: N/A Registration No.: N/A

Petition No.: N/A Regulatory Action: N/A

Risk Assessment Type: Cancer Assessment Case No.: N/A

TXR No.: 0057055 CAS No.: 79-94-7

MRID No.: N/A 40 CFR: N/A

FROM: Jess Rowland, Co-Chair

Karlyn Middleton, Co-Chair

Cancer Assessment Review Committee

Health Effects Division (7509P)

TO: Dr. David Lai 

Office of Pollution Prevention and Toxics

Risk Assessment Division (7403M)

The Cancer Assessment Review Committee (CARC) met on August 20, 2014 to evaluate the 

cancer classification of tetrabromobisphenol-A in accordance with the EPA’s Final Guidelines for 

Carcinogen Risk Assessment (March, 2005). Attached please find the final Cancer Assessment 

Document. 
2

CANCER ASSESSMENT DOCUMENT

EVALUATION OF THE CARCINOGENIC POTENTIAL OF 

Tetrabromobisphenol A (TBBPA) 

For the Office of Pollution Prevention and Toxics 

CANCER ASSESSMENT REVIEW COMMITTEE 

HEALTH EFFECTS DIVISION 

OFFICE OF PESTICIDE PROGRAMS 

September 17, 2014 
3

EXECUTIVE SUMMARY 

On August 20, 2014, the Cancer Assessment Review Committee (CARC) of the Health Effects 

Division (HED) of the Office of Pesticide Programs (OPP) evaluated the carcinogenic potential of 

Tetrabromobisphenol A (TBBPA). Dr. David Lai of the Office of Pollution Prevention and Toxics 

(OPPT), Risk Assessment Division, presented the results of a cancer bioassay with TBBPA 

conducted in Wistar Han rats and B6C3F1/N mice by the National Toxicology Program. 

Toxicology, metabolism, and mutagenicity studies for TBBPA were also discussed, as well as 

structure-activity relationships. 

Groups of 50-60 male and 50-60 female Wistar Han rats and male and female B6C3F1/N mice 

were administered 0, 250, 500, or 1,000 mg/kg-bw/day of TBBPA in corn oil by gavage, 5 days 

per week, for up to 105 weeks. Survival of the treated groups was similar to that of the vehicle 

control group. In rats, the mean body weights of males at 500 and 1000 mg/kg/day were 

generally at least 10% less than the vehicle control group after study week 25; body weights of 

females at all dose levels were similar to those of the vehicle control throughout the study. There 

were no treatment-related clinical signs of toxicity at any dose level in either sex. In mice, 

survival at the high dose (1,000 mg/kg/day) in both sexes was significantly (p<0.001) lower than 

that of the vehicle control groups. Increased mortality was seen as early as 6 months into the 

study and coincided with the initial difference of body weight gain in female mice at 1000 

mg/kg/day. Histopathology findings suggests that decreased survival may have been due in part 

to gastrointestinal toxicity, although the various gastrointestinal lesions observed in the high dose 

groups did not always demonstrate an increase in severity over those in the other treatment 

groups. After study week 25, the mean body weights of females at 1000 mg/kg/day were 

decreased (10% to 25%) when compared to the vehicle controls. Body weights of all dosed 

groups of males and of females in the 250 and 500 mg/kg groups were generally similar to those 

of the vehicle control groups throughout the study. No clinical findings related to chemical 

exposure were observed. 

Tumors of the testes and uterus were seen in males and female rats, respectively. In males, the 

incidences of interstitial cell adenoma of the testis were slightly increased at 500 mg/kg/day (2%) 

and 1000 mg/kg/day (6%) compared to vehicle controls (0%). The CARC did not consider the 

testicular tumors to be treatment-related since no pair-wise statistical significance (high dose) 

or dose trend were observed and the total incidences (4/200) in this study were comparable to the 

historical control incidences in two-year studies (4/150). In addition, there were no supportive 

precursor lesions in the testes. In female rats, the incidence of uterine epithelial tumors (combined 

adenoma, adenocarcinoma, or malignant mixed Müllerian tumor) were significantly increased at 

250 mg/kg/day (12%), 500 mg/kg/day (32%), and 1000 mg/kg/day (38%) when compared to the 

vehicle control group (12%). The CARC determined that the uterine tumors were 

treatment-related since there was a clear dose response and a dose trend (p<0.01) observed, and 

the tumors were corroborated by the occurrence of precursor lesions (endometrial hyperplasia) at 

relevant dose levels. 

Tumors of the liver and large intestine as well as hemangiomas/hemangiosarcomas of all organs 

were seen in male mice. Although the liver adenomas in male mice at the high dose showed 

statistical significance, the CARC determined that the tumors of the liver and large intestines 

were not treatment-related since the incidences were within the historical control range and there 
4

were no supportive precursor lesions. The CARC also determined that the hepatoblastomas 

were not treatment-related due to lack of statistical significance (pairwise at high dose) or dose 

trend for hepatoblastomas alone or combined with carcinomas. 

The CARC also determined that the adenomas and carcinomas observed in the large 

intestine (cecum or colon) of male mice were not treatment-related since there was no 

statistical significance on pairwise (high dose) or dose trend. Additionally, there were no 

supportive precursor lesions in the stomach. 

The incidence of hemangioma or hemangiosarcoma was increased at 250 mg/kg/day (10%) and 

500 mg/kg/day (18%) when compared to vehicle controls (6%). These lesions occurred in a 

variety of organs, such as the bone marrow, liver, lung serosa, lymph nodes, skin, spleen, and 

vertebra. The CARC determined that the hemangiomas/hemangiosarcomas observed in male 

mice were treatment-related due to the presence of a dose trend and high dose incidence at the 

upper limit of the historical control range. 

There was no evidence of carcinogenicity in female mice. Mode of action data that meets the 

2006 International Programme on Chemical Safety (IPCS) Human Relevance Framework were not 

available for evaluation. There is no concern for mutagenicity.

In accordance with the Agency’s 2005 Guideline of Carcinogen Risk Assessment, 

Tetrabromobisphenol A is classified as “Likely to be Carcinogenic to Humans” based on the 

presence of uterine epithelial tumors (combined adenoma, adenocarcinoma, or malignant mixed 

Mülllerian) in female Wistar Hans rats and hemangiomas/hemangiosarcomas in male B6C3F1 

mice. There was no evidence of carcinogenicity in female mice. There were no mutagenicity 

concerns. 

In accordance with the Agency’s 2005 Guideline of Carcinogen Risk Assessment, a low dose 

linear extrapolation model (Q1*) is appropriate for quantification of human risk. 
5

I. INTRODUCTION 

On August 27, 2014, the Cancer Assessment Review Committee (CARC) of the Health Effects 

Division (HED) of the Office of Pesticide Programs (OPP) evaluated the carcinogenic potential of 

Tetrabomobisphenol A (TBBPA). Dr. David Lai, Risk Assessment Division, Office of Pollution 

Prevention and Toxics (OPPT) presented the data on TBBPA. 

II. BACKGROUND INFORMATION 

Tetrabromobisphenol A (TBBPA) is a crystalline powder with a M.W. of 543.9 g/mole. It has 

low water solubility (0.063 mg/l at 21oC; 0.24 mg/l at 25oC), low vapor pressure (4.72 x 10-9 at 

25oC), and a moderately high log P value (5.9). About 4% of the particles are <15 μm in 

diameter (EURAR, 2006). 

B r Br

H 3 C

H O O H

H 3 C

B r Br

III. EVALUATION OF CARCINOGENICITY STUDIES 

Reference: NTP (2013). NTP Technical Report. Toxicological studies of tetrabromobisphenol A 

(CAS NO.79-94-7) in F344/NTAC rats and B6C3F1/N mice and toxicology and carcinogenesis 

study of tetrabromobisphenol A in WISTAR HAN [Crl:WI(Han)] rats and B6C3F1/N mice 

(Gavage studies), NTP TR 587. National Toxicology Program, Research Triangle Park, NC. 

1. Carcinogenicity Study in Wistar Han Rats 

Groups of 50-60 male and 50-60 female Wistar Han rats were administered 0, 250, 500, or 1,000 

mg/kg-bw/day TBBPA in corn oil by gavage, 5 days per week for up to 105 weeks. Survival of 

the treated groups was similar to that of the vehicle control group. The mean body weights of 

male rats at 500 and 1000 mg/kg/day group were generally at least 10% less than the vehicle 

control group after study week 25; body weights of female rats at all dose levels were similar to 

those of the vehicle control throughout the study. There were no treatment-related clinical signs 

of toxicity at any dose level in either sex. 

A. Tumor Data 

Tumors of the testes and uterus were seen in males and female rats, respectively (Tables 1 and 2). 

In male rats, the incidences of interstitial cell adenoma of the testis were slightly increased at 500 

(1/50) and 1,000 mg/kg/day (3/50) groups as compared to controls (0/50) (Table 1). In female rats, 

the incidences of adenocarcinoma and of adenoma, adenocarcinoma, or malignant mixed 

Müllerian tumor (combined), were significantly increased at 500 and 1,000 mg/kg/day groups 

(Table 2). 
6

Table 1. Testicular Tumors in Male Wistar Han Rats Following Gavage Dosing of TBBPA 

Interstitial Cell, 

Adenomas 

Vehicle 

Control 

250 

mg/kg/day 

500 

mg/kg/day 

1000 

mg/kg/day 

Overall rate 0/50 (0%) 0/50 (0%) 1/50 (2%) 3/50 (6%) 

Adjusted ratea 0.0% 0.0% 2.2% 6.8% 

Terminal rateb 0/33 (0%) 0/28 (0%) 1/38 (3%) 3/39 (8%) 

First incidence (days) —c — 727 (T) 727 (T) 

Poly-3 test P=0.023 — P=0.526 P=0.138 

Data obtained from NTP Report TR 587 

a Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

b. Observed incidence at termination 

c. No neoplasm in animal group 

Historical control incidences: 4/150 (2.7%±2.3%; range 0% to 4%) 

Table 2. Uterine Tumors in Female Wistar Han Rats Following Gavage Dosing of TBBPA 

Interstitial Cell, Adenomas, 

Adenocarcinomas, or 

Malignant Mixed Mullerian 

tumors 

Vehicle 

Control 

250 

mg/kg/day 

500 

mg/kg/day 

1000 

mg/kg/day 

Overall rate 6/50 (12%) 11/50 (22%) 16/50 (32%) 19/50 (38%) 

Adjusted ratea 13.9% 24.2% 38.8% 42.2% 

Terminal rateb 3/34 9%) 5/34 (15%) 10/29 (35%) 11/33(33%) 

First incidence (days) 668 548 321 442 

Poly-3 test P=0.001 P= 0.168 P=0.007 P=0.002 

Data obtained from NTP Report TR 587 

a Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

b. Observed incidence at termination 

B. Non-Neoplastic Lesions 

No treatment-related non-neoplastic lesions were seen in the testes at any dose level. In females, 

endometrial atypical hyperplasia was seen in all dose groups (Table 3). 

Table 3. Non-neoplastic Lesion of the Uterus in Female Wistar Han Rats 

Lesion Vehicle 

Control 

250 

mg/kg/day 

500 

mg/kg/day 

1000 

mg/kg/day 

Endometrium, Hyperplasia, Atypical 2 13* 11* 13**P<0.01

C. NTP Conclusion. 

The National Toxicology Program (NTP) concluded that under the conditions of the 2-year 

gavage studies, there was equivocal evidence of carcinogenic activity of tetrabromobisphenol A 

in male Wistar Han rats based on the occurrence of testicular adenoma. There was clear evidence 

of carcinogenic activity of tetrabromobisphenol A in female Wistar Han rats based on increased 

incidences of uterine epithelial tumors (predominantly uterine adenocarcinoma). 

2. Carcinogenicity Study in B6C3F1.N Mice 

Groups of 50-60 male and 50-60 female B6C3F1 mice were administered 0, 250, 500, or 1,000 
7

mg/kg-bw/day TBBPA in corn oil by gavage, 5 days per week for up to 105 weeks. Survival at 

the high dose (1,000 mg/kg/day) in both sexes was significantly (p<0.001) lower than that of the 

vehicle control groups. Increased mortality was seen as early as 6 months into the study and 

coincided with the initial difference of body weight gain in female mice at 1000 mg/kg/day. 

Histopathology findings suggests that decreased survival may have been due in part to 

gastrointestinal toxicity, although the severities of the various gastrointestinal lesions in the high 

dose groups were not always increased over those in the other dosed groups. After study week 

25, the mean body weights of females at 1000 mg/kg/day were decreased (10% to 25%) when 

compared to the vehicle controls. Body weights of all dosed groups of males and of 250 and 

500 mg/kg females were generally similar to those of the vehicle control groups throughout the 

study. No clinical findings related to chemical exposure were observed. 

A. Tumor Data 

In the male mice, the incidence of multiple hepatocellular adenoma was significantly (p<0.05) 

increased in males at 500 mg/kg/day. In addition, the incidences of hepatoblastomas were 

significantly increased in males at 250 mg/kg/day and 500 mg/kg/day when compared to vehicle 

controls (2/50) (Table 4). 

Table 4. Liver Tumors in Male B6C3F1/N Mice Following Gavage Dosing of TBBPA 

Vehicle 

Control 

250 

mg/kg/day 

500 

mg/kg/day 

Hepatocellular adenoma, multiple 12 (24%) 20 (40%) 28* (56%) 

(p<0.05) 

Hepatocellular carcinoma, multiple 2 4 5 

Hepatoblastomas 

Overall rate 2/50 (4%) 11/50 (22%) 8/50 (16%) 

Adjusted ratea 4.6% 25.6% 17.6% 

Terminal rateb 1/33 (3%) 7/25 (28%) 7/39 (18%) 

First incidence (days) 619 535 727 

Poly-3 test p=0.065 p=0.006 p=0.052 

Data obtained from NTP Report TR 587 

a Number of animals with neoplasm per number with live examined microscopically 

b. Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

c. No neoplasm in animal group 

Historical control incidences for adenomas: 145/250 (58% ± 5.1%; range 52% to 64% 

Historical control incidences for hepatoblastomas: 9/250 (3.6%±2.6%; range 0% to 6% 

As shown in Table 5, the incidences of adenoma or carcinoma (combined) of the large intestine 

(cecum or colon) were seen in male mice. As shown in Table 6, hemangioma or hemangiosarcomas (all organs) occurred with significant positive trends in male mice. These lesions 

occurred in a variety of organs such as the bone marrow, liver, lung serosa, lymph nodes, skin, 

spleen, and vertebra. No evidence of carcinogenicity was found in female mice. 

   
8

Table 5. Large Intestine Tumors in Male B6C3F1/N Mice Following Gavage Dosing of TBBPA 

Cecum or Colon: Adenoma or 

Carcinoma 

Vehicle 

Control 

250 

mg/kg/day 

500 

mg/kg/day 

Overall rate 0/50 (0%) 0/50 (0%) 3/50 (6%) 

Adjusted ratea 0.0% 0.0% 6.5% 

Terminal rateb 0/33 (3%) 0/25 (28%) 3/39 (5%) 

First incidence (days)c - - 513 

Poly-3 test p=0.039 - p=0.131 

Data obtained from NTP Report TR 587 

a Number of animals with neoplasm per number with live examined microscopically 

b. Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

c. No neoplasm in animal group 

Historical control incidences: 0/250 

Table 6. Hemangioma/Hemangiosarcomas (All Organs) in Male B6C3F1/N Mice Following Gavage 

Dosing of TBBPA 

All organs: Hemangioma or 

Hemangiosarcoma 

Vehicle 

Control 

250 

mg/kg/day 

500 

mg/kg/day 

Overall rate 3/50 (6%) 5/50 (10%) 9/50 (18%) 

Adjusted ratea 6.9% 11.9% 19.8% 

Terminal rateb 2/33 (6%) 3/25 (12%) 9/39 (23%) 

First incidence (days) 645 602 730 (terminal) 

Poly-3 test p=0.047 p=0.338 p=0.069 

Data obtained from NTP Report TR 587 

a Number of animals with neoplasm per number with live examined microscopically 

b. Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality 

Historical control incidences: 32/250 (12.8%±5.4%; range 6% to 18%) 

B. Non-Neoplastic Lesions 

No treatment-related neoplastic lesions were see in the liver or the intestine at any dose level. 

C. NTP Conclusion 

NTP concluded that under the conditions of the bioassay, there was some evidence of 

carcinogenic activity of tetrabromobisphenol A in male B6C3F1/N mice based on increased 

incidences of hepatoblastoma. The increased incidences of large intestine neoplasms and 

hemangiosarcoma (all organs) may have been related to chemical administration. There was no 

evidence of carcinogenic activity of TBBPA in female B6C3F1/N mice. 

III. TOXICOLOGY

a. Mutagenicity 

TBBPA was tested for bacterial mutagenicity in two independent assays and results were negative 
9

in both assays. In the first assay, tetrabromobisphenol A (100 to 10,000 μg/plate) showed no 

evidence of mutagenicity in S. typhimurium strains TA98, TA100, TA1535, or TA1537, with or 

without exogenous metabolic activation from induced hamster or rat liver S9. In the second assay, 

conducted with the same lot of tetrabromobisphenol A that was used in the 2-year studies, no 

mutagenic activity was detected in S. typhimurium strains TA98 or TA100 or in E. coli strain WP2 

uvrA; all tests were conducted with and without rat liver S9, and the highest concentration tested 

was 6,000 μg/plate. In vivo, no increases in micronucleated NCEs were observed in male or 

female B6C3F1/N mice following 3 months of administration of tetrabromobisphenol A by gavage 

over a dose range of 10 to 1,000 mg/kg (NTP 2103). 

b. Structure-Activity Relationship 

Based on the chemical structure, there is no structural alert of genotoxicity potential; this is 

supported by the available, predominantly negative genotoxicity data. With respect to 

carcinogenicity potential, there are very few suitable structural analogs available for SAR 

consideration. Bisphenol A (BPA) and 3,3’,4,4’,5,5’-hexabromobiphenyl (PBB 169) are two of 

the most frequently cited analogs for TBBPA. In a 1982 NTP cancer bioassay of BPA, there was 

“no convincing evidence” that BPA was carcinogenic for F344 rats or B6C3F1 mice of either sex. 

BPA has been suspected to contribute to increase in breast and prostate cancer in exposed humans 

because of its endocrine disruptor activity but convincing evidence remains to be developed. The 

ring substitution of four bromine atom the rings to BPA is expected to significantly affect the 

physicochemical properties, toxicokinetics and adverse health effects. A recent detailed review of 

TBBPA concluded that it should not be considered as an “endocrine disruptor” (Colnot et al., 

2014). The analogy between TBBPA and PBB 169 is not valid. The substitution of bromine at the 

4,4’-position is expected to abolish the biopersistence of PBB. TBBPA also cannot bind to AhR 

receptor because it is nonplanar. 

c. Toxicity 

Acute oral, dermal, and inhalation studies have been performed on TBBPA. These studies show 

that TBBPA has low acute toxicity by all routes of exposure (oral LD50 > 5,000 mg/kg-bw in rats; 

dermal LD50 > 10,000 mg/kg-bw in rabbits, and inhalation LC50 > 10,000 mg/m3

 in rats and mice) 

(EURAR, 2006; Canada 2012; ECHA 2014). Available data show that TBBPA is not a skin, eye 

or respiratory irritant, and not a skin or respiratory sensitizer in animals or humans (EURAR, 

2006, Canada, 2012). 

The chronic/subchronic toxicity of TBBPA was investigated in a number of repeated-dose 

studies and has been reviewed in the European Union Risk Assessment Report (EURAR, 2006). 

Overall, the repeated-dose toxicity studies show that TBBPA has a low hazard concern. 

In a 14-day inhalation study in rats, the EU concluded that no adverse effects were reported up to 

the limit dose of 18 mg/L, with the exception of signs of mechanical irritation in all treatment 

groups due to the high dust levels. In a 21-day dermal study, TBBPA was administered to rabbits 

at dose levels up to 2,500 mg/kg/day for 6 hours/day, 5 days/week. No toxicologically significant 

effects were identified. In a 90-day oral gavage study, rats were administered TBBPA at dose 

levels of 0, 100, 300, or 1,000 mg/kg/day. No neurobehavioral effects were observed during the 

weekly functional observational battery evaluations. Slight changes in hematological evaluations 

and clinical chemistry were reported; however, the EU concluded that these effects were not 
10

toxicologically significant. Statistically significant decreases in serum T4 were reported in males 

and females, but no accompanying change in serum T3, thyroid stimulating hormone (TSH), or 

histopathology of the liver, thyroid, parathyroid, and pituitary was reported. The EU concluded 

that the decreases in serum T4 were not considered to be adverse. Absolute spleen weight was 

decreased in males in the top two dose groups; no histopathological findings were noted. An 

increase in relative epididymis weight was reported in the middle dose group; however, no 

changes in relative epididymis weight or histopathology were identified in the high dose group. 

The EU concluded that these findings were of no toxicological significance. 

In a study of newborn rats dosed from day 4 to day 21 after birth by gavage, an effect on the 

kidneys (polycystic lesions associated with the dilation of tubules) was noted at 200 or 600 mg/kg‐

bw/day but not at 40 mg/kg/day (NOAEL). No similar effect was found in 5-week old rats dosed 

at 2,000 or 6,000 mg/kg‐bw/day for 18 days (Fukuda et al., 2004). The EU (EURAR) suggested 

that the kidney effects observed in the newborn rats are likely due to the immature metabolic 

capability and/or immature kidneys of such young animals. 

In a recent subchronic toxicity study, groups of 10 male and 10 female F344/NTac rats and 

B6C3F1 mice were administered 0, 10, 50, 100, 500, or 1,000 mg/kg-bw/day TBBPA in corn oil 

by gavage, 5 days per week for up to 14 weeks (NTP, 2013). In the rats, dose-related decreases in 

serum T4 levels occurred on day 4 and at week 14 in 500 and 1,000 mg/kg- bw/day males and 

females. Significant increases occurred in liver weights of 500 and 1,000 mg/kg-bw/day rats and 

significant decreases occurred in spleen weights of 500 and 1,000 mg/kg-bw/day males. In the 

mice, liver weights of 500 mg/kg males and 1,000 mg/kg males and females were significantly 

greater than those of the vehicle controls. 

No effects on reproduction, fertility, or developmental toxicity including neurobehavioural 

abnormalities (e.g., motor activity, learning and memory) were observed in an OECD-compliant 

two-generation study in Sprague Dawley rats at doses of 0., 10, 100 or 1,000 mg/kg-bw/day. The 

NOAEL for these effects was determined to be 1,000 mg/kg. In this study, there was a significant 

decrease in serum T4 levels in F0 and F1 offspring at doses of 100 and 1,000 mg/kg-bw/day. 

Mean serum T3 levels were also significantly lower in F0 males at the highest dose (1,000 mg/kgbw/day), but no changes were found in the F0 females or in the male or female F1 offspring. 

There were also no effects on the TSH levels or microscopic changes in the list or pituitary gland. 

Furthermore, there is no dose-response relationship and following the 30-day recovery period, 

serum T4 levels returned to control levels. The EU concluded that the thyroxine effects were not 

toxicologically significant (EURAR, 2006). 

TBBPA did not alter brain development and there were no significant dose-related effects on T4, 

T3 or TSH at postnatal day (PND) 20 or postnatal week 11 after pregnant Sprague Dawley rats 

were fed TBBPA at dietary levels of 0, 100, 1,000, or 10,000 ppm from gestation day (GD) 10 to 

PND 20. In a pilot range-finding study (Velsicol Chemical Corporation, 1978c) and two standard 

developmental toxicity studies, no developmental effects were observed at doses up to 10,000 

mg/kg-bw/day (Saegusa et al., 2009). 

Van der Ven et al (2008) reported the results of a one-generation reproduction study in Wistar

rats. In this study, dietary exposure was for 70 days (male) and 14 days (female) prior to mating, 

during mating and throughout gestation and lactation at 0, 3, 10, 30, 100, 300, 1,000, or 3,000 
11

mg/kg-bw/day. There were no effects of all reproduction parameters examined including sperm 

count or morphology. The main adverse effects were decreased plasma T4 levels (both sexes), 

increased T3 levels (females), and increased weight of testis and pituitary gland in the males of 

the F1 generation. However, there were no clear dose response relationships of these endpoints 

and some of the changes reported are not statistically significantly different from the controls; no 

histopathological changes were observed in any of the assessed organs including the testes, 

pituitary gland and thyroid gland to explain the increased organ weights or hormones changes. 

Concerns have been expressed regarding the use of modeling software, methodology and conduct 

of this study (Banasik et al., 2009). These effects were not considered critical endpoints by the 

Health and Environment Canada (Canada, 2012). 

Neurobehavioral effects in offspring from the above one-generation reproduction study were also 

investigated. Auditory response with brainstem auditory evoked potential (BAEP), an 

electrophysiological response elicited by auditory stimuli and recorded from the scalp or brain 

surface as waveform with a series of positive and negative peaks, was examined. The authors 

reported that BAEP thresholds and wave IV latency were increased in exposed female offspring in 

the low frequency range. In the males, absolute latency of wave IV and interpeak latencies II-IV 

were also reported at low frequencies (Lilienthal et al., 2008). However, as pointed out by Strain et 

al., (2009), there was no consistent pattern of the BAEP alterations reported and a number of 

methodological confounding factors (e.g., animal age, body temperature) have been identified. In 

addition, there are a number of other limitations/deficiencies in the study of Lilienthal et al., (2008) 

which are not in compliance with the OPPTS Test Guidelines on Neurophysiology: Sensory 

Evoked Potential (OPPTS 870.6855, August 1998). According to the EPA test guidelines, a 

pigmented strain of rat is the preferred animal species to be tested since albino strains of animals 

have abnormalities of the visual and auditory systems. Furthermore, at least 10 nulliparous and 

nonpregnant rats per group should be used, and positive control groups exhibiting functional 

changes in the sensory systems to be tested are required. Instead, the study of Lilienthal et al., 

(2008) used groups of 5-6 pregnant Wistar rats which are albino rats, and did not include positive 

controls. 

No differences in performance were observed in a study assessing developmental neurotoxicity 

of TBBPA in NMRI mice administered 0.75 and 11.5 mg/kg orally on day PND 10 (Eriksson et 

al., 1998, 2001). As different from pentabromo-diphenyl ethers (PBDE), TBBPA did not affect 

neonatal development of the brain and neural behavior, learning and memory of adult mice 

(Viberg et al., 2002, 2004). Changes in several proteins involved in maturation of the brain, 

neuronal growth and synaptogenesis in the neonatal brains were observed in mice exposed to 

PBDE but not in those exposed to TBBPA (Viberg and Eriksson, 2011). The results of these 

studies appear to be consistent with the findings in a recent cross-sectional study on 515 

adolescents in Belgium, which showed that PBDE exposure, but not TBBPA, was associated 

with changes in the neurobehavioral function in humans (Kiciriski et al., 2012). 

No reproductive effects were reported in a study feeding a diet containing 0%, 01%, 0.1%, or 1% 

TBBPA to pregnant ICR mice from the first day of gestation to weaning at postnatal day 27. 

Based on enlargement of hepatocytes and very slight focal necrosis of hepatocytes in female 

offspring, a LOAEL of 140 mg/kg-bw/day was determined (Tada et al., 2006). 
12

IV. COMMITTEES ASSESSMENT OF WEIGHT-OF-EVIDENCE 

a. Testicular tumors: The CARC did not consider the testicular tumors to be treatment-related 

since there was no dose trend nor pair-wise statistical significance compared to high dose 

group, and the total all-group incidence (4/200) in the study was within the historical 

control range (0-4%). In addition, there were no supportive precursor lesions in the testes. 

b. Uterine tumors: The CARC determined that the uterine epithelial tumors (combined 

adenoma, adenocarcinoma, malignant mixed Müllerian) observed in female rats at the high 

dose were treatment-related based on the increased incidences at all dose levels (12% at 

250 mg/kg/day, 32% at 500 mg/kg/day and 38% at 1000 mg/kg/day) when compared to 

controls (12%), a statistically significant dose trend (p<0.01), and the presence of 

supportive precursor lesions. 

c. Liver tumors: Although the liver adenomas in male mice at the high dose showed statistical 

significance, the CARC determined that they were not treatment-related since the 

incidences were within the historical control range and there were no supportive precursor 

lesions. The CARC determined that the hepatoblastomas were not treatment-related due to 

lack of statistical significance (pairwise at high dose) or dose trend for hepatoblastomas 

alone or combined with carcinomas. 

d. Large Intestine tumors: The CARC determined that the adenoma or carcinoma observed in 

the large intestine (cecum or colon) of male mice were not treatment-related given lack of 

statistical significance on pairwise (high dose) or dose trend and no supportive precursor 

lesions in the intestines. 

e. Hemangioma/hemangiosarcomas (all organs): These lesions occurred in a variety of organs 

such as the bone marrow, liver, lung serosa, lymph nodes, skin, spleen and vertebra. The 

incidence was increased at 250 mg/kg/day (10%) and 500 mg/kg/day (18%) when 

compared to vehicle controls (6%). The CARC determined that the hemangiomas/ 

hemangiosarcomas observed in male mice were treatment-related due to the presence of a 

dose trend and mortality-adjusted incidence in the high dose group at the upper limit of the 

historical control range (18%). 

There was no evidence of carcinogenicity in female mice. Mode of action data that meets the 2006 

IPCS Human Relevance Framework were not available for evaluation. There is no concern for 

mutagenicity. 

V. CLASSIFICTION OF CARCINOGENIC POTENIAL 

In accordance with the Agency’s 2005 Guideline of Carcinogen Risk Assessment, 

Tetrabromobisphenol A is classified as “Likely to be Carcinogenic to Humans” based on the 

presence of uterine tumors (adenoma, adenocarcinoma, malignant mixed mullerian) in female 

Wistar Hans rats and hemangiomas/hemangiosarcomas in male B6C3F1/N mice. There was no 

evidence of carcinogenicity in female mice. There were no mutagenicity concerns. 
13

VI. QUANTIFICATION 

In accordance with the Agency’s 2005 Guideline of Carcinogen Risk Assessment, a low dose 

linear extrapolation model (Q1*) will be used for quantification of human risk. 

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