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Description of key information

Three studies are available for the repeated dose oral toxicity endpoint:
Repeated dose toxicity: oral.001 (28 day) - NOAEL (rat) = 1000 ppm in diet
Repeated dose toxicity: oral.002 (90 day) - NOAEL (rat) = 1000 mg/kg bw/day
Repeated dose toxicity: oral.003 (90 day) - NOAEL (rat) >100 mg/kg
One study is available for the repeated dose dermal toxicity endpoint:
Repeated dose toxicity: dermal.001 (21 day) - NOAEL (rabbit): 2500 mg/kg bw/day
3-month oral toxicity studies in mice and in rats were added to the updated dossier (215). These studies are preliminary to the 2-year carcinogenicity studies performed by NTP (NTO TR 587) and were considered supportive data.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
2 500 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Additional information

The 2002 rat 90 d study is the key repeated dose study for human health assessment. The test article was a composite of 3 commercial TBBPA products. The study was performed according to Good Laboratory Practices and according to US EPA OPPTS and OECD guidelinein CD® [Crl: CD® (SD) IGS BR] rats.  It consisted of three treatment groups and one vehicle (corn oil) control group (ten rats/sex/group). Recovery animals (five rats/sex) wereincluded in the control and high-dose group and evaluated over a 6-week post-treatment period. TBBPA was administered orally by gavage daily for 13 weeks at dose levels of 0, 100,300, and 1000 mg/kg/day at a constant volume of 5 mL/kg/day. The control animals received the vehicle at the same volume and dosing regimen as the treated groups. Animals were observed daily cage side for survivability, injury, and availability of feed and water. Other observations conducted weekly during the study included detailed physical and neurobehavioral evaluations, and measurements of body weights and food consumption. A Functional Observational Battery (FOB) was conducted pretest and at Week 12. Motor activity (MA) was also evaluated during Week 12. Ophthalmoscopic examinations were conducted pretest, study termination, and following recovery .Other evaluations conducted at termination and following recovery included: hematology, clinical chemistry , urinalysis, organ weights, and pathological examinations (macroscopic and microscopic). Thyroid hormone levels [Thyroid Stimulating Hormone (TSH), T3 (3,5,3' -triiodothyronine), and T4 (thyroxine or 3,5,3'5'-tetraiodothyronine)] were evaluated of animals at 33 days and at termination. These same hormone levels were evaluated following recovery.

Homogeneity of the dosing suspensions at the low and high concentration levels was determined on mixes used the first week of study. Mean concentration recoveries from the periodic analyses of dosing suspensions used on study were 102.5%, 110.2%, and 106.8% of nominal for the l00, 300, and 1000 mg/kg/day groups, respectively.

A total of six females (two control and four in the 1000 mg/kg/day group) died or were euthanizedin extremis.The mortality/moribundity seen in these groups was considered related to dosing injury and not treatment related.

                               

No effect of treatment was seen in clinical or neurobehavioral evaluations, body weights, food consumption, ophthalmological examinations, MA, FOB evaluations, hematology or urinalysis evaluations. Likewise, no effect of treatment was evident from organ weights, or from the macroscopic or microscopic examinations.

After 90 days of dosing, total bilirubin values were statistically higher than the control means (males: 0.14 ± 0.05; females: 0.13 ± 0.05) in males in the 1000 mg/kg/day dose (0.34 ± 0.024) (p<0.01) group and in females in the 300 (0.19 ± 0.03) (p<0.05) and 1000 mg/kg/day (0.2 ± 0.06) groups (p<0.01 ). Mean serum alkaline phosphatase (ALP) levels after 90 days of dosing in the female 1000 mg/kg/day (98.9 ± 49.47) group was statistically higher than that of the control mean (58.4 ± 28.46) (p<0.05). A slight increase, but non-statistically different, was also observed in males. Although these differences were considered possibly due to test article administration, neither of these changes was of sufficient magnitude as to be biologically or toxicologically meaningful or adverse. Serum bilirubin and ALP levels in control and treated groups of both sexes were comparable after the end of the recovery period.

With respect to serum hormone levels, mean TSH and T3 levels were statistically comparable between control and treated animals at all time points (Day 33, terminal and recovery euthanasia). Mean T4 levels were statistically lower than the control mean (Day 33: 4.96 ± 0.84; terminal: 5.09 ± 0.80) in the 100 (Day 33: 3.66 ± 0.88; terminal: 3.27 ± 0.67), 300 (Day 33: 3.42 ± 0.71; terminal: 2.61 ± 0.87) and 1000 (Day 33: 3.39 ± 0.55; terminal: 3.09 ± 0.91) mg/kg/day male dose groups at days 33 and 90 (p<0.01). Mean T4 1evels were also statistically lower than the control mean (4.27 ± 0.96) in females in the l00 (3.31 ± 1.08), 300 (3.24 ± 0.85) and 1000 (3.33 ± 0.84) mg/kg/day dose groups at Day 33 (p<0.05). Mean T4 1evels in all female dose groups were statistically comparable to the control mean at Day 90. At the recovery euthanasia, mean T4 1evels were comparable in the control and 1000 mg/kg/day male and female groups. The change in T41evels seen in the 1000 mg/kg/day group was reversible and levels comparable to control were seen following recovery.

The decrease in serum T 4 levels was considered a possible effect of test article administration. TBBPA has been shown to competitively displace T4 from transthyretin (TTR), a major serum T4-binding protein in the rat,in vitro(Meerts et al. 2000. Toxicological Sciences, 56,95-104). That portion of serum T4 displaced from its binding site would be available for metabolism and elimination, thereby leading to a decrease in serum levels. The half-life of T4 in the rat is short due to its transport by TTR, and thus this species is sensitive to perturbations in T4 levels. For example, the plasma T4 half-life in rats is 12-24 hours while T4's half-life in humans is 5-9 days (Capen, C. 1996. Chapter 21. Toxic Responses of the Endocrine System. In: Casarett & Doull's Toxicology, The Basic Science of Poisons. Fifth Edition. Ed. Curtis Klaassen. McGraw-Hill, New York. 474-006). In humans, circulating T4 is bound primarily to thyroxin binding globulin, but this high affinity binding protein is not present in rodents. This mechanism, displacement of T4 from TTR-binding by TBBPA with subsequent metabolism and elimination in the liver, may account for the decreased mean serum T4 levels in treated animals. Because the decrease in T4 1evels was not of sufficient magnitude to alter mean serum TSH or T3 levels, thyroid histopathology, thyroid weight, or other parameters indicative of thyroid pathology (e.g. body weight, etc.), the decrease in serum T4 1evels was not considered adverse. The reduction in serum T4 1evels was not accompanied by evidence of toxicity or adverse effects, and the animals were clinically normal.

Thus, in this rat 90-day oral toxicity study with TBBPA, the No Observed Adverse Effect Level (NOAEL) was 1000 mg/kg/day, the highest dose tested. No effect on mortality, clinical signs, body or organ weights, histopathology, urinalysis, ophthalmology, FOB, MA, serum TSH, serum T3 or serum chemistries was observed. Differences were observed for bilirubin and ALP, but neither of these changes were found to be biologically or toxicologically meaningful or adverse. Serum T4 levels were decreased in treated animals, but the decrease was not of sufficient magnitude to induce adverse effects.

The NOAEL from the rat 90-d study will be used for the CSA for both the oral and dermal routes. The 90-d is of longer duration than the rabbit 21 dermal, was conducted according to current guidelines and GLPs, and included analytical confirmation of dose levels. The dermal study is of lesser quality.

Justification for classification or non-classification

Taking the above data into account, tetrabromobisphenol A does not require classification as a repeat dose toxicant according to the criteria described in Directive 67/548/EEC and the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No.1272/2008.