19
Chlorinated Paraffins

THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on chlorinated paraffins.1 The subcommittee used that information to characterize the health risk from exposure to chlorinated paraffins. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to chlorinated paraffins.

PHYSICAL AND CHEMICAL PROPERTIES

The term “chlorinated paraffins” is commonly applied to chlorinated n-alkanes manufactured from straight-chain hydrocarbons (n-paraffins). Commercial chlorinated paraffins are mixtures that contain chlorinated paraffins of several carbon chain lengths with varying degrees of chlorination. Commercial chlorinated paraffins have carbon chain lengths between 10 and 38 carbon atoms and percent chlorination between 10% and 72%.

Chlorinated paraffins are named according to their average n-paraffin chain length and percent chlorination. For instance, a chlorinated paraffin that has an

1  

Category includes chlorinated α-olefins which do not differ significantly from chlorinated paraffins with regard to structure, physical characteristics, or toxicity (EPA 1994).



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Toxicological Risks of Selected Flame-Retardant Chemicals 19 Chlorinated Paraffins THIS chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological, and exposure data on chlorinated paraffins.1 The subcommittee used that information to characterize the health risk from exposure to chlorinated paraffins. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to chlorinated paraffins. PHYSICAL AND CHEMICAL PROPERTIES The term “chlorinated paraffins” is commonly applied to chlorinated n-alkanes manufactured from straight-chain hydrocarbons (n-paraffins). Commercial chlorinated paraffins are mixtures that contain chlorinated paraffins of several carbon chain lengths with varying degrees of chlorination. Commercial chlorinated paraffins have carbon chain lengths between 10 and 38 carbon atoms and percent chlorination between 10% and 72%. Chlorinated paraffins are named according to their average n-paraffin chain length and percent chlorination. For instance, a chlorinated paraffin that has an 1   Category includes chlorinated α-olefins which do not differ significantly from chlorinated paraffins with regard to structure, physical characteristics, or toxicity (EPA 1994).

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Toxicological Risks of Selected Flame-Retardant Chemicals average carbon chain length of 24 carbons and is 70% chlorine would be referred to as “C24, 70% chlorine.” The name may also include the range of carbon chains used in the manufacture of the mixture (e.g. C10–13, 58% chlorine). Chlorinated paraffins with average carbon chain lengths of 10–13 carbons (C10–13) are referred to as short-chain chlorinated paraffins. C14–20 chlorinated paraffins are categorized as medium-chain paraffins, while C20–30 chlorinated paraffins are referred to as long-chain paraffins. If chlorinated paraffins are used as flame retardants in residential furniture, long-chain chlorinated paraffins with 70% chlorination by weight are most likely to be used in a fabric backcoating application (Dr. Gary Stevens, University of Surrey, personal communication). The physical and chemical properties of chlorinated paraffins vary depending on their carbon chain length and degree of chlorination (see Table 19–1). Chlorinated paraffins are insoluble in water or lower alcohols but can form emulsions or suspensions (EPA 1975). Chlorinated paraffins with low chlorine content (i.e., 35%) are usually mobile liquids. Chlorinated paraffins with higher degrees of chlorination (i.e., 40–60%) are viscous oils, while even higher chlorination of n-paraffins results in a waxy solid with a glassy sheen. Commercial-grade chlorinated paraffins contain several contaminants. Alkenes (i.e., olefins) are unavoidably formed during dehydrohalogenation of chlorinated paraffins. Isoparaffins comprise about 1% of a chlorinated paraffin mixture; aromatic compounds are present at levels usually less than 100 ppm. Carbon tetrachloride, methylene chloride, chloroform, perchloroethylene, and metals have been detected in trace amounts (0.1–7.4 ppm) in chlorinated paraf- TABLE 19–1 Physical and Chemical Properties of Representative Chlorinated Paraffins (adapted from IARC 1990) Paraffin feedstock Average chain length Chlorine content (%) Density (25°C, g/mL) Viscosity (25°C, P) Pour-pointa (°C) Heat stability (% HCl after 4 hr at 175°C) C10-C13 (short-chain) C12 60 1.36 35 −10 0.10 C13-C17 (medium chain) C15 52 1.25 16 −10 0.10 C17-C30 (long-chain) C24 39 42 48 70 1.12 1.17 1.23 1.65 7 30 125 Solid −20 0 10 NA 0.20 0.20 0.25 0.15 aLowest temperature at which a substance flows under a specific condition.

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Toxicological Risks of Selected Flame-Retardant Chemicals fins (EPA 1975). Epoxidized soya bean oils, pentaerythritol, organometallic tin compounds, lead oxide, and cadmium compounds are added as stabilizers to chlorinated paraffins (IARC 1990). OCCURRENCE AND USE Approximately 70 million pounds of chlorinated paraffins were produced in the U.S. in 1998 (Chlorinated Paraffins Industry Association 1999). About half of all chlorinated paraffins consumed in the U.S. are used as extreme-pressure lubricant additives in the metal working industry (IARC 1990). Chlorinated paraffins have been used as flame retardants in commercial furniture, particularly in automobile upholstery. Chlorinated paraffins (CxH(2x−y+2)Cly) have been proposed as possible candidates for use as flame retardants in residential upholstered furniture in the U.S. (Fire Retardant Chemicals Association 1998). A recent survey of North American chlorinated paraffin industry did not identify textiles as a major area for use of chlorinated paraffins as flame retardants (Chlorinated Paraffins Industry Association 1999). Currently, chlorinated paraffins are not used as flame retardants in residential furniture in the U.S. (Fire Retardant Chemicals Association 1998) but are used as a flame-retardant backcoating for residential furniture upholstery in the United Kingdom. For flame-retardant applications, chlorinated paraffins with approximately 70% chlorine are used. The carbon chain length of chlorinated paraffins used in flame retardants is dependent on the commercial application. C10–13, 70% chlorine, is typically used as a flame retardant (FR) in rubber and soft plastics. C18–30, 70% chlorine, is used in rigid plastics such as polyesters and polystyrene (IARC 1990). Long-chain, 70% chlorinated paraffins are used in upholstery backcoating in combination with antimony trioxide. TOXICOKINETICS Absorption Short-chain Chlorinated Paraffins No absorption data were located for any short-chain chlorinated paraffin following exposure by the dermal, oral, or inhalation routes. Medium-chain Chlorinated Paraffins C14–17, 52% chlorine, was not absorbed through human skin in vitro at any detectable level after 56 hr of continuous contact (Scott 1989). About 0.70%

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Toxicological Risks of Selected Flame-Retardant Chemicals (Standard deviation [SD]=0.15%) was recovered in excreta, expired air, and tissues of male Sprague-Dawley rats 96 hr after dermal application of 66 mg/cm2 (≈2.0 g/kg body weight) of C18, 50–53% chlorine (Yang et al. 1987). About 25% of an oral dose of 500 mg/kg C18, 50% chlorine, was recovered after 24 hr in the excreta and 86% at 96 hr in Sprague-Dawley rats indicating that medium-chain chlorinated paraffin is absorbed to some extent through the rat GI tract. Long-chain Chlorinated Paraffins Less than 0.1% of a topically applied dose of C28, 47% chlorine (66 mg/cm2 or 2.0 g/kg body weight), was recovered after 96 hr in the excreta of Sprague-Dawley rats (Yang et al. 1987). Distribution and Excretion Short-chain Chlorinated Paraffins Serrone et al. (1987)2 reported that the highest levels of radioactivity in rats were found in the liver, kidney, adipose tissue, and the ovary following oral administration of C10–13, 58% chlorine. Most of the dose was excreted in the feces. Radiolabeled C12, 17.4%, 55.9%, and 68.5% chlorination, were found to distribute to the liver, body fat, intestinal mucosa, bone marrow, salivary glands, and thymus within 24 hr of intravenous injection or oral gavage in C57Bl mice (Darnerud et al. 1982). Radioactivity continued to be detected in the liver, fat, adrenal cortex, and gonads after 4–12 d of exposure and retention in the liver and body fat increased with degree of chlorination. Intravenous injection of C12, 17.4% and 55.9% chlorine, resulted in the retention of radioactivity in the central nervous system 30–60 d after injection. About 52% of C12, 17.4% chlorination, was converted to CO2 12 hr after administration and about 32% and 8% of the administered doses of C12, 55.9% chlorination, and C12, 68.5% chlorination, respectively, were converted to CO2 over the same time period (Darnerud et al. 1982). 2   Summary of studies conducted by International Research Development Corporation for the Chlorinated Paraffin Manufacturers Toxicology Testing Consortium (Aochem France, Caffaro Italy, Diamond Shamrock Chemical USA, Dover Chemical USA, Dynamit-Nobel AG Germany, Hercules Inc. USA, Hoechst AG Germany, Huls AG Germany, Imperial Chemical Industries plc UK, Keil Chemical USA, Neville Chemical USA, Rhone-Poulenc France, and Witco Chemical USA).

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Toxicological Risks of Selected Flame-Retardant Chemicals Medium-chain Chlorinated Paraffins Birtley et al. (1980) reported that radio-labeled chlorinated paraffin was distributed to the body fat and liver of Wistar rats fed either 0.4 or 40 ppm of C14–17, 52% chlorine, in their diet for 10 or 8 wk, respectively. Equilibrium was reached in the liver and body fat within 1 and 7 wk, respectively. No radioactivity was detected in the brain or adrenal glands. Radioactivity decreased to below background levels in the livers of the 0.4-ppm dose group within 3 wk after discontinuation of exposure. The half-life for radioactivity in the abdominal fat was estimated to be 8 wk. No attempts were made to chemically characterize the radioactivity in any tissue. 14C-C16, 34% chlorination, was readily absorbed and distributed to the intestinal mucosa, bone marrow, and exocrine glands when fed to C57B1 mice (Darnerud and Brandt 1982). When 14C-C16, 34% chlorination was given by intravenous administration, 33% of the dose was exhaled as CO2 within 12 hr and 44% thereafter after administration. Radiolabeled C16, 69% chlorine (1.6 µmol/kg), was distributed to the bile, liver, kidney, and intestinal contents in C57B1 mice and quail within 24 hr after oral administration (Biessmann et al. 1983). Radioactivity was retained in the fat for >12 d and >30 d for quail and mice, respectively. In mice, radioactivity accumulated in the corpora lutea 1–4 d after exposure. In both species, 66 and 43 percent of radioactivity was eliminated in the feces following intravenous and oral administration, respectively, within 96 hr of administration. About 1% of an administered dose of C16, 69% chlorination, was converted to CO2 by C57B1 mice within 8 hr after gavage or intravenous injection. Urinary excretion was 3% in both cases. In quail, a combined 58% of the administered dose was eliminated in the urine and feces. Radioactivity was detected in the liver, kidney, adipose tissue, and ovary in F-344 rats administered radio-labeled C14–17, 52% chlorine, by oral gavage (Serrone et al. 1987). Most of the administered dose was excreted in the feces. Poon et al. (1995) reports that radioactivity accumulated in both the liver and fat of rats fed 5–5,000 ppm (0.3–300.0 mg/kg-d, estimated dose levels) C14–17, 52% chlorine, in their food for 90 d. Levels in the liver were approximately 20–60 times higher than in feed while radioactivity levels in fat were equal to those in the diet when measured at d 90 of the study. Yang et al. (1987) found that about 3.3% of the radioactivity from a single oral dose of medium-chain paraffin (500 mg/kg) was distributed to the liver, intestines, and the fat 96 hr after dosing. About 0.12% of the radioactivity of a topically applied dose of 66 mg/cm2 (≈2.0 g/kg body weight) of [14C]-labeled C18, 50–53% chlorine, was present in intestines, liver, and fat, of male and female rats 96 hr after exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals Long-chain Chlorinated Paraffins Radioactivity was detected in the liver, ovaries, blood, and adipose tissue in F-344 rats administered C20–30, 43% chlorine, or C22–26, 70% chlorine, by oral gavage (Serrone et al. 1987). Radioactivity levels were highest in the liver in both males and females. Radioactivity (i.e., the radio-labeled compound) was slowly eliminated from these animals, but no elimination rates or half-lives were determined. Metabolism No studies were found that attempted to identify the primary urinary metabolites of chlorinated paraffins formed in rodents or humans following exposure by any route. Ahlman et al. (1986) reported that injection of the radio-labeled short-chain chlorinated paraffin C16, 65% chlorine, into the portal vein of Sprague-Dawley rats resulted in the excretion into the bile of N-acetylcysteine and glutathione conjugates. Less than 3% of the radioactivity that was excreted into the bile represented the unchanged parent compound. Darnerud (1984) found that pretreatment of C57B1 mice with P450 inhibitors 30 min before administration of [14C]-C12, 69% chlorine, significantly decreased the rate and the amount of degradation of this compound to 14CO2. Pretreatment of mice with the P450 inducer phenobarbital significantly increased the rate and the amount of 14CO2 formed. Pretreatment with P450 inducers 3-methylcholanthrene or Arochlor 1254 did not increase [14C]-C12, 69% chlorine, degradation to 14CO2. Administration of C14–17, 52% chlorine, to C57B1 mice for 3 consecutive days enhanced the metabolism of C14–17, 52% chlorine, to 14CO2. Pretreatment with C10–13 did not significantly affect the rate of metabolism of C14–17, 52% chlorine. Further studies showed that piperonyl butoxide-induced P450 enzymes may be important in the metabolism of highly chlorinated paraffins. Enzyme Induction Induction of enzyme activity in rats following administration of chlorinated paraffin has been reported by a number of authors. Epoxide hydrolase and glutathione transferase activity was induced in male Sprague-Dawley rats injected with C14–17, 58% chlorination; C10–23, 70% chlorination; or C23, 70% chlorination; but not C22–26, 42% chlorination, 1 g/kg-d for 5 d (Meijer et al. 1981). Hepatic uridine diphosphate (UDP)-glucuronosyltransferase and amino-

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Toxicological Risks of Selected Flame-Retardant Chemicals pyrine N-demethylase activities were increased in male and female Sprague-Dawley rats fed 5,000 ppm C14–17, 52% chlorination, in feed for 13 wk (Poon et al. 1995). However, no significant alterations in arylhydrocarbon hydroxylase and 7-ethoxyresorufin O-deethylation activities were observed in either sex. Nilsen et al. (1980, 1981) and Nilsen and Toftgard (1981) found that hepatic P450 protein content and liver weights were increased and deethylation activity was inhibited in rats 24 hr after intraperitoneal injection of short-chain chlorinated paraffin (Table 19–2). These effects were not observed for medium- or long-chain chlorinated paraffins. Microsomal glucuronidation of thyroxin (T4) was significantly increased in male rats treated with chlorinated paraffins by oral gavage (1 g/kg-d) for 14 d (Wyatt et al. 1993). The observed increase corresponded directly with statistically significant increases in plasma thyroid stimulating hormone (TSH) and enzyme activity characteristic of peroxisome proliferation. Mice receiving similar treatment were comparably more sensitive for these effects than rats. The authors concluded that increased T4 glucuronidation levels could have caused the thyroid neoplasia observed in rodents exposed to C12, 60% chlorination for 2 years (NTP 1986a). Elcombe et al., Zeneca Central Toxicology Laboratory (1999, unpublished material) reported that oral administration of C10–13, 56%chlorine; C10–13, 58% chlorine; or C14–17, 40% chlorine, for 14 d at 1 g/kg-d caused the induction of hepatic enzymes in male and female F-344 rats and B6C3F1 mice. Specifically, P450 4A1, 2B1, and 2B2 protein levels were elevated in treated animals. Ethoxycoumain-O-deethylation (ECOD), pentoxyresorufin-O-depentylation (PROD), lauryl acid hydroxylation (LAH), and liver β-oxidation activities were also increased following treatment. Increases in liver weight, hepatocellular hypertrophy, peroxisome proliferation, and proliferation of the smooth endoplasmic reticulum occurred in both rats and mice. In mice, PROD activities were not induced and only P450 4A1 protein levels were increased. No liver effects including enzyme induction were observed in male guinea pigs after oral administration of the aforementioned chlorinated paraffins for 14 consecutive days at 2 g/kg-d. Oral exposure to C20–30, 43% chlorine, did not increase hepatic microsomal P450 content or hepatic enzyme activities in mice or rats. The effects of oral administration of C20–30, 43% chlorine, was not assessed in male guinea pigs. S.C.Hasmall et al., Zeneca Central Toxicology Laboratory (1999, unpublished material), provided further evidence that male guinea pigs respond differently to C10–13, 58% chlorine, as compared with rats or mice. A statistically significant increase in hepatic p-nitrophenol-glucuronosyl transferase activity was observed in male guinea pigs given 1,000 mg/kg daily for 14 d. However,

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 19–2 Effect of Carbon Chain Length and Percent Chlorination on Liver Weight, P450 Content, and O-Deethylation of 7-Ethoxyresorufin in Rats Treated with Chlorinated Paraffins by Intraperitoneal Injection Substance Liver Weight/Body Weight Ratio nmol P450/mg Liver Protein O-Deethylation of 7-Ethoxyresorufin Short-chain chlorinated paraffins C10–13, 49% chlorine 0.048±0.002a 0.65±0.07 80±6 C10–13, 59% chlorine 0.046±0.002a 0.73±0.09a 39±5a C10–13, 71% chlorine 0.042±0.001a 0.71±0.05a 37±4a Medium-chain chlorinated paraffins C14–17, 50% chlorine 0.038±0.001a 0.62±0.08 84±6 Long-chain chlorinated paraffins C18–26, 49% chlorine 0.034±0.001 0.65±0.08 86±13 Controls 0.034±0.001 0.55±0.07 80±8 ap<0.05. Source: Adapted from Nilsen et al. 1980, 1981. neither liver β-oxidation nor T4-glucuronosyl transferase activities were affected as compared with nonexposed controls. Similar results were reported for cultured guinea pig hepatocytes exposed to C10–13, 58% chlorine (Williams et al., Zeneca Central Toxicology Laboratory, 1999, unpublished material). HAZARD IDENTIFICATION3 Chlorinated paraffins are complex mixtures that are expected to differ with respect to their chemical content between “batches” or “runs” and between manufacturers. Chlorinated paraffins may differ in the number of carbons in the chain, chlorine content, and trace contaminants. Therefore, any toxicological risk assessment should be based on toxicological data generated for the specific commercial chlorinated paraffin to be used as an FR in residential furniture. Ideally, separate risk assessments should be conducted for each commercial chlorinated paraffin using toxicological data specific for that particular mixture. 3   In this section, the subcommittee reviewed toxicity data on chlorinated paraffins, 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 Exposure Irritation Birtley et al. (1980) assessed the dermal irritancy of seven classes of chlorinated paraffins in female Wistar rats (see Table 19–3). Topical application of 0.1 mL of chlorinated paraffin every other day for up to 6 d produced varying degrees of skin irritation in most cases. Chlorinated paraffins containing 10–13 and 14–17 carbons produced mild skin irritation independent of the degree of chlorination. Moderate skin irritation was inconsistently observed for C10–13, 70% chlorination. Irritating chlorinated paraffins also produced mild erythema and desquamation responses by the third application. These responses improved with continued application. The authors noted that skin irritation may have been partly caused by chemical stabilizers. All chlorinated paraffins of longer chain length were characterized as nonirritating. In studies summarized by EPA (1975), Abasov (1970) reported that KhP 470 produced no marked effect when applied to the skin. Systemic Effects No subchronic or chronic toxicity studies were identified for chlorinated paraffins following dermal exposure. Available LD50 data for dermal application of chlorinated paraffins are summarized in Table 19–4. The dermal LD50 in rabbits for Chlorowax 500C (C12, 59% chlorine) was reported to be greater than 10 g/kg body weight (Diamond Chemical Co. 1975, as cited in EPA 1975). Birtley et al. (1980) reported no evidence of systemic toxicity in female Wistar rats topically treated with chlorinated paraffins (0.1 mL) every other day for up to 6 d with the chlorinated paraffins described in Table 19–3. However, TABLE 19–3 Summary of Chlorinated Paraffins Assessed for Dermal Toxicity by Birtley et al. (1980) in Female Wistar Rats Number of Carbon Atoms in n-Paraffin Chain Extent of Chlorination of n-Paraffin (by weight) 41–50% 51–60% 61–70% 10–13 X X X 14–17   X   20–30 X X X

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Toxicological Risks of Selected Flame-Retardant Chemicals the report does not specify which chlorinated paraffins were tested for systemic toxicity. Injection of male Sprague-Dawley rats with short- or medium-chain chlorinated paraffins produced various clinical and hepatic effects, mainly peroxisome proliferation (Nilsen et al. 1980, 1981; Nilsen and Toftgard 1981; Meijer et al. 1981). These studies are summarized in the Metabolism section. Neurological Effects Intravenous injection of mice with C10–13, 49% chlorination (300 mg/kg) produced a statistically significant decrease in motor capacity as compared with vehicle control mice (Eriksson and Kihlström 1985). Motor capacity was not significantly decreased in mice injected with this chlorinated paraffin at 30, 97.5, 165, or 232.5 mg/kg. Decreases in motor activity apparently did not occur in mice injected with C10–13, 70% chlorine, at 30, 97.5, 165, 232.5, or 300 mg/kg. The authors noted that at higher dose levels, both chlorinated paraffins caused an unwarranted cessation of movement (one forepaw in the air during walking). No other studies were found regarding the effects of chlorinated paraffins on the nervous system. Other Systemic Effects No studies were identified that investigated the immunological, reproductive, developmental, or carcinogenic effects of chlorinated paraffins following dermal exposure. Inhalation Exposure There were no clinical signs of toxicity in rats exposed to Chlorowax 500C at exposure concentration of 3.3 mg/L for one hr (Diamond Shamrock Chemical Company 1975, as reviewed by EPA 1975). No other studies were located that investigated the systemic toxicity of chlorinated paraffins following inhalation exposure. No studies were identified that investigated the immunological, neurological, reproductive, developmental, or carcinogenic effects of chlorinated paraffins following inhalation exposure.

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Toxicological Risks of Selected Flame-Retardant Chemicals TABLE 19–4 Acute and Short-term Toxicity Studies of Chlorinated Paraffins Duration, Route Effects NOAEL/LOAEL Reference Short-chain chlorinated paraffins C10–13, 56% Cl2 14 d, gavagea Significant increase in relative liver weights. Peroxisome proliferation, hepatocyte hypertrophy. Increase in total microsome P450 content. Increased hepatic P450 4A1, 2B1, and 2B2 protein levels. Induction of ECOD, PROD, LAH, and liver β-oxidation activities. ND Elcombe et al., Zeneca Central Toxicology Laboratory, 1999, unpublished material 14 d, gavagea Significant increase in relative liver weights, peroxisome proliferation, and hepatocyte hypertrophy. Total P450 microsomal content increased. Increased hepatic P450 4A1 protein levels. Induction of ECOD, LAH, and liver β-oxidation activities. ND Elcombe et al., Zeneca Central Toxicology Laboratory, 1999, unpublished material 14 d, gavagea Increase in relative liver weight. No changes in liver morphology. No enzyme activity induction (ECOD, PROD, EROD, LAH, β-oxidation). ND Elcombe et al., Zeneca Central Toxicology Laboratory, 1999, unpublished material 14 d, gavagea Statistically significant decreases in body weight gain, relative liver weight. Increase in p-nitrophenol-glucuronosyl transferase activity at 1,000 mg/kg-d. Neither liver β-oxidation nor T4-glucuronosyl transferase activities were affected at either dose levels as compared with nonexposed controls. ND S.C.Hasmall et al., Zeneca Central Toxicology Laboratory, 1999, unpublished material

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Toxicological Risks of Selected Flame-Retardant Chemicals hypertrophy and hyperplasia and the eventual formation of follicular cell carcinoma (Wyatt et al. 1993). Hypertrophy and hyperplasia of the thyroid have been reported to occur in F-344 rats exposed to short-chain chlorinated paraffins for 90 d (Serrone et al. 1987). At this time, there is no adequate explanation for the formation of kidney tumors observed in male rats. It has been suggested that an unidentified sex-specific protein may stimulate sustained DNA synthesis in the kidney following chronic administration of short-chain chlorinated paraffins (Wyatt et al. 1993). Increased protein accumulation has been observed in dosed males accompanied by nephropathy, manifested by increased incidences of regenerating tubules. Immunocytochemical staining for α2u-globulin in the tubules shows that this protein is present but is not the predominant protein that accumulates, and no hyaline droplets have been observed in male rats treated with high doses of short- or medium-chain chlorinated paraffins for 90 d (Wyatt et al. 1993). No hypothesis has been presented for the possible mechanisms associated with the increased incidence of alveolar and bronchiolar carcinomas in male mice or mononuclear cell leukemia in male rats. The subcommittee does acknowledge that these tumor types, along with kidney tumors in male rats, did not occur across species, and therefore less weight should be given to these findings in the evaluation of the carcinogenicity of C10–13, 58% chlorine. Medium-chain Chlorinated Paraffins Currently, there are no human or animal data available for evaluating the carcinogenicity of medium-chain chlorinated paraffins. Long-chain Chlorinated Paraffins Currently, there are no epidemiological or cancer bioassay data for long-chain chlorinated paraffins (C22–26) paraffins with 70% chlorination, which are the type of chlorinated paraffin that are most likely to be used as FRs in residential furniture. Meijer et al. (1981) tested a long-chain chlorinated paraffin of similar chemistry (C10–23, 70% chlorine) for mutagenicity in three strains of S. typhimurium and found that this compound was negative for mutagenicity at all concentrations tested in two of the three strains. A positive response was observed in one strain at the highest concentration tested, but this may have been a chance occurrence since no dose-response for mutagenicity was observed. The authors also point out that no toxic effects were seen suggesting

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Toxicological Risks of Selected Flame-Retardant Chemicals that this compound may not penetrate into bacterial cells. No other genotoxicity data are known to be available for long-chain chlorinated paraffins with 70% chlorination. The subcommittee believes that the best study available for evaluating the carcinogenicity of long-chain chlorinated paraffins with 70% chlorination is the NTP (1986b) rodent carcinogenicity bioassay for the long-chain chlorinated paraffin C22–26, 43% chlorine (see Table 19–7). In this bioassay, no tumor types were consistently elevated across species in F-344 rats and B6C3F1 mice administered C23, 43% chlorine, for 103 wk. In mice, there was a dose-related increase in the incidence of malignant lymphoma among males as compared with controls. The incidence of hepatocellular adenomas and carcinomas combined was elevated in female mice in the high-dose group, but the incidence of this tumor category was not significant across dose levels as determined by incidental tumor tests for trend. However, early mortality due to infection was common among females in both the treated and control groups and may have prevented the identification of increased incidences in late-forming tumor-types. In rats, the incidence of pheochromocytomas of the adrenal medulla was increased in females, and no tumor types were found to be significantly increased in F-344 males exposed to chlorinated paraffin as compared with controls. C22–26, 43% chlorine, was not genotoxic in the Ames assay with or without exogenous metabolic activation (NTP 1986b) and did not induce chromosomal aberrations in F-344 rats administered toxic doses (Serrone et al. 1987). Based on the animal and genotoxicity data for C22–26, 43% chlorine, the subcommittee concluded that there is limited evidence for its carcinogenicity in rodents. This conclusion is in agreement with that of IARC (1990) and EPA (1994). Derivation of a Cancer Potency Factor The subcommittee concluded that the derivation of cancer potency factor (i.e., 0.1/LED10) for long-chain chlorinated paraffins is not warranted based on the lack of cancer data for long-chain chlorinated paraffins, 70% chlorine, and the limited evidence for the carcinogenicity of C23, 43% chlorine. The subcommittee does acknowledge that there are adequate data for the carcinogenicity for C10–12, 60% chlorine, in rodents, but these chlorinated paraffins are not likely to be used as FRs in residential furniture. Therefore, the subcommittee concluded that the derivation of a cancer potency estimate for short-chain chlorinated paraffins was not necessary.

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Toxicological Risks of Selected Flame-Retardant Chemicals EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure Dermal exposure to chlorinated paraffins was estimated using the dermal exposure 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 chlorinated paraffins and also assumes 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 skin, clothing, and the upholstery did not impede dermal exposure to chlorinated paraffins present in the backcoating. It was also assumed that there would be sufficient water present from sweat to facilitate dissolution of chlorinated paraffins from the backcoating and absorption through the skin. In this scenario, only the dissolution rate of chlorinated paraffins from the backcoating is assumed to be the limiting factor in absorption by the body. It is assumed that all of the chlorinated paraffins that dissolves is immediately absorbed into the body by the sitting person. Dermal exposure was estimated using Equation 1 in Chapter 3. For this calculation, the subcommittee estimated an upholstery application rate (Sa) for chlorinated paraffins of 3 mg/cm2. The extraction rate (µw) for chlorinated paraffins was estimated to be 0.025 based on extraction data for hexabromocyclododecane in polyester fiber (McIntyre et al. 1995). The release rate from the fiber for estimating extraction was 0.04/d at 28°C calculated using the equation 2d/2 πR (d=film thickness, R=fiber radius) with a correction from fiber to film of a factor of 0.63. Using these assumptions, an estimated absorbed daily dose of 0.59 mg/kg was calculated for chlorinated paraffins. In the absence of a dermal RfD, the subcommittee believes it is appropriate to use the oral RfD for C22–26, 70% chlorine, as the best estimate of the internal dose from dermal exposure. A hazard index of 1.97 was calculated for this first iteration by dividing the estimated daily dermal dose of 0.59 mg/kg-d by the oral RfD for chlorinated paraffins of 0.3 mg/kg-d. This hazard index of 1.97 indicates that dermal exposures to long-chain chlorinated paraffins at the worst-case levels might be a health

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Toxicological Risks of Selected Flame-Retardant Chemicals concern. The subcommittee recommends that the dermal absorption of these substances from treated fabric be investigated. Alternative Iteration The estimated dermal daily dose for chlorinated paraffins can be calculated using an estimate of the dermal penetration rate for chlorinated paraffins (Chapter 3, Equations 2 and 3). Instead of assuming that all dissolved chlorinated paraffins immediately penetrates the skin and enters systemic circulation, it is assumed that the skin slows the absorption of chlorinated paraffins to a specific amount of chemical absorbed per unit of time. This estimate can be measured experimentally and is referred to as the skin permeability coefficient Kp. However, the dermal penetration constant for chlorinated paraffins has not been measured experimentally. However, Kp can be estimated from a correlation between the octanol-water partition coefficient (Kow) and molecular weight (mass/unit amount of substance) using Equation 2 in Chapter 3 yielding an alternate Kp of 5.77×10−5 cm/d. The water solubility of long-chain chlorinated paraffin, 70% chlorination, was not available. Therefore the alternative exposure estimate could not be calculated. However, it was determined that the calculated dose rate for chlorinated paraffins would only be a concern in this scenario if the water solubility of long-chain chlorinated paraffins exceeded 650 g/liter—which is not possible. Inhalation Exposure Particles Inhalation exposure estimates for chlorinated paraffins were calculated using the exposure scenario described in Chapter 3. This scenario assumes that a person spends 1/4th of his or her lifetime in a 30-m3 room containing 30 m2 of chlorinated paraffins-treated fabric and the room is assumed to have a air-change rate of 0.25/hr. It is also assumed that 50% of the chlorinated paraffins present in 25% of the surface area of the treated fabric is released over 15 yr and 1% of released particles are small enough to be inhaled. Particle exposure was estimated using Equations 4 and 5 in Chapter 3. The subcommittee estimated an upholstery application rate (Sa) for chlorinated paraffins of 3 mg/cm2. The release rate (µr) for chlorinated paraffins from upholstery fabric was estimated to be 2.3×10−7/d (see Chapter 3, Equation 5)

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Toxicological Risks of Selected Flame-Retardant Chemicals yielding a room airborne particle concentration (Cp) of 1.1 µg/m3 and a short time-average exposure concentration of 0.28 µg/m3. The time-averaged exposure concentration for particles was calculated using Equation 6 in Chapter 3. In the absence of relevant inhalation exposure data, the subcommittee chose to estimate inhalation RfCs from oral RfDs The subcommittee, however, recognizes that it is not an ideal approach and also recognizes that the estimated RfC levels might be considerably different than actual levels (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 oral RfDs to inhalation RfCs is highly conservative; it assumes that all of the inhaled compound is deposited in the respiratory tract and 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 this FR. The RfC should be used as interim or provisional levels until relevant data become available for the derivation of inhalation RfC. To calculate a hazard index for the inhalation route, a provisional inhalation RfC of 1.05 mg/m3 was derived using the oral RfD for C22–26, 70% chlorine (see the following section for the derivation of the oral RfD) and Equation 7 in Chapter 3. Division of the time-average exposure concentration of 0.28 µg/m3 by the provisional RfC for chlorinated paraffins of 1.05 mg/m3 yields a hazard index of 2.7×10−4. This suggests that under the subcommittee’s worst-case exposure assumptions, Chlorinated paraffins would not be considered to be a toxic risk by the inhalation route of exposure. Vapors Volatility data for chlorinated paraffins were not located. Therefore, the subcommittee did not calculate worst-case exposure estimates for this exposure. Oral Exposure The assessment of noncancer toxicological risk for oral exposure to chlorinated paraffins is based on the oral exposure scenario described in Chapter 3.

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Toxicological Risks of Selected Flame-Retardant Chemicals This scenario assumes a child is exposed to chlorinated paraffins by sucking on 50 cm2 of fabric backcoated with chlorinated paraffins, 1 hr/d for two yr. The subcommittee estimated an upholstery application rate (Sa) for chlorinated paraffins of 3 mg/cm2. Oral exposure was calculated using Equation 15 in Chapter 3. The extraction rate (µw) for chlorinated paraffins was estimated to be 0.025 based on extraction data for hexabromocyclododecane in polyester fiber (McIntyre et al. 1995). The release rate from the fiber for estimating extraction was 0.04/d at 28°C calculated using the equation 2d/2 πR (d=film thickness, R=fiber radius) with a correction from fiber to film of a factor of 0.63. The worst-case average oral daily dose for chlorinated paraffins was estimated to be 0.16 mg/kg-d. Division of the dose estimate by the oral RfD for chlorinated paraffins of 0.3 mg/kg-d gives a hazard index of 0.053. This suggests that under the subcommittee’s worst-case exposure assumptions, chlorinated paraffins do not pose a noncancer toxicological risk when incorporated into residential furniture upholstery at the estimated application levels. Cancer Dermal Exposure There are inadequate data for assessing the carcinogenicity of chlorinated paraffins when exposure occurs by the dermal route of exposure. Inhalation Exposure There are inadequate data for assessing the carcinogenicity of chlorinated paraffins when exposure occurs by inhalation. Oral Exposure EPA has concluded that long-chain chlorinated paraffins should not be classified as potential carcinogens (EPA 1994). This conclusion is based on limited evidence for the carcinogenicity of the long-chain chlorinated paraffin, C22–26, 43% chlorine, in rodents and the fact that cancer data are not available for long-chain chlorinated paraffin, 70% chlorine. It is the opinion of the subcommittee that long-chain chlorinated paraffins are not likely to be human carcinogens and derivation of a cancer potency factor for this class of chlorinated paraffins is

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Toxicological Risks of Selected Flame-Retardant Chemicals not warranted (see Cancer in Quantitative Toxicity Assessment for conclusions regarding short- and medium-chain chlorinated paraffins). RECOMMENDATIONS FROM OTHER ORGANIZATIONS The subcommittee is not aware of any exposure limits recommended by the regulatory agencies or other organizations. DATA GAPS AND RESEARCH NEEDS Chronic toxicity data are not available for C22–26, 70% chlorine, for any route of exposure. Properly conducted reproductive/developmental studies on chlorinated paraffins are not available. Human dermal absorption data for chlorinated paraffins are not available either. Information on the teachability of long-chain chlorinated paraffins from latex or other types of backcoating following exposure to simulated human secretions (saliva, sweat) is also needed. The volatility of C22–26, 70% chlorine, is also not reported in the literature. Based on a dermal hazard index greater than one, the dermal absorption of chlorinated paraffins from treated fabric should be investigated. REFERENCES Abasov, D.M. 1970. Toxicology of new chloroparaffin KhP 470. Tr. Azerb. Nauch.-Issled. Inst. Gig. Tr. Profzabol. 5:180–183. As cited in EPA (1975). Ahlman, M., A.Bergman, P.O.Darnerud, B.Egestad, and J.Sjovall. 1986. Chlorinated paraffins: Formation of sulphur-containing metabolites of polychlorohexadecane in rats. Xenobiotica 16(3):225–232. Ashby, J., P.A.Lefevre, and C.R.Elcombe. 1990. Cell replication and unscheduled DNA synthesis (UDS) activity of low molecular weight chlorinated paraffins in the rat liver in vivo. Mutagenesis 5(5):515–518. Bentley, P., I.Calder, C.Elcombe, P.Grasso, D.Stringer, and H.J.Wiegand. 1993. Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem. Toxicol. 31(11):857–907. Biessmann, A., P.O.Darnerud, and I.Brandt. 1983. Chlorinated paraffins: Disposition of a highly chlorinated polychlorohexadecane in mice and quail. Arch. Toxicol. 53(1):79–86. Birtley, R.D., D.M.Conning, J.W.Daniel, D.M.Ferguson, E.Longtstaff, and A.A. Swan. 1980. The toxicological effects of chlorinated paraffins in mammals. Toxicol. Appl. Pharmacol. 54(3):514–525.

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Toxicological Risks of Selected Flame-Retardant Chemicals Cattley, R.C., J.DeLuca, C.Elcombe, P.Fenner-Crisp, B.G.Lake, D.S.Marsman, T.A. Pastoor, J.A.Popp, D.E.Robinson, B.Schwetz, J.Tugwood, and W.Wahli. 1998. Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regul. Toxicol. Pharmacol. 27(1 pt. 2):47–60. Chlorinated Paraffins Industry Association. 1999. Letter to Darryl Arfsten (NRC), from Robert J.Fensterheim, Executive Director, CPIA, regarding chlorinated paraffins for use in furniture flame retardants. September 29, 1999. Chlorinated Paraffins Industry Association, Washington, DC. Darnerud, P.O. 1984. Chlorinated paraffins: Effect of some microsomal enzyme inducers and inhibitors on the degradation of 1–14C-chlorododecanes to 14CO2 in mice. Acta Pharmacol. Toxicol. 55(2):110–115. Darnerud, P.O., and I.Brandt. 1982. Studies on the distribution and metabolism of a 14C-labeled chlorinated alkane in mice. Environ. Pollut. (Series A) 27:45–56. Darnerud, P.O., A.Biessmann, and I.Brandt. 1982. Metabolic fate of chlorinated paraffins: Degree of chlorination of [1–14C]-chlorododecanes in relation to degradation and excretion in mice. Arch. Toxicol. 50(3–4):217–226. Diamond Shamrock Chemical Company. 1975. Personal Communication, Cleveland, OH. EPA (U.S. Environmental Protection Agency). 1975. Investigation of Selected Potential Environmental Contaminants: Chlorinated Paraffins. Final Report. Office of Toxic Substances, U.S. Environmental Protection Agency, Washington DC. EPA-560/2–75–007. EPA (U.S. Environmental Protection Agency). 1994. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Final Rule. Fed. Regist. 59(Nov. 30):61462 Eriksson, P., and J.E.Kihlstrom. 1985. Disturbance of motor performance and thermoregulation in mice given two commercial chlorinated paraffins. Bull. Environ. Contam. Toxicol. 34(2):205–209. Eriksson, P., and A.Nordberg. 1986. The effects of DDT, DDOH-palmitic acid, and a chlorinated paraffin on muscarinic receptors and the sodium-dependent choline uptake in the central nervous system of immature mice. Toxicol. Appl. Pharmacol. 85(2):121–127. EUSCTEE (European Union Scientific Committee for Toxicity, Ecotoxicity, and the Environment). 1998. Opinion on the results of the Risk Assessment of: Alkanes, C10– 13, chloro {SCCP} carried out in the framework of Council Regulation (EEC) 793/93 on the evaluation and control of the risks of existing substances—Opinion expressed at the 6th CSTEE plenary meeting, Brussels, 27 November 1998. [Online]. Available: http://europa.eu.int/comm/dg24/health/sc/sct/out23_en.html Fire Retardant Chemicals Association. 1998. Textile Flame Retardant Applications by Product Classes for 1997 Within and Outside of the United States: Halogenated Oelfins and Paraffins. Fire Retardants Chemicals Association. Lancaster, PA. Gosselin, R.E., H.C.Hodge, R.P.Smith, and M.N.Gleason. 1976. Clinical toxicology of Commercial Products. 4th Edition. Baltimore: Williams and Wilkins. Cited in the Hazardous Substance Data Bank file for Chlorinated Paraffins. File updated March 3, 1998.

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Toxicological Risks of Selected Flame-Retardant Chemicals Hatlelid, K. 1999. Toxicity Review for Chlorinated Paraffins. Memorandum, dated March 25, 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. IARC (International Agency for Research on Cancer). 1990. Chlorinated Paraffins. In: LARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 48. Some Flame Retardants and Textile Chemicals, and Exposure in the Textile Manufacturing Industry. Lyon, France: IARC Press. 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. Meijer, J., M.Rundgren, A.Astrom, J.W.DePierre, A.Sundvall, and U.Rannug. 1981. Effects of chlorinated paraffins on some drug-metabolizing enzymes in rat liver and in the Ames test. Adv. Exp. Med. Biol. 136(Pt. A):821–828. Nilsen, O.G., and R.Toftgard. 1981. Effects of polychlorinated terphenyls and paraffins on rat liver microsomal cytochrome P-450 and in vitro metabolic activities. Arch. Toxicol. 47(1): 1–11. Nilsen, O.G., R.Toftgard, and H.Glaumann. 1980. Changes in rat liver morphology and metabolic activities after exposure to chlorinated paraffins. Pp. 525–528 in Mechanisms of Toxicity and Hazard Evaluation: Proceedings of the Second International Congress on Toxicology, Brussels, Belgium, July 6–11, 1980. B.Holmstedt, R.Lauwerys, M.Mercker, and M.Roberfrold, eds. New York: Elsevier/North Holland Biomedical Press. Nilsen, O.G., R.Toftgard, and H.Glaumann. 1981. Effects of chlorinated paraffins on rat liver microsomal activities and morphology. Importance of the length and the degree of chlorination of the carbon chain. Arch. Toxicol. 49(1): 1–13. 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. NTP (National Toxicology Program). 1986a. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C12, 60% chlorine) in F344/N rats and B6C3F1 Mice (Gavage Studies). NTP TR 308. NIH Publication No. 86–2564. U.S. Department of Health and Human Services, National Institutes of Health. NTP (National Toxicology Program). 1986b. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C23, 43% chlorine) in F344/N rats and B6C3F1 Mice (Gavage Studies). NTP TR 305. NIH Publication No. 86–2561. U.S. Department of Health and Human Services, National Institutes of Health. Poon, R., P.Lecavalier, P.Chan, C.Viau, H.Håkansson, I.Chu, and V.E.Valli. 1995. Subchronic toxicity of a medium-chain chlorinated paraffin in rat. J. Appl. Toxicol. 15(6):455–463. Scott, R.C. 1989. In vitro absorption of some chlorinated paraffins through human skin. Arch. Toxicol. 63(5):425–426. Serrone, D.M., R.D.Birtley, W.Weigand, and R.Millischer. 1987. Toxicology of chlorinated paraffins. Food. Chem. Toxicol. 25(7):553–562.

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Toxicological Risks of Selected Flame-Retardant Chemicals Warngard, L., Y.Eager, Y.Kato, K.Kenne, and U.G.Ahlborg. 1996. Mechanistical studies of the inhibition of intercellular communication by organochlorine compounds. Arch. Toxicol. Suppl. 18:149–159. Wyatt, I., C.T.Courts, and C.R.Elcombe. 1993. The effect of chlorinated paraffins on hepatic enzymes and thyroid hormones. Toxicology 77(1–2):81–90. Yang, J.J., T.A.Roy, W.Neil, A.J.Krueger, and C.R.Mackerer. 1987. Percutaneous and oral absorption of chlorinated paraffins in the rat. Toxicol. Ind. Health 3(3):405–412.

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