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Toxicological Risks of Selected Flame-Retardant Chemicals 4 Hexabromocyclododecane THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on hexabromocyclododecane (HBCD). The subcommittee used that information to characterize the health risk from exposure to HBCD. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to HBCD. PHYSICAL AND CHEMICAL PROPERTIES HBCD is a cyclic aliphatic flame retardant. Its physical and chemical properties are presented in Table 4–1. OCCURRENCE AND USE HBCD is a solid, white powder that is used as a flame retardant additive for thermoplastic polymers. Its principal use is in expanded polystyrene foams and other styrene resins. It may also be used in latex binders, unsaturated polyesters, and polyvinyl chloride wire, cable, and textile coatings. When used in textiles, it is applied as a back coating to the fabric, encapsulated in a polymer matrix. Textile applications include residential and commercial furniture, up-
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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 4–1 Physical and Chemical Properties of HBCD Property Value Reference Chemical formula C12H18Br6 CHEMID 1999 Chemical structure CAS Registry # 25637–99–4 (mixed isomers) CHEMID 1999 Molecular weight 641.7 Hatlelid 1999 Melting point 185–195°C Hatlelid 1999 Vapor pressure 4.7×10−7 mm Hg Stenzel and Nixon 1997 Density 2.24 g/cm3 Hatlelid 1999 Solubility in water 0.0034 mg/L Stenzel and Markley 1997 Partition coefficient (Log Kow) 5.6 MacGregor and Nixon 1997 holstery seating in transportation, draperies, and wall coverings (FRCA 1998). HBCD is usually applied with antimony trioxide as a back coating in a mass ratio of 2:1 (i.e., about 6–15% HBCD and 4–10% antimony oxide by weight). TOXICOKINETICS No human data on the toxicokinetics of HBCD were located for any route. No toxicokinetic studies via the dermal or inhalation exposure routes were reported in experimental animals. However, in a report by Dean and Leong (1977), rats exposed dermally to a high dose of HBCD in saline experienced diarrhea and slight weight loss. This finding indicates that at least some absorption occurs via the dermal route. In an unpublished study by Vesicol Chemical Corporation (1980), rats
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Toxicological Risks of Selected Flame-Retardant Chemicals administered a single oral dose of 1.93 mg of radiolabeled HBCD eliminated 86% of the dose within 72 hr. (The total dose administered was 7–9 mg/kg body weight.) Absorption from the gastrointestinal tract reportedly occurred rapidly, with a half-life of 2 hr. However, the amount of the absorbed fraction was not reported. HBCD was reported to be rapidly metabolized and eliminated in the feces and urine following absorption, with 70% of the administered radioactivity eliminated in the feces and another 16% eliminated in the urine 72 hr after dosing. A two-compartment model was constructed, with non-adipose tissues in one compartment and adipose tissue in the other. Elimination from the adipose compartment was reported to be slower than elimination from the non-adipose compartment, although elimination half-times were not provided in the review. In another study by Arita et al. (Marcia Hardy, Albermarle Corporation, Pers. Commun., August 3, 1999), HBCD was orally administered to male Wistar rats (number not reported) in olive oil at 500 mg/kg-d for 5 d. HBCD was found to be present only in adipose tissue, and in none of the other organs examined (i.e., spleen, pancreas, liver, kidneys, and heart). HBCD was found to be excreted in the feces, with an average of 32–35% of the cumulative administered dose excreted. No HBCD was found in the urine. Although differences in study design, including the test vehicle and the analytic methods used, may account for some of the difference in the results, both studies by Vesicol Chemical Corporation (1980) and Arita et al. (Maria Hardy, Albermarle Corporation, Pers. Commun., August 3, 1999) suggest that following acute oral doses, HBCD is rapidly absorbed from the gastrointestinal tract, distributed primarily to the body fat, and eliminated rapidly, primarily in the feces. HAZARD IDENTIFICATION1 Dermal Exposure Irritation McDonnell (1972) reported no irritant effects in men or women (number not reported) who wore 1-inch squares of Tyvek T-12 fabric treated with 10% HBCD for 6 d on their arms or legs. No details on the method of fabric treatment or description of fabric samples were provided. 1 In this section, the subcommittee reviewed the data on toxicity of HBCD, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Hatlelid 1999).
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Toxicological Risks of Selected Flame-Retardant Chemicals Dermal Sensitization Momma et al. (1993) and Nakamura et al. (1994) reported positive sensitization reactions in guinea pig maximization tests using HBCD induction concentrations of 5% for intradermal injection and 25% for topical application, and HBCD topical challenge concentrations up to 5%. Several studies demonstrated no effects or slight erythema and scaling in rabbits following application of HBCD to the skin for up to 24 hr (Zeller 1962; Dean and Leong 1977; Lewis and Palanker 1978; Crown 1984). A recent guinea pig maximization test conducted by Microbial Associates (1996) found no effects from HBCD. This study used a 5% concentration for the intradermal injection and neat HBCD (moistened with corn oil) for the topical application in both the induction and challenge phases. The previous positive tests (Momma et al. 1993; Nakamura et al. 1994) also used a 5% concentration for the intradermal injection, but used 5% or lower concentrations for the topical applications. The reason for the discrepancy between the Microbial Associates (1996) study and the earlier studies is not apparent. However, the negative results in the Microbial Associates (1996) study, which appears to have been well conducted and used the highest possible concentration for topical induction and challenge, raise questions about the potential of HBCD to produce even a mild sensitization reaction in humans. Systemic Effects Several acute toxicity studies in rats and rabbits were conducted via the dermal route of exposure. However, no subchronic or chronic dermal exposure studies were located in the literature. Dean and Leong (1977) shaved skin of two male and two female rabbits and applied HBCD (in 0.9% saline) at a dose of 20 g/kg and occluded the skin for 24 hr. The authors observed diarrhea and slight weight loss in one of two males and one of two female New Zealand white rabbits. No effects were noted in rabbits (number, sex, and strain not reported) after a similar exposure to 8 g/kg of HBCD (Lewis and Palanker 1978). Other Systemic Effects No immunological, neurological, reproductive, developmental, or carcinogenic effects were identified following dermal exposure to HBCD.
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Toxicological Risks of Selected Flame-Retardant Chemicals Inhalation Exposure Systemic Effects No subchronic or chronic inhalation exposure studies were located in the literature; however, one acute inhalation exposure study was found. Lewis and Palanker (1978) reported no effects in groups of rats (10 rats/group, 5 males and 5 females) exposed to HBCD at a concentration of 200 g/m3 for 1 hr. Rats exposed to 200 g/m3 for 4 hr exhibited only slight dyspnea. The study authors concluded that acute exposures to very high concentrations of HBCD dust were well tolerated by the rats. Other Systemic Effects No studies were identified in the literature that investigated the immunological, neurological, reproductive, developmental, or carcinogenic effects of HBCD following inhalation exposures. Oral Exposure A summary of toxicity studies from oral exposures to HBCD is presented in Table 4–2. Systemic Effects No data on oral exposures to HBCD were located for humans. Several studies reported that a single oral dose of 10 g/kg in rats produced hypoactivity, diarrhea, and matted hair, while a single oral dose of 5 g/kg had no effects and this dose was identified as a no-observed-adverse-effects level (NOAEL) (Dean and Leong 1977; Lewis and Palanker 1978; Nissimov 1984). In mice, a single oral dose of 6.4 g/kg produced apathy, trembling, and death (Schulze 1962). Zeller and Kirsch (1969) conducted a 28-d feeding study in which groups of 20 rats (10 male and 10 female Sprague-Dawley rats were fed diets containing 0%, 1%, 2.5%, or 5.0% of HBCD for 28 d. Based on food intake and body weight data obtained from the study, the estimated doses in the 0%, 1%, 2.5%, and 5% groups were determined to be 0, 900, 2,400, and 4,700 mg/kg-d in males and 0, 900, 2,300, and 4,900 mg/kg-d in females. No mortality was reported. Rats in the 2.5% and 5% groups were in poor condition after the first
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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 4–2 Oral Noncancer Studies of Hexabromocyclododecane Animal, Species, Sex, Number Dose Duration, Route Effects NOAEL/LOAEL Reference Rat, Sprague-Dawley, M/F, 10/dose 0, 900, 2,350, 4,800 mg/kg-d 28 d, diet Increased absolute and relative liver weight; thyroid follicular hyperplasia LOAEL: 900 mg/kg-d Zeller and Kirsch 1969b Rat, Sprague-Dawley, M/F, 20/dose 0, 100, 200, 450, 925 mg/kg-d 90 d, diet Dose-related increase in absolute and relative liver weight in both sexes; dose-related increased incidence and severity of liver fatty accumulation; slight decrease in male body weight NOAEL: 450 mg/kg-d LOAEL: 925 mg/kg-d Zeller and Kirsch 1970b Rat, Sprague-Dawley, M/F, 6/dose 0, 125, 350, 1,000 mg/kg-d 28 d, gavage in corn oil Dose-related increase in liver weight NOAEL: ND LOAEL: ND Chengelis 1997b Rat, Wistar, F, 13–14/dose 0, 0.01, 0.1, 1% (HDT ≈ 900 mg/kg-d) Gestation d 0–20, diet No developmental effects; increase in maternal liver weight NOAEL: ~500 mg/kg-d Murai et al. 1985a Rat, Crl:CD®(SD)16 SBR, F, 8/dose 0, 125, 250, 500, 750, 1,000 mg/kg-d Gestation d 0–20, gavage No developmental effects; increase in maternal body weight at d 19–20 NOAEL: ~1,000 mg/kg-d Stump 1999a Mice, NR, M/F, 50/dose 0, 100, 1,000, 10,000 ppm (HDT=~1,300 mg/kg-d) 18 mo, diet No effect on growth; no effect on survival; in males, liver hypertrophy, fatty change, vacuolation; altered foci NOAEL: 100 ppm (13 mg/kg-d) LOAEL: 1,000 ppm (130 mg/kg-d) Kurokawa et al. (Marcia Hardy, Albermarle Corp., Pers. Commun., Aug. 3, 1999)c F, female; HDT, highest dose tested; LOAEL, lowest-observed-adverse-effect level; M, male; ND, not determined; NOAEL, no-observed-adverse-effect level; NR, not reported. aPublished study. bUnpublished Good Laboratory Practice study. cUnpublished non-Good Laboratory Practice study.
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Toxicological Risks of Selected Flame-Retardant Chemicals 2 wk of the study; observations in both dose groups included alopecia and unsteady gait. For males and females in the 5% group, the following variables were reduced: food intake (13–22%), final body weight (14–24%), and body weight gain (37–46%). For all groups, hematology and urinalysis results were similar to those of controls. For males and females in the 1%, 2.5%, and 5% groups, there were statistically significant (p<0.001) dose-related increases in liver weight, liver:body weight ratio, and liver:heart weight ratio. There were no effects on kidney or heart weight. Histopathological examination revealed thyroid follicular hyperplasia in both males and females in the 1%, 2.5%, and 5% groups that increased in severity with dose. Marked hyperplastic thyroid tissue with adenomatous proliferation and epithelial hyperactivity was observed in the 5% group. Females in the 5% group also showed inhibited oogenesis, with reduced numbers of mature and developing follicles present in the ovaries. The testes and epididymides of males in the 5% group were normal. Using this study, a LOAEL of 1% (equivalent to 900 mg/kg-d) for HBCD was identified, based on markedly increased absolute and relative liver weights and thyroid follicular hyperplasia. No NOAEL was identified. Based on findings in the 28-d study, Zeller and Kirsch (1970) treated groups of 20 male and 20 female Sprague-Dawley rats with 0%, 0.16%, 0.32%, 0.64%, or 1.28% of HBCD in the diet for 90 d. Based on food intake and body weight data obtained from the study, the doses in the 0%, 0.16%, 0.32%, 0.64%, and 1.28% groups were estimated to be 0, 100, 200, 400, and 900 mg/kg-d in males and 0, 100, 200, 500, and 950 mg/kg-d in females. Additional groups of 10 rats of each sex were treated with 0% or 1.28% of HBCD in the diet for 90 d, and observed for an additional 42 d prior to killing. One male rat in the 1.28% group died on the 43rd day of the study. It is not clear whether this death was related to treatment. No clinical signs were noted in any group. Body weight was slightly, but consistently, reduced (≈4%) throughout the study in the males from the 1.28% group; body weight was not reduced in females. Food intake was not affected in any group. Hematology and urinalysis results were similar to those of controls in all groups. There were statistically significant (p<0.05) differences in liver weight, liven:body weight ratio, and liver:heart weight ratio in males and females in the 0.16%, 0.32%, 0.64%, and 1.28% groups in comparison to controls. Other organ weight changes were not clearly related to treatment. Histopathological examination revealed treatment-related changes in the liver consisting of dose-related increases in the incidence and severity of lipoid phanerosis (fatty accumulation) (see Table 4–3). In the 1.28% recovery group maintained for 6 wk after the end of the exposure period, food intake and body weight gain were similar to controls. Liver histology was also similar to controls. Liver weight and liver:body weight
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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 4–3 Summary of Histological Findings in the Liver of Male and Female Rats Fed Diets Containing up to 1.28% HBCD for 13 Wk (Data from Zeller and Kirsh 1970) Male (n=20)a Female (n=20) VS VS DAD VS VS DAD 0 3 1 1 10 0 5 0.16% 8 0 0 11 0 4 0.32% 8 3 1 9 0 7 0.64% 11b 1 2 17b 2 6 1.28% 10b 9b 6b 14 2 10 aThis summary appears to include histological findings in the male from the 1.28% group that died during the study, although this is not stated explicitly in the report. bp<0.05 by Fisher Exact Test conducted by Syracuse Research Corporation. Abbreviations: DAD, disseminated adipose droplets; MS, moderately slight adipose specks; VS, very slight adipose specks. ratio remained significantly elevated compared to controls, but the difference was much less than it was at the end of the exposure period. The 1.28% dose level (approximately 925 mg/kg-d) was chosen as the LOAEL based on increased liver weight (absolute and relative in both sexes) accompanied by an increased incidence of distinctly abnormal fatty accumulation in the liver and, in males, a small reduction in body weight gain. The 0.64% level (approximately 450 mg/kg-d, the mean dose level for males and females) was selected as the NOAEL because the more subtle changes in liver weight and histology were not determined to be clearly adverse. A recent 28-d study was conducted by Chengelis (1997). Groups of six male and six female Sprague-Dawley rats (about 43-d-old) were administered 0, 125, 350, or 1,000 mg/kg-d of HBCD by gavage in corn oil for 28 consecutive days. Absolute liver weight was statistically increased in high-dose males and in mid-and high-dose females, while relative liver weights were increased in the mid-and high-dose males and in low-, mid-, and high-dose females. These increased liver weights were not, however, accompanied by related histopathological or serum chemistry changes. There was also a slight increase in severity of colloid loss in the thyroid in males in the 1,000-mg/kg-d group, but no other differences in the thyroid in comparison to controls were observed. Both the increases in liver weight and in colloid loss were reduced in additional groups of six rats of each sex that were treated with 1,000 mg/kg-d of HBCD for 28 d,
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Toxicological Risks of Selected Flame-Retardant Chemicals but then were allowed to recover for 2 wk before being killed. The authors concluded that the NOAEL was 1,000mg/kg-d (Chengelis 1997). Kurokawa et al. (Marcia Hardy, Albermarle Corporation, Pers. Commun., August 3, 1999) fed groups of 50 male and female mice diets containing 0, 100, 1,000, or 10,000 ppm of HBCD (equivalent to about 0, 13, 130, or 1,300 mg/kg-d) for 18 mo. Survival and growth rates for the treated groups were similar to controls. Liver changes were observed in male but not in female mice in the 1,000- and 10,000-ppm groups, including hypertrophy, vacuolation/fatty change, and altered foci. Reproductive and Developmental Effects Two reproductive/developmental studies found in the literature identified no reproductive or developmental effects in treated rats (Murai et al. 1985; Stump 1999). Murai et al. (1985) conducted a reproductive/developmental study in rats. Groups of 20 female Wistar rats were fed a diet containing 0%, 0.01%, 0.1%, or 1% HBCD (determined by study authors to be equivalent to about 0, 5, 50, and 500 mg/kg-d, based on daily food consumption of pregnant rats) on d 0–20 of gestation. Bodies of pregnant rats were observed every day through pregnancy, and body weight and food consumption were measured. Fourteen pregnant rats per group were killed on d 20, and major organs were examined. Six dams from each dose group were delivered naturally, and the growth of each fetus was observed. There was a slight, but significant decrease in maternal food intake and a significant increase in maternal liver weight in the 1% group (magnitude of these changes was not reported). No differences in body weights were observed between the administration and control groups. HBCD was reported as having no effect on the number of implants; the number of resorbed, dead, or live fetuses; the body weight of live fetuses; the incidence of external, visceral, or skeletal anomalies; or delivery, nursing, lactation, or neonatal development. No abnormality in parturition, weaning status, or growth of newborns was observed at the maternal toxic dose of 1%. Based on the available reviews, this study appears to have identified a NOAEL of 1% (500 mg/kg-d) in the diet for developmental effects. Stump (1999) conducted a developmental toxicity study in rats. Groups of eight female Crl:CD®(SD)IGS BR rats were dosed orally by gavage with 125, 250, 500, 750, or 1,000 mg/kg-d of HBCD dissolved in corn oil. A concurrent control group received corn oil. During gestation, all females were observed twice daily for appearance and behavior, and body weight and food consumption were recorded. On d 20 of gestation, laparohysterectomy was performed, uteri and ovaries were examined, and the numbers of fetuses, early and late
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Toxicological Risks of Selected Flame-Retardant Chemicals resorptions, total implantations, and corpora lutea were recorded. Maternal animals were autopsied and fetuses were examined. Mean maternal body weights were significantly increased in the 250-, 500-, 750-, and 1,000-mg/kg-d dose groups in comparison to controls during gestation d 19–20; however, this increase may be attributed to elevated food consumption observed on d 19–20. No dose-related effects were observed for the mean percentage of viable fetuses per litter or for postimplanation losses. One fetus in the 125-mg/kg-d dose group had multiple external malformations (mandibular micrognathia, microphthalmia [unilateral], and aglossia) that were considered spontaneous in origin. No other external malformations or developmental variations were observed in fetuses. Based on the findings of this study, a NOAEL of 1,000 mg/kg-d was determined for developmental effects. Cancer Kurokawa et al. (Marcia Hardy, Albermarle Corporation, Pers. Commun., August 3, 1999), (see Systemic Effects section) fed mice diets containing 0, 100, 1,000, or 10,000 ppm (equivalent to about 0, 13, 130, or 1,300 mg/kg-d) for 18 mo. For the male mice, hypertrophy and vacuolization/fatty changes in the liver were observed in the 1,000- and 10,000-ppm dose groups, and an increase in altered foci was seen in the 1,000-ppm group but not at the 10,000-ppm level. No changes were observed in the female mice. Since no correlation was observed between the dosage and incidence of neoplastic changes in the liver in male mice, the study authors concluded there was no evidence of carcinogenicity. Other Systemic Effects No studies were identified that examined immunological or neurological effects following oral exposure to HBCD. Genotoxicity The weight of the evidence suggests that HBCD is not genotoxic. Negative results have been reported for HBCD in assays for mutagenicity in yeast and Salmonella, and for chromosonal aberrations in human peripheral blood lymphocytes at doses up to the limits of solubility and toxicity (Brusick 1976; Baskin and Phillips 1977; Oesch 1978; Shoichet and Ehrlich 1978; Zeiger et al.
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Toxicological Risks of Selected Flame-Retardant Chemicals 1987; Pinto 1989; Gudi and Schadly 1996). However, a study by Helleday et al. (1999) identified statistically significant increases in recombination frequency in the Sp5 and SPD8 cell lines. QUANTITATIVE TOXICITY ASSESSMENT2 Noncancer Dermal Assessment The limited dermal data available suggest that HBCD is at most a mild skin irritant and a mild allergen, if allergenic at all (Momma et al. 1993; Nakamura et al. 1994). Acute exposure to high dermal doses of HBCD apparently produced systemic toxicity (diarrhea and slight weight loss) in rabbits (Dean and Leong 1977), but the systemic effects of long-term dermal exposure have not been published. The lack of information on systemic effects from subchronic or chronic dermal exposure to HBCD precludes the derivation of an RfD based on dermal toxicity data. However, the oral RfD was used in this risk assessment in place of the dermal RfD as the best estimate of internal dose from dermal exposure (derivation of the oral RfD is presented below). Inhalation RfC The subcommittee did not identify any inhalation studies of sufficient duration (i.e., subchronic or chronic) for deriving an RfC. The available data are limited to two acute studies (Dean and Leong 1977; Lewis and Palanker 1978). The subcommittee concluded that there are insufficient inhalation toxicity data on HBCD to derive an inhalation RfC. Oral RfD On the basis of its review of the oral toxicity data, the subcommittee determined that the 13-wk rat study by Zeller and Kirsch (1970) is appropriate for deriving an RfD for HBCD (see Systemic Effects section for additional de- 2 In this section, the subcommittee reviewed the data on toxicity of HBCD, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Hatlelid 1999).
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Toxicological Risks of Selected Flame-Retardant Chemicals tails). The 925-mg/kg-d dose level was chosen as the LOAEL based on increased liver weight (absolute and relative in both sexes) accompanied by an increased incidence of distinctly abnormal fatty accumulation in the liver and, in males, a small reduction in body weight gain. The 450-mg/kg-d dose level (the mean value for males and females) was selected as the NOAEL because the more subtle changes in liver weight and histology at this dose level are not considered to be adverse effects. An uncertainty factor of 3,000 was applied (10 for extrapolation from rats to humans, 10 for intraspecies variation, 10 for extrapolation from subchronic to chronic duration, and 3 to account for database deficiencies including lack of a two-generation reproductive study and a developmental toxicity study in a second species). Therefore, based on a NOAEL of 450 mg/kg-d and an uncertainty factor of 3,000, an RfD of 0.2 mg/kg-d was calculated for HBCD (see Table 4–4). Confidence in the critical study (Zeller and Kirsch 1970 is medium. The study included an adequate number of rats of both sexes and investigated a variety of endpoints, but reporting of experimental methods and results was only marginally adequate. Confidence in the database is low because of the lack of availability of other subchronic/chronic studies. Therefore, confidence in the oral RfD is low. Cancer In an 18-mo feeding study of HBCD in mice, Kurokawa et al. (Marcia Hardy, Albermarle Corporation, pers. commun., August 3, 1999) found no TABLE 4–4 Oral Reference Dose for HBCD Critical effect Species Effect level (mg/kg-d) Uncertainty factors RfD (mg/kg-d) Reference Increased liver weights, accompanied by abnormal fatty accumulation observed at the LOAEL of 925 mg/kg-d Male and female rats NOAEL: 450 UFA: 10 UFH: 10 UFS: 10 UFD: 3 Total: 3,000 0.2 Zeller and Kirsch (1970) NOAEL, no-observed-adverse-effect level; RfD, reference dose; UFA, extrapolation from animals to humans; UFH, intraspecies variability; UFS, extrapolation from a study of less-than-lifetime duration; UFD, inadequate or deficient toxicity database.
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Toxicological Risks of Selected Flame-Retardant Chemicals evidence of carcinogenicity at dietary concentrations up to 10,000 ppm of HBCD. The available genotoxicity data suggest that HBCD is not genotoxic. The potential carcinogenicity of HBCD in humans cannot be determined based on inadequate data for an assessment of carcinogenicity via the dermal, inhalation, or oral routes. EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Assessment Dermal Exposure The assessment of noncancer risk for the dermal route of exposure is based on the scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery backcoated with HBCD and also assumes that 1/4th of the upper torso is in contact with the upholstery, and clothing presents no barrier. Exposure to other chemicals present in the backcoating was not included in this assessment. First Iteration As a first estimate of exposure, it was assumed that the skin and clothing of the person sitting on the couch, and the fabric of the couch, would present no barrier to movement of HBCD. In addition, it was assumed that there would be sufficient water present (e.g. from sweat) to allow dissolution of the HBCD in the water, and transfer to the skin and into the body of the sitting individual. The only limiting factor on the transfer rate using these assumptions results from the limited dissolution rate from the fabric—all the HBCD that dissolves is assumed to be absorbed immediately by the sitting individual. Dermal exposure was estimated using Equation 1 in Chapter 3. For this calculation, the subcommittee estimated an upholstery application rate (Sa) for HBCD of 5 mg/cm2. The extraction rate (µw) by water for HBCD was estimated to be 0.025/d based on extraction data for HBCD in polyester fiber (McIntyre et al. 1995). This release rate was calculated as 0.04/d at 28°C from the fiber, with a correction from fiber to film of a factor of 0.63 (2d/2πR for film thickness d, fiber radius R). Using these values, the estimated dermal absorbed dose rate was determined to be 0.98 mg/kg-d. Although lack of sufficient data precludes deriving a dermal RfD, the oral RfD (0.2 mg/kg-d) is used as the best estimate of internal
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Toxicological Risks of Selected Flame-Retardant Chemicals dose from dermal exposure to calculate the hazard index. The hazard index of 4.9, derived by dividing the dermal absorbed dose rate of 0.98 mg/kg-d by the oral RfD of 0.2 mg/kg-d, indicates that HBCD might pose a noncancer risk by the dermal absorption route when used as an upholstery fabric flame retardant. Therefore an alternative iteration of the exposure assessment was performed. Alternative Iteration For the alternative iteration of the dermal assessment, the same exposure assumptions were made as in the first iteration, except that the assumption of immediate absorption of all the HBCD that dissolves was modified. Instead, an estimate of the rate that HBCD could penetrate the skin was determined, assuming that HBCD dissolves up to its solubility limit in water. This rate of penetration was then factored into the exposure assessment. The rate of penetration of a chemical through skin may be estimated using the skin permeability coefficient (Kp, with dimensions of velocity)—the total mass penetration rate is the product of water concentration, permeability coefficient, and skin area. This coefficient has not been measured for HBCD. However, it was estimated from the octanol-water partition coefficient (Kow, dimensionless) and molecular weight (m, mass/unit amount of substance) using a correlation (Potts and Guy 1992) based on Equation 2 in Chapter 3. The value estimated from this correlation is 4.99×10−2 cm/d for HBCD. Using equation (5) in Chapter 3 in conjunction with the permeability coefficient (4.99×10−2 cm/d) and the water solubility specific to HBCD (3.40×10−3 mg/L), the dose rate of HBCD, using this alternative iteration, was estimated to be 1.33×10−6 mg/kg-d. The hazard index was then calculated by dividing the dermal absorbed dose rate (1.33×10−6 mg/kg-d) by the oral RfD (0.2 mg/kg-d), as the best estimate for internal dose from dermal exposure. The hazard index of 6.67 ×10−6 indicates that HBCD used as an upholstery fabric flame retardant is not likely to pose a noncancer risk via the dermal exposure route. Inhalation Exposure Particles Inhalation exposure to HBCD in the particulate phase was calculated using the scenario described in Chapter 3. This scenario assumes that a person spends 1/4th of his or her life in a room with low air-change rates (0.25/hr) and with a relatively large amount of fabric upholstery treated with HBCD (30 m2 in a
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Toxicological Risks of Selected Flame-Retardant Chemicals 30-m3 room), with this treatment gradually being worn away over 25% of its surface to 50% of its initial quantity over the 15-yr lifetime of the fabric. A small fraction, 1%, of the worn-off HBCD is released into the indoor air as small particles that may be inhaled. Particle exposure was estimated using Equations 4 through 6 in Chapter 3. The release rate (µr) for HBCD from upholstery, 2.3×10−7/d (Equation 5), was used in conjunction with the upholstery application rate (Sa for HBCD of 5 mg/cm2 to calculate a room airborne particulate concentration of 1.9 µg/m3 (Equation 4). Factoring in the fraction of a day a person spends in the room containing upholstery (0.25), the time-average exposure concentration was determined to be 0.48 µg/m3 (Equation 6). For the purpose of estimating a hazard index for the inhalation of HBCD and in the absence of relevant inhalation exposure data, the subcommittee chose to estimate the inhalation RfC from the oral RfD. The subcommittee, however, recognizes that this is not an ideal approach and also recognizes that the estimated RfC might be considerably different than the actual reference concentration (if inhalation data were available). Extrapolating from one route of exposure (oral) to another (inhalation) requires specific knowledge about the uptake kinetics into the body by each exposure route, including potential binding to cellular sites. The subcommittee believes that its extrapolation of the oral RfD to the inhalation RfC is highly conservative; it assumes that all of the inhaled compound is deposited in the respiratory tract and is completely absorbed into the blood. The NRC Committee on Toxicology (NRC 1985) has used this approach when inhalation exposure data were insufficient to derive inhalation exposure levels. The subcommittee believes that such an approach is justified for conservatively estimating the toxicological risk from exposure to HBCD. This RfC should be used as an interim or provisional level until relevant data become available for the derivation of an inhalation RfC for calculating the hazard index. Therefore, a provisional RfC of 0.7 mg/m3 was derived by using the oral RfD of 0.2 mg/kg-d and Equation 7 in Chapter 3. A hazard index of 6.8×10−4 was estimated by dividing the exposure concentration (0.48 µg/m3) by the provisional inhalation RfC (0.7 mg/m3). This indicates that under the worst-case exposure scenario, HBCD, used as an upholstery flame retardant, is not likely to pose noncancer risk via inhalation of HBCD in the particulate phase. Vapors In addition to the possibility of release of HBCD in particles worn from upholstery fabric, the subcommittee considered the possibility of its release by
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Toxicological Risks of Selected Flame-Retardant Chemicals evaporation. The approach to estimate vapor exposure is described in Chapter 3 and uses a scenario similar to that previously described for exposure to HBCD in the particulate phase. Using Equations 8 through 10 in conjunction with the saturation vapor concentration (Cv) (0.016 mg/m3) and the application density (Sa) of 5 mg/cm2 for HBCD, the equilibrium room-air concentration of HBCD was estimated to be 0.014 mg/m3. From Equation 11, it was determined that this vapor concentration could be maintained for approximately 1,200 yr. Factoring in the fraction of a day a person spends in the room containing upholstered fabric (0.25), the time-average exposure concentration was determined to be 3.4 µg/m3. Division of this exposure concentration (3.4 µg/m3) by the provisional inhalation RfC (0.7 mg/m3) results in a hazard index of 5×10−3, indicating that under the worst-case scenario, exposure to HBCD, used as an upholstery-fabric flame retardant, is not likely to pose a noncancer risk via the inhalation route, when exposures occur in the vapor phase. Oral Exposure The assessment of the noncancer risk for the oral exposure route is based on the scenario described in Chapter 3. This scenario assumes a child is exposed to HBCD through sucking on 50 cm2 of fabric backcoated with HBCD daily for 2 yr, 1 hr/d. The dose rate to the child was calculated using Equation 15 in Chapter 3. Using these values, the average oral dose rate was estimated to be 0.026 mg/kg-d, compared with an oral RfD of 0.2 mg/kg-d, giving a hazard index of 0.13. The subcommittee concludes that HBCD used as an upholstery-fabric flame retardant is not likely to pose a noncancer risk by the oral route. Cancer Assessment Based on inadequate carcinogenicity data from any route of exposure, the subcommittee concluded that the potential carcinogenicity of HBCD cannot be determined. RECOMMENDATIONS FROM OTHER ORGANIZATIONS Occupational exposure limits for HBCD have not been established by the Occupational Safety and Health Administration (OSHA), the American Confer-
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Toxicological Risks of Selected Flame-Retardant Chemicals ence of Government Industrial Hygienists (ACGIH), or the National Institute of Occupational Safety and Health (NIOSH). DATA GAPS AND RESEARCH NEEDS There are no subchronic or chronic inhalation or dermal bioassays to evaluate systemic toxicity or carcinogenicity of HBCD. There are no dermal absorption studies. HBCD has a high octanol water partition coefficient, low vapor pressure, and low solubility in water. It is used as a fabric backcoating and is encapsulated in a polymer matrix. Therefore, direct exposure is likely to be minimal. Based on existing review of toxicity and use information, the conservative exposure assumptions, and a hazard index of less than 1 for all exposure routes, the subcommittee concludes that no further research is needed for assessing health risks from HBCD. REFERENCES Baskin, A.D., and B.M.Phillips 1977. Mutagenicity of Two Lots of FM-100, Lot 53 and Residue of Lot 3322 in the Absence and Presence of Metabolic Activation. Industrial Bio-Test Laboratories, Northbrook, IL. EPA/OTS Doc. #86–900000267. Brusick, D. 1976. Mutagenicity Evaluation of 421–32B: Final Report. LBI Project No. 2547. Litton Bionetics Inc., Kensington, Md. Sponsored by Ciba-Geigy Corp., Ardsley, NY. EPA/OTS Doc. #86–900000265. Chengelis, C.P. 1997. A 28-day Repeated Dose Oral Toxicity Study of HBCD in Rats. Wil Research Laboratories, Inc., Ashland, OH. Laboratory Study No. WIL-186004. Sponsored by Chemical Manufacturers Association, Brominated Flame Retardant Industry Panel, Arlington, VA. Sponsor Project No. BFRIP 2.0-WIL HBCD. ChemID. 1999. Chemical ID Data Base. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. Crown, S. 1984. HBCD (FR—1206) Primary Skin Irritation Study in Rabbits. LSRI Report No. DSB/059/FR. Life Science Research Israel, Ltd., Ness Ziona, Israel. Sponsored by Dead Sea Bromine Works Ltd., Beer Sheva, Israel. EPA/OTS Doc. #86–900000433. Dean, W.P., and B.K.J.Leong. 1977. Acute toxicity studies in rabbits and rats. International Research and Development Corp. Sponsor: Velsicol Chemical Corporation. Study No. 163–499. EPA/OTS Doc. #86–900000266. FRCA (Fire Retardant Chemicals Association). 1998. Textile Flame Retardant Applications by Product Classes for 1997 Within and Outside of the United States. Submitted to: U.S. Consumer Product Safety Commission. Prepared by: Fire Retardant Chemicals Association. Gudi, R., and E.H.Schadly. 1996. Chromosome Aberrations in Human Peripheral
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Toxicological Risks of Selected Flame-Retardant Chemicals Blood Lymphocytes. Microbiological Associates, Inc., Rockville, Md. Study No. G96AO61.342. Sponsor: Chemical Manufacturers Association, Arlington, VA. Hatlelid, K. 1999. Toxicity Review of Hexabromocyclododecane. Memorandum, dated March 2, 1999, from Kristina Hatlelid, Toxicologist, Division of Health Sciences to Ronald L.Medford, Assistant Executive Director for Hazard Identification and Reduction. U.S. Consumer Product Safety Commission, Washington, DC. Helleday, T., K.-L. Tuominen, A.Begman, and D.Jenssen. 1999. Brominated flame retardants induce intragenic recombination in mammalian cells. Mutat. Res. 439:137–147. Lewis, C.A., and A.L.Palanker. 1978. Technical and Toxicity Data on Brominated Flame Retardants Including Hexabromocyclododecane. Consumer Product Testing Co. Inc., Fairfield, N.J. Experiment Reference No. 78385–1 and 78385–2. Sponsored by Saytech Inc., Sayreville, NJ. EPA/OTS Doc. #FYI-OTS-0794–0947. MacGregor, J.A., and W.B.Nixon. 1997. Hexabromocyclododecane (HBCD): Determination of n-Octanol/Water Partition Coefficient. Wildlife International LTD. Project No. 439C-104. Sponsor: Chemical Manufacturers Association, Brominated Flame Retardant Industry Panel, Arlington, VA. McDonnell, M.E. 1972. Studies on Decabromodiphenyl Ether, Hexabromocyclododecane and 4-vinylcyclohexane. Haskell Laboratory Report No. 185–72. Haskell Laboratories. EPA/OTS Doc. #86–900000119S. McIntyre, J.E., I.Holme, and O.K.Sunmonu. 1995. The desorption of model compounds from poly(ethylene terephthalate) fibre. Colourage 41(13)77–81. Microbiological Associates. 1996. Maximization Test in Guinea Pigs. Microbiological Associates Study No. M96AO61.1X64. Sponsored by Chemical Manufacturers Association, Arlington, VA. Momma, J., M.Kaniwa, H.Sekiguchi, K.Ohno, Y.Kawasaki, M.Tsuda, A.Nakamura, and Y.Kurokawa. 1993. Dermatological evaluation of a flame retardant, hexabromocyclododecane (HBCD) on guinea pig by using the primary irritation, sensitization, phototoxicity and photosensitization of skin. [Article in Japanese; English abstract]. Eisei Shikenjo Hokoku 111:18–24. Murai, T., H.Kawasaki, and S.Kanoh. 1985. Studies on the toxicity of insecticides and food additives in pregnant rats. (7) Fetal toxicity of hexabromocyclododecane. [Article in Japanese]. Pharacometrics 29(6):981–986. Nakamura, A., J.Momma, H.Sekiguchi, T.Noda, T.Yamano, M.-A.Kaniwa, S. Kojima, M.Tsuda, and Y.Kurokawa. 1994. A new protocol and criteria for quantitative determination of sensitization potencies of chemicals by guinea pig maximization test. Contact Dermatitis 31(2):72–85. Nissimov, S. 1984. Acute Oral Range Finding Study in the Rat. LSRI Schedule No. DSB/052/HBCD. Life Science Research Israel, Ltd., Ness Ziona, Israel. Sponsored by Dead Sea Bromine Works Ltd., Beer Sheva, Israel. EPA/OTS Doc. #86–900000433. NRC (National Research Council). 1985. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 5. Committee on Toxicology. Board on Toxicology and Environmental Health Hazards, National Research Council. Washington, DC: National Academy Press.
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Representative terms from entire chapter: