SCREENING LEVEL HAZARD CHARACTERIZATION FOR HIGH PRODUCTION VOLUME CHEMICALS SPONSORED CHEMICAL Benzene, l,l'-[l92-ethanediylbis(oxy)]bis[2,4,6-tribromo-] (CAS No. 37853-59-1) [9th CI name: Benzene, 1,!'-[!,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] June 2008 INTERIM Prepared by High Production Volume Chemicals Branch Risk Assessment Division Office of Pollution Prevention and Toxics Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460-0001 ------- SCREENING-LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making publicly available screening-level health and environmental effects information on chemicals manufactured in or imported into the United States in quantities greater than one million pounds per year. In the Challenge Program, producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the environment. The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Challenge Program on approximately 1,400 sponsored chemicals. OPPT is using a hazard- based screening process to prioritize review of the submissions. The hazard-based screening process consists of two tiers described below briefly and in more detail on the Hazard Characterization website3. Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as submitted by the sponsor. It does not include evaluation of the quality or completeness of the data. In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors. EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar chemical structures, properties and biological activities may be grouped together and their data shared across the resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all category members. As part of Tier 2, evaluation of chemical category rationale and composition and data extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance. The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing chemicals review process. These hazard characterizations are technical documents intended to support subsequent decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on HPV chemicals and provide information previously not readily available to the public. The public, including sponsors, may offer comments on the hazard characterization documents. The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk- based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action. 1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm. 2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm. 3 U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html). 4 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm. 5 OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf. 6 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm. 2 ------- SCREENING LEVEL HAZARD CHARACTERIZATION Benzene, l,l'-[l92-ethanediylbis(oxy)]bis[2,4,6-tribromo-] Introduction The sponsor, Chemtura Corporation, formerly Great Lakes Chemical Corporation, submitted an initial Test Plan and Robust Summaries to EPA for Benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] (CAS No. 37853-59-1) dated December 23, 2002. EPA posted the submission on the ChemRTK HPV Challenge website on January 23, 2003 (http ://www. epa. gov/chemrtk/pubs/summaries/benzethan/c 14170tc.htm). EPA comments on the original submission were posted on the website on May 28, 2003. Public comments were also received and posted to the website. In a letter to EPA dated November 15, 2006, the Sponsor stated that it had either completed or was completing proposed testing as indicated in the test plan and would provide a final HPV submission and updated robust summaries upon completion of these studies. The final submission has not yet been received by EPA. This screening level hazard characterization is based primarily on the review of the test plan and robust summaries of studies submitted by the sponsor under the High Production Volume Chemicals Challenge Program. In preparing the hazard characterization, EPA considered its own comments and public comments on the original submission. A summary table of SIDS endpoint data with the structure of the sponsored chemical is included in the appendix. The screening-level hazard characterization for environmental and human health toxicity is based largely on SIDS endpoints and is described according to established EPA or OECD effect level definitions and hazard assessment practices. Sum m ;m-Conclusion The submitted measured log Kow of ' 14 is suhstauiialK lower llian I lie estimated \ alue of 14 ISased on low water soluhiliis. chemical structure and high melting poim of ilns chemical. IP \ does noi h;i\ e confidence mi ihc measured \alne I lie sponsor needs io resol\e iIns discrepant Therefore. al iliis lime, llie log kow eiidpomi remains a dala gap I lie poieniial acnie lia/ard of hen/ene. I. I'-| 1.2-elhanedi> Ihisiow )|his|2.4.<>-ii'ihionio-1 lo aquatic organisms cannoi he e\ahialed because of a discrepancy in log Kow \ allies and an inadequate acnie fish lo\icil> studs In addilion. ihere is a lack of measured dala lor aquatic iii\ eriehrales and ai|iialie plains io\icil>. \enie oral lo\icil> of hen/ene. I. I -| 1,2-et liaued i> Ihisiow )|his|2.4.<>-ii'ihionio-1 in rals and dogs is low \enie dermal lo\icil> of hen/ene. I. I'-| l.2-elhanedi> Ihisiow i|his|2.4.<>-ii"ihionio-| in rahhils and acnie inhalation io\icil> mi rals is low r.en/ene. 1.1 '-| 1.2-elh;inecli> Ihisiow )|his|2.4.(>-ii'ihionio|- was slighiK irritating lo rahhn skin. howe\ er no skin sensiii/alion was ohser\ ed w lien lesied in hiimans Repealed oral e\posiire al e\lieniel> high doses resulted in changes in hematology parameters (decreased er\ throes te counts, hematocrit and hemoglobin and leukocuc counts), a slight increase in alkaline phosphatase acli\ it\ and decrease glucose concentrations l.i\er. adrenal, pancreas, pniiiiars and iiierns showed lesions of a minimal lo mild se\ent\ Repealed inhalation exposure resulted mi changes in hematology. clinical chemistr\ and urinals sis panimelers and scattered loci or loams ;il\ eolar macrophages in lungs. Repealed dermal exposure showed no toxicity in rahhils There were no effects on repiodiictiNe organs in the repeated-dose toxicity studies In de\elopnienial toxicity studies with rats no maternal to\icil\ orde\elopnienial effects were noted np tii lo.uuu nig kg-hw da> lien/eiie. I. I"-| 1.2- ethanedis Ihisiow )|his|2.4.(>-ti'ihronio-| did not induce gene mutations I lie potential health lia/ard of lieu/cue. 1.1'-| l.2-ethaiiedi> Ihisiow i|his|2.4.(>-iiihi'onio-| is low Log Kow. io\icil\ to aquatic orgaiiisnis and chromosomal aberrations iin viini test) eudpouits were identified as dala gaps under the I ll'V ( halleuge Rrograni 3 ------- 1. Physical-Chemical Properties and Environmental Fate A summary of physical-chemical properties and environmental fate data submitted is provided in the Appendix. For the purpose of the screening-level hazard characterization, the review and summary of these data was limited to the octanol-water partition coefficient and biodegradation endpoints as indicators of bioaccumulation and persistence, respectively. Octanol-Water Partition Coefficient Log Kow: 3.14 (measured) 9.14 (estimated) The submitted measured log Kow of 3.14 is substantially lower than the estimated value of 9.14. Based on low water solubility, chemical structure and high melting point of this chemical, EPA does not have confidence in the measured value. The sponsor needs to resolve this discrepancy. Therefore, at this time, the log Kow endpoint remains a data gap. Biodegradation In a Biodegradation test using acclimated inoculum, only 1.41 % of the test substance had degraded in 211 days. (Although the test does not follow OECD guidelines for ready or inherent tests, the results of the test lead to the conclusion that the test substance would not biodegrade in 28 days under an inherent test with acclimated inoculum or under a ready test with unacclimated inoculum.) Benzene, l,l'-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo]- is not readily biodegradable. Conclusion: The Log Kow of benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] remains as a data gap because of alack of confidence in the measured value. Benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] is not readily biodegradable, indicating that it has the potential to persist in the environment. 2. Environmental Effects - Aquatic Toxicity Acute Toxicity to Fish, Aquatic Invertebrates and Aquatic Plants EPA considers the data for aquatic toxicity inadequate for the purposes of the HPV Challenge Program. The acute fish toxicity test is inadequate because it was performed above the water solubility limit. In addition, the concerns discussed above about the log Kow value raise questions about using estimation for the ecological effects endpoints. Therefore, aquatic toxicity endpoints remain as data gaps. Conclusion: The potential acute hazard of benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] to aquatic organisms cannot be evaluated because of a discrepancy in log Kow values and an inadequate acute fish toxicity study. In addition, there is a lack of measured data for aquatic invertebrates and aquatic plants toxicity. 3. Human Health Effects Acute Oral Toxicity (1) Spartan rats (5/sex/dose) were administered a commercial product Firemaster 680 (either non-micronized or micronized benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] suspended in 0.5 %Methocel) via gavage at 10,000 mg/kg-bw and were observed for 14 days. None of the animals died during the study. All rats exhibited normal body weight gains. Upon necropsy, 2 females receiving the micronized material exhibited hydrometra. LDS0 > 10,000 mg/kg-bw 4 ------- (2) Beagle dogs (two /sex) were administered Benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] via gavage at 10,000 mg/kg-bw and observed for 14 days. None of the animals died. White discolored feces, soft feces (1 female) and lacrimation (2 males and 1 female) were noted. No adverse effects on body weight were found. LDS0 LDS0 > 10,000 mg/kg-bw Acute Inhalation Toxicity (1) Spartan rats (5/sex) were exposed to benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] dust (micronized commercial product, Firemaster 680) at 36.68 mg/L for 4 hours and observed for 14 days. No rats died during exposure or the 14 days observation period. Signs of toxicity during the exposure included eye squint, erythema, slight dyspnea, slight bradypnea, salivation, nasal porphyrin discharge and increased, then decreased motor activity. Three rats exhibited gray foci in the lungs during necropsy. LC50 > 36.68 mg/L (2) Charles River rats (5/sex) were exposed to benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] vapor at a nominal concentration of 13.08 mg/L for 4 hours and were observed for 14 days. No mortality was seen during the exposure or the 14 day post-observation period. There was no effect on body weight gains and the necropsy did not reveal any test substance-related gross pathological alternations. LCS0 > 13.08 mg/L Acute Dermal Toxicity Albino rabbits (2 males) were administered a single dermal dose of Benzene, l,l'-[l,2-ethanediylbis(oxy)]bis[2,4,6- tribromo-] at a concentration of 10,000 mg/kg-bw under a sleeve of rubber snuggle fastened about the clipped trunk for 24 hours and observed for 14 days. Neither animal died during the study. There was no mention of any clinical signs of toxicity. LDS0 > 10,000 mg/kg-bw Repeated-Dose Toxicity (1) Charles River rats (15/sex/dose) were administered benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] in the diet at concentrations of 0, 0.1, 1.0 and 10.0% (approximately 0, 71.1, 729, and 8329 for males and 0, 84.6, 874, and 9364 for females, respectively) for 106 days. There were no clinical signs of toxicity and no treatment-related effects on body weights, body weight gains and food consumption. Females given 1.0 and 10% diet had lower average erythrocyte counts, hematocrit, hemoglobin (at 10% diet) and total leukocyte counts. Males given 10% diet had lower total leukocyte counts, hemoglobin and hematocrit values. Slight increases in the serum alkaline phosphatase activity in males fed 10% diets and low blood glucose levels in high-dose males and females were also seen. Histopathological examination revealed changes in liver included focal or multifocal enlargement of hepatocytes, focal sinusoidal or portal lymphoid infiltrations. The severity of these liver lesions was minimal in all animals. No significant histological changes were evident in the livers of animals fed either 0.1 or 1.0%. In addition, histopathological changes in the high dose male and female animals included increased incidence of mild unilateral or bilateral hypervolemia of the adrenal gland, increased incidence of focal cytoplasmic vacuolization of basophils and focal hyperplasia in the pituitary, increased incidence of focal interstitial lymphoid infiltrations in the pancreas and hydrometra of the uterus. All lesions were graded as minimal to mild. None of these changes were considered by the study personnel to be treatment related. Nine out of 10 control- and 10/10 treated-males and all females exhibited minimal to mild chronic murine pneumonia and mild-moderate chronic tracheitis. The majority of control and high dose males and females also had aggregates of alveolar macrophages in the lungs. LOAEL = 8329/874 (m/f) mg/kg-bw/day (based on effects on hematological parameters, liver, adrenal gland, pituitary and pancreas) NOAEL = 729/85 (m/f) mg/kg-bw/day 5 ------- (2) Spartan rats (5/sex/dose) were exposed to benzene, 1,1 '-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] dust via inhalation at concentrations of 0, 5 or 20 mg/L for 4 hours/day, 5 days/week for 21 days. There were no deaths during the study. Clinical observations noted in all groups included clear nasal discharge, soft stool, respiratory congestion, and nasal or ocular porphyrin discharge at a higher frequency in treated rats compared to controls. There was no effect of treatment on body weight or food consumption. There was a slight, dose-dependent decrease in leukocytes in females exposed to 5 mg/L/day and 20 mg/L/day. Serum pyruvic transaminase activity was increased in females exposed to 5 and 20 mg/L compared to control, but was less than control in males exposed to 5 and 20 mg/L. High dose males had an increased albumin, slight-trace occult blood, epithelial cells and calcium oxalate crystals in the urine. There was a dose-related increase in absolute lung weight in males. Microscopic findings were limited to the lungs of treated animals and included scattered foci or foamy alveolar macrophages in their lungs. LOAEL = 5 mg/L/day (based on the effects on hematology, clinical chemistry and urinalysis parameters and histopathological changes in the lung NOAEL = Not established (3) New Zealand white rabbits (3/sex/dose) were administered benzene, l,l'-[l,2-ethanedyilbis(oxy)]bis[2,4,6- tribromo-] dermally onto the abraded and intact skin at 0, 50, 500 and 5000 mg/kg-bw/day, 6 hours/day, 5 days/week for 4 weeks. There were no treatment-related mortalities or clinical signs. Most rabbits in the control and treated groups exhibited very slight to slight erythema during the study. One rabbit exposed to 5000 mg/kg- bw/day had very slight to moderate erythema. In one high-dose male, body weight was markedly decreased. There were no test-substance related changes in hematological, biochemical or urinalysis parameters, organ weights or histopathology. NOAEL = 5000 mg/kg-bw/day (based on no effects at the highest does tested) Reproductive Toxicity No data were submitted to address the reproductive toxicity endpoint for benzene, 1,1 '-[1,2- ethanediylbis(oxy)]bis[2,4,6-tribromo-]. Evaluations of reproductive organs reported in the repeated-dose dietary toxicity study of 106 days and an available developmental toxicity study were used to address the reproductive toxicity endpoint for the purposes of the HPV Challenge Program. In the repeated-dose toxicity study (1) described previously, there were no treatment-related effects on gonad weights, testes, prostate, prostatic urethra, and epididymis in males and ovaries and uterus in females. Histopathological examination of these organs did not show any microscopic changes. Developmental Toxicity (1) Charles River CD pregnant rats (25/dose) were administered benzene, l,l'-[l,2-ethanediylbis(oxy)]bis[2,4,6- tribromo-] via gavage at 0, 100, 1000 and 10,000 mg/kg-bw/day during 6 to 15 days of gestation. There were no maternal deaths. There were no changes in appearance or behavior attributable to treatment with the test substance at 100 or 1000 mg/kg-bw/day. Slightly reduced mean maternal body weight gains during treatment (not significant) and a slight increase in the occurrence of red vaginal discharge were observed in the 10,000 mg/kg-bw/day group. The number of animals exhibiting this condition was not listed in the report. All gravid animals delivered live fetuses. There were no statistically significant differences between groups in the mean number of viable or nonviable fetuses, early or late resorptions, corpora lutea and mean number of implantations. There was a statistically significant (p<0.05) increase in the mean number of total implantations/dam at the high dose compared to controls. There were no significant differences in the male to female sex ratio or mean fetal body weights. There were no statistically significant differences of malformations and in the number of litters or the number of fetuses with anomalies between treated and control animals. There was a slight increase (not significant) in the number of animals with unossified sternebrum number 5 and /or 6 in fetuses from rats at the low dose compared to control. The incidence of this variation in rats treated with 1000 or 10,000 mg/kg-bw/day was similar to control. The incidences of other variations were similar between control and treated animals. NOAEL (maternal/developmental toxicity) = 10,000 mg/kg-bw/day (based on no-effects at the highest dose tested) 6 ------- (2) Charles River CD pregnant rats (5/dose) were administered benzene, l,l'-[l,2-ethanediylbis(oxy)]bis[2,4,6- tribromo-] via gavage at 0, 30, 100, 300, 1000, 3000 and 10,000 mg/kg-bw/day during 6 to 15 days of gestation. Survival in all groups was 100 %. The test substance had no effect on body weight gains, appearance or behavior. There was no effect of test material on the number of resorptions, implantations or corpora lutea. NOAEL (maternal and developmental toxicity) = 10,000 mg/kg-bw (based on no effects at the highest dose tested) Genetic Toxicity - Gene mutation In vitro (1) Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 were exposed to benzene, 1,1 '-[1,2- ethanediylbis(oxy)]bis[2,4,6-tribromo-] at concentrations of 100, 333, 1000, 3333 and 10,000 (ig/plate in the presence and absence of metabolic activation. A precipitate was noted at 1000 (ig/plate and above. Cytotoxic concentration was greater than 10,000 |ig/plate. None of the concentrations caused an increase in the number of mutants in the presence or absence of metabolic activation. Positive controls responded appropriately. Benzene, l,l'-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] was not mutagenic in this assay (2) Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 were exposed to benzene, 1,1'-[1,2- ethanedyilbis(oxy)]bis[2,4,6-tribromo- at concentrations of 0.25, 0.5, 5.0 and 50 (ig/plate in the presence and absence of metabolic activation. Cytotoxic concentration was greater than 50 ng/plate. The test substance did not demonstrate dose-dependent mutagenic activity in the presence or absence of metabolic activation. Benzene, l,l'-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] was not mutagenic in this assay Sensitization (1) In a multiple insult test, fifty healthy male human volunteers [white (53.3%), black (33.3%), Mexican (8.8%), or American Indian (4.2%)] were dermally exposed to benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] under occlusion for a total of 10 applications. A new site was used for each application. There was a rest period of 10-14 days after the last application. Subjects were then challenged with test material in a manner identical to that used for the sensitizing doses (except that challenge doses were applied at a different site than sensitizing doses). Challenge site was examined at 48 and 72 hours. Forty five of the 50 subjects completed the study. No evidence of irritation was observed during the sensitizing phase of the study. Conclusion Acute oral toxicity of benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] in rats and dogs is low. Acute dermal toxicity of benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] in rabbits and acute inhalation toxicity in rats is low. Benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] was slightly irritating to rabbit skin; however no skin sensitization was observed when tested in humans. Repeated oral exposure at extremely high doses resulted in changes in hematology parameters (decreased erythrocyte counts, hematocrit and hemoglobin and leukocyte counts), a slight increase in alkaline phosphatase activity and decrease glucose concentrations. Liver, adrenal, pancreas, pituitary and uterus showed lesions of a minimal to mild severity. Repeated inhalation exposure resulted in changes in hematology, clinical chemistry and urinalysis parameters and scattered foci or foamy alveolar macrophages in lungs. Repeated dermal exposure showed no toxicity in rabbits. There were no effects on reproductive organs in the repeated-dose toxicity studies. In developmental toxicity studies with rats no maternal toxicity or developmental effects were noted up to 10,000 mg/kg-bw/day. Benzene, 1,1 '-[1,2- ethanediylbis(oxy)]bis[2,4,6-tribromo-] did not induce gene mutations. The potential health hazard of Benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] is low. 7 ------- 4. Hazard Characterization The submitted measured log Kow of 3.14 is substantially lower than the estimated value of 9.14. Based on low water solubility, chemical structure and high melting point of this chemical, EPA does not have confidence in the measured value. The sponsor needs to resolve this discrepancy. Therefore, at this time, the log Kow endpoint remains a data gap. The potential acute hazard of benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] to aquatic organisms cannot be evaluated because of a discrepancy in log Kow values and an inadequate acute fish toxicity study. In addition, there is a lack of measured data for aquatic invertebrates and aquatic plants toxicity. Acute oral toxicity of benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] in rats and dogs is low. Acute dermal toxicity of benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] in rabbits and acute inhalation toxicity in rats is low. Benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] was slightly irritating to rabbit skin; however no skin sensitization was observed when tested in humans. Repeated oral exposure at extremely high doses resulted in changes in hematology parameters (decreased erythrocyte counts, hematocrit and hemoglobin and leukocyte counts), a slight increase in alkaline phosphatase activity and decrease glucose concentrations. Liver, adrenal, pancreas, pituitary and uterus showed lesions of a minimal to mild severity. Repeated inhalation exposure resulted in changes in hematology, clinical chemistry and urinalysis parameters and scattered foci or foamy alveolar macrophages in lungs. Repeated dermal exposure showed no toxicity in rabbits. There were no effects on reproductive organs in the repeated-dose toxicity studies. In developmental toxicity studies with rats no maternal toxicity or developmental effects were noted up to 10,000 mg/kg-bw/day. Benzene, 1,1 '-[1,2- ethanediylbis(oxy)]bis[2,4,6-tribromo-] did not induce gene mutations. The potential health hazard of Benzene, l,r-[l,2-ethanediylbis(oxy)]bis[2,4,6-tribromo-] is low. 5. Data Gaps Log Kow, toxicity to aquatic organisms and chromosomal aberrations (in vitro test) endpoints were identified as data gaps under the HPV Challenge Program. 8 ------- APPENDIX Summary Tabic of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program End points Sponsored Chemical Benzene, l,r-|l,2-cthanediylbis(o\y)|bis|2,4,6-tribromo-| (CAS No." 37853-59-1) Structure Br / Br Summary (if Physical-Chemical Properties and Environmental Fate Data Melting Point (°C) 224 Boiling Point (°C) 502 Vapor Pressure (hPa at 25°C) <0.000001 Log Kow 3.14 (m) 9.15(e) Water Solubility (mg/L at 25°C) 0.2 Indirect (OH ) Photodegradation Half-life (t1/2) 8.6 hours Stability in Water (Hydrolysis) Half-life (t1/2) Does not have hydrolyzable groups Fugacity (Level III Model) Air (%) Water (%) Soil (%) Sediment (%) 0.068 1.17 37.3 61.5 Biodegradation at 28 days (%) Not Readily Biodegradable Summary of Environmental Effects - Aquatic Toxicity Data Fish 96-h LC50 (mg/L) Data gap Aquatic Invertebrates 48-h ECS0 (mg/L) Data gap Aquatic Plants 96-h EL50 (mg/L) Data gap 9 ------- Summary Tabic of the Screening Information Data Set as Submitted underthe U.S. HPV Challenge Program Endpoints Sponsored Chemical Benzene, l,r-[l,2-ethancdiylbis(oxy)]bis[2,4,6-tribromo-| (CAS No. 37853-59-1) Summary of Human Health Data Acute Oral Toxicity LDS0 (mg/kg-bw) >10000 >10000 Acute Dermal Toxicity LDS0 (mg/kg-bw) >10000 Acute Inhalation Toxicity LC50 (mg/L) >36.68 >13.08 Repeated-Dose Toxicity - Oral NOAEL/LOAEL (mg/kg-bw/day) NOAEL = 729/85 (m/f) LOAEL = 8329/874 (m/f) Repeated-Dose Toxicity - Inhalation NOAEL/LOAEL (mg/L/day) NOAEL = Not established LOAEL = 5 Repeated-Dose Toxicity - Dermal NOAEL/LOAEL (mg/kg/bw) NOAEL = 5000 (hdt) Reproductive Toxicity - Oral feed NOAEL/LOAEL (mg/kg-bw/day) Evaluation of repeated-dose toxicity study showed no effects on reproductive organs. Developmental Toxicity NOAEL/LOAEL (mg/kg-bw/day) (maternal/developmental toxicity) NOAEL = 10,000 Genetic Toxicity - Gene Mutation In vitro Negative Genetic Toxicity - Chromosomal Aberrations In vivo Data gap Other information (Sensitization (human)) Not sensitizing (m) = measured; (e) = estimated; (m/f) = males/females; hdt = highest dose tested 10 ------- |