Chen und Blancato, 1989 8 6.5 x 10 7  1.4 x 10 6 EPA, 2000 a, b 9 8.8 x 10 6 Clewell et al., 1995 10 6 x 10 7  2 x 10 6 Clewell et al., 2001 11 1.1 x 10 6 Reitz et al., 1996 12 5.7 x 10 7 These risk estimates are based on the experimental data in adult animals exposed for lifetime 13 published by Maltoni et al. ( 1981; 1984). There are only slight differences in the human cancer risk 14 estimated by Clewell and Reitz who both used pharmacokinetic ( PBPK) models for the transfer of the 15 animal data on the human situations. These data are in good agreement with the unit risk estimates derived 16 from epidemiologic data, confirming the order of magnitude. However, these risk estimates were only 17 validated with data from adult animals and epidemiologic data from the workplace. A higher sensitivity of 18 children was not incorporated into quantification ( see data from Drew et al., 1983; Maltoni et al., 1981). 19 Chen and Blancato ( 1989) use a modified multistage model for risk estimation on base of liver 20 tumors, considering pharmacokinetic models. Additionally, increased sensitivity in early life stages has been 21 considered. They evaluated female and male animals separately, expressed by the range of tumor 22 incidences. 23 The most recently published risk estimate by EPA ( 2000a, b) is based on the animal experiments 24 published by Maltoni et al. ( 1981, 1984). Differences in the metabolism between animals and humans have 25 been taken into consideration by use of a pharmacokinetic model. The increased sensitivity of children was 26 taken into consideration. Additionally, tumors in sites other than the liver were considered. Unit risk 27 estimates based on epidemiologic studies were regarded as uncertain due to the shortcomings of the 28 epidemiologic studies. Besides the unit risk estimate for full lifetime exposure ( birth through death) of 8.8 x 29 10 6 per µ g/ m3, EPA provided an estimate of risk for early life exposure of 4.4 x 10 6 per µ g/ m3 and an 30 estimate of risk for adult only exposure of 4.4 x 10 6 per µ g/ m3. This unit risk for adults is based on the 31 PBPK modeling from Clewell et al. ( 2001), with only slight modifications in some parameters. 32 3.6. Summary 33 Acute exposure of experimental animals towards VC results in narcotic effects, cardiac 34 sensitization, and hepatotoxicity. Narcotic effects are characterized by a typical sequence of events from 35 Vinyl chloride PROPOSED 1: 3/ 2004 28 euphoria and dizziness, followed by drowsiness and loss of consciousness. Finally, animals die due to 1 respiratory failure. Prodan et al. ( 1975) reported LC50 values for mice, rats, rabbits, and guinea pigs of 2 117,500 ppm, 150,000 ppm, 240,000 ppm and 240,000 ppm, respectively, for 2 hours. Dead animals 3 showed congestion of the internal organs ( especially lung, liver and kidney), lung edema and hemorrhagia 4 ( Prodan et al., 1975; Mastromatteo et al., 1960). No lethality was seen in mice after exposure to 100,000 5 ppm for 2 hours ( Prodan et al., 1975). However, Tátrai and Ungváry ( 1981) reported that exposure of mice 6 to 1,500 ppm for 24 h resulted in death of all animals, reduction of exposure time to 12 h resulted in death 7 of 90% of the animals. These results are not in accordance with other lethality data. 8 Short term exposure ( up to 30 minutes) of experimental animals to VC concentrations of 100,000 9 to 300,000 ppm resulted mainly in ataxia, motor activity, side position and unconsciousness, slow and 10 shallow respiration, the typical reactions observed before the onset of narcosis ( Mastromatteo et al., 1960). 11 Narcosis was observed in rats and mice after 30 min exposure to 200,000 ppm VC ( Mastromatteo et al., 12 1960). Short term exposure ( 5 min) of dogs to VC induced cardiac sensitization towards epinephrine ( EC50: 13 50,000 or 71,000 ppm in two independent experiments) ( Clark and Tinston, 1973; 1982). These effects 14 were also seen in mice at higher concentrations ( Aviado and Belej, 1974). In monkeys, only myocardial 15 depression after inhalation of 2.5 10% VC was observed. It is not clearly stated whether an addition 16 challenge with epinephrine was applied or not ( Belej et al., 1974). Single inhalation exposure of rats for 6 17 hours to 100,000 ppm VC resulted in histopathological changes of the liver ( vacuolization), but was not 18 observed in lower concentrations ( 50,000 ppm) ( Jaeger et al., 1974). However, in mice Tátrai and Ungváry 19 ( 1981) reported that stasis of the liver developed 2 and 4 h after the beginning of inhalation. The authors 20 observed decreasing enzyme activities in liver and subcellular liver damage at exposure concentrations of 21 1,500 ppm VC for 2 h; after 24 h shock liver developed. Repeated exposure of rats to 1,500 ppm VC for 22 up to 9 days during pregnancy caused increased relative and absolute liver weights without light 23 microscopic visible changes ( Ungváry et al., 1978). In another developmental study increased absolute and 24 relative liver weights have been observed in rats exposed intermittently to 2,500 ppm from day 6  15 of 25 pregnancy, the NOAEL was 500 ppm ( John et al., 1977; 1981). In rats exposed to 5,000 ppm for 7 26 hours/ day and 5 days/ week after 4 weeks vacuolized liver cells were observed ( Feron et al., 1979). 27 No investigations of reproductive or developmental toxicity after single exposure are published. 28 John et al. ( 1977, 1981) investigated developmental effects after repeated exposure in mice, rats and 29 rabbits. Developmental toxicity ( e. g. delayed ossification) was only observed at maternal toxic 30 concentrations. Ungváry et al. ( 1978) reported that in maternal rats which were exposed to 1,500 ppm VC 31 for 24 h/ d during the first ( day 1 9) or second ( day 8 14) trimester of gestation maternal liver toxicity 32 occurred. Frequency of resorptions was significantly increased in the group exposed during the first 33 trimester. A recently published developmental toxicity study in rats ( exposure on day 6 19 of gestation 34 towards 10, 100 or 1100 ppm VC, 6 h/ d) indicated that up to 1100 ppm embryo fetal development was not 35 affected by VC exposure. The only toxic effects observed were an increased relative organ to body weight 36 ratio for the kidney and liver at 1100 ppm and for the kidney at 100 ppm in dams ( Thornton et al., 2002). 37 In a 2 generation study in rats no adverse effects on embryo fetal development or reproductive capability 38 were observed over 2 generations in concentrations up to 1100 ppm ( F0: exposure: 10 weeks premating, 3 39 weeks mating, gestation, lactation; F1: identical exposure pattern; F2: until postnatal day 21). The primary 40 target organ of VC, the liver, was affected as evidenced by an increase in liver weight and/ or 41 histopathologically identified cellular alterations, such as centrilobular hypertrophy and induction of altered 42 hepatocellular foci at 100 and 1,000 ppm, with increased incidence in the F1 generation ( Thornton et al., 43 2002). 44 Vinyl chloride PROPOSED 1: 3/ 2004 29 Positive results on genotoxicity after in vitro and single and repeated in vivo treatment ( e. g. 1 induction of micronuclei, 4  6 h, 50,000 ppm; chromosomal aberrations, 6  24 h, 25,000 ppm) have been 2 reported for VC ( WHO, 1999a). Elevated DNA adducts were seen after single 5 hour exposure of adult 3 rats to 250 ppm ( Bolt   1976). Watson et al. ( 1991) exposed adult male Fisher 344 rats for 6 hours to 4 atmospheres containing 1, 10, 45 ppm VC. The alkylation frequencies of 7( 2' oxoethyl) guanine ( OEG) in 5 liver DNA were 0.026, 0.28 and 1.28 residues OEG per 106 nucleotides respectively. With these air 6 concentrations, there was no evidence to indicate the formation of the cyclic adducts 1, N6 ethenoadenine 7 (  A) or 3, N4 ethenocytosine (  C). The threshold for detection of these adducts were about 1 adduct per 1 x 8 108 nucleotides. Adult rats repeatedly ( 5 days) exposed to 10 ppm VC for 6 hours/ day showed slightly 9 elevated etheno adducts for N2,3 ethenoguanine (  G) compared to control ( 200 ± 50 vs. 90 ± 40 fmol/ 10 µ mol guanine) ( Swenberg et al., 2000). Higher adduct levels were seen in young animals than in adult 11 animals after identical treatment ( Fedtke et al., 1990; Laib et al., 1989; Ciroussel et al. ( 1990). OEG are 12 not likely to cause mutations, however, the cyclic adducts  A,  C,  G have miscoding potential; respective 13 mutations ( e. g., G> A transitions, A> T transitions) were observed in VC induced tumors ( Barbin, 2000). 14 Despite relevant repair, no full reduction to background was observed for these adducts two weeks after a 5 15 day exposure ( 4 hours/ day) to 600 ppm ( Swenberg et al., 2000). 16 Induction of liver tumors has been reported in rats after subacute ( 5 week and 33 days, 17 respectively) exposure ( Maltoni et al., 1981; 1984; Froment et al. , 1994). The liver is the primary 18 localization of tumors after chronic exposure ( for review see EPA, 2000a, b). Vinyl chloride induces lung 19 tumors in mice after single one hour exposure to 5,000 ppm or 50,000 ppm ( Hehir et al., 1981). After a 20 single 12 hour exposure to 1,500 ppm of mice a hepatocellular adenoma developed. The respective 21 concentration was lethal to most of the animals ( Tátrai and Ungváry, 1981). Suzuki ( 1983) reported that 22 short term exposure ( 6 h/ d; 5 d/ w; 4 weeks) of young CD1 mice ( 5  6 weeks old at first exposure) to VC 23 resulted in lung tumor formation. Additionally, subcutaneous and hepatic hemangiosarcoma were found in 24 this study. Short term exposure experiments from Drew et al. ( 1983), Maltoni et al. ( 1981) and Froment et 25 al. ( 1994) also indicated increased susceptibility of newborn and young animals towards tumor formation. 26 Hepatoma ( Maltoni et al., 1981) or hepatocellular carcinoma ( Froment et al., 1994) developed to a greater 27 extent in young than in adult animals. Laib et al. reported that hepatocellular ATPase deficient foci ( pre 28 malignant stages) were observed in rats which were exposed to VC. Relevant foci areas were demonstrated 29 after short periods of exposure during animal growth, eg., exposure to 2,000 ppm for 11 days ( exposure 30 period: from day 1 to 11) or for 21 days ( from day 7 28). The foci persisted until histological examination 31 at the age of 4 month ( Laib et al., 1985b). 32 Vinyl chloride PROPOSED 1: 3/ 2004 30 4. SPECIAL CONSIDERATIONS 1 4.1. Metabolism and Disposition 2 Krajewski et al. ( 1980) estimated the retention of VC after inhalation through a gasmask in 5 male 3 human volunteers by measuring the difference between inhaled and exhaled concentrations. Exposure to 4 concentrations between 3 and 24 ppm VC for 6 hours revealed an average retention of 42%, independent 5 from VC concentration. Thirty minutes after the beginning initially higher retention values ( maximum 46% 6 on average) dropped down and stayed on a relative constant level. Interindividual retention rates varied 7 from 20.2% to 79% at 12 ppm. Immediately after cessation of inhalation the VC concentration in the 8 expired air dropped rapidly. After 30 minutes less than 5% of the initial chamber concentration could be 9 measured. Buchter et al. ( 1978) determined a retention rate of 26  28% at 2.5 ppm VC in two individuals 3 10  5 min after the start of inhalation. Given the variability of VC retention found by Krajewski these values 11 may be attributed to interindividual differences. WHO ( 1999a) reports an average of 30  40% absorption 12 after inhalation, without citing the relevant studies. 13 An absorption of inspired VC of about 40% was calculated for rats ( calculation based on the 14 decline of 14C VC in a closed system) ( Bolt et al., 1976). In Rhesus monkeys VC is also efficiently 15 absorbed after inhalation as can be deduced from data on the metabolic elimination ( no further 16 quantification) ( Buchter et al., 1980). 17 Whole body ( excluding the head) exposure of rhesus monkeys to radioactive VC indicated that only 18 very little VC was absorbed through the skin ( about 0.031% and 0.023% at 800 and 7,000 ppm, 19 respectively after 2  2.5 h) ( ATSDR, 1997). No further data on dermal absorption are available. 20 The percentage of the dose remaining in the carcass after oral application after 72 h was 10, 11, 21 and 2% for the 0.05, 1 and 100 mg/ kg doses. The data suggest that almost complete elimination of VC 22 occurred ( Watanabe et al., 1976b). Seventy two hours after exposure to 10 and 1,000 ppm radioactive VC 23 14 and 15%, respectively, of the recovered 14C activity remained in the carcass of rats, VC per se was not 24 found in tissues. Radioactivity was detected in the liver, skin, plasma, muscle, lung fat and kidney, 25 representing non volatile metabolites of VC ( Watanabe et al., 1976a) or incorporation into C1 pool ( Laib et 26 al., 1989). 27 Data on serum concentrations of VC are scarce. Ungváry et al. ( 1978) exposed pregnant rats to 28 2,000  12,000 ppm VC; they determined blood concentrations ranging from 19 µ g/ ml at 2,000 ppm to 29 48.4 µ g/ ml at 12,000 ppm VC indicating no direct proportionality between air VC concentration and blood 30 concentration. Feron et al. ( 1975) reported a peak blood concentration of 1.9 µ g/ ml 10 min after gavage of 31 300 mg/ kg VC; this value is much smaller than expected compared to blood concentrations after inhalation 32 which might be due to the effective presystemic hepatic clearance of VC after oral uptake. 33 Similar to other inhalation anaesthetics, maximal blood concentration of VC after inhalation 34 exposure depends on the partial pressure of VC in the air. Blood respectively brain concentration, which 35 directly correlates with the depth of narcosis ( see below) and  presumably  with cardiac sensitization level, 36 can be controlled by changing the concentration of VC in the air, i. e. by changing the partial pressure of 37 VC in the air. If equilibrium is reached between the partial pressure of VC in the air and in the blood 38 ( steady state), no further increase of VC concentration in the blood is possible, even if the exposure time is 39 prolonged ( Forth et al., 1987). The time necessary to set up steady state mainly depends on the blood/ air 40 partition coefficient of a substance. The blood/ air partition coefficient of VC in humans is 1.2 ( Csanady 41 Vinyl chloride PROPOSED 1: 3/ 2004 31 and Filser, 2001), similar to that of the inhalation anaesthetic isoflurane ( 1.4; Forth et al., 1987). For this 1 substance the equilibrium is reached after about 2 hours, derived by graphical extrapolation of the data on 2 isoflurane ( Goodman and Gilman, 1975). For VC, in much lower concentrations an elimination half time of 3 VC of 20.5 minutes has been derived ( Buchter, 1979; Bolt et al., 1981). From that, for low concentrations 4 a steady state concentration for VC in blood of about 5 x 20.5 = 102.5 minutes can be calculated by 5 standard estimation rules. Thus, in high or low concentrations a relevant increase of internal concentrations 6 of VC is not to be expected after more than 2 hours of exposure. However, for shorter periods of exposure 7 a relevant influence of time on the built up of VC on internal concentrations has to be taken into account. 8 VC is oxidized by cytochrome P450 2E1 to the highly reactive epoxide 2 chloroethylene oxide 9 which can directly interact with DNA and proteins or spontaneously rearrange to 2 chloroacetaldehyde 10 which might bind to proteins and DNA. 2 Chloroethylene oxide can also be transformed to glycol aldehyde 11 by epoxide hydrolase or react with glutathione leading to the formation N acetyl S( 2 hydroxyethyl) 12 cysteine. Chloroacetaldehyde is oxidized by aldehyde dehydrogenase to 2 chloroacetic acid which reacts 13 with glutathione leading to the formation of thiodiglycolic acid ( which leads to the liberation of carbon 14 dioxide). Comparison of in vitro metabolism with rat liver microsomes and in vivo experiments in rats 15 show that virtually all the metabolic activation of VC in vivo occurs in the liver ( WHO, 1999a). After low 16 doses VC is metabolically eliminated and non volatile metabolites excreted mainly in the urine. At doses 17 that saturate the metabolism, the major route of excretion is exhalation of unchanged VC. Excretion of 18 metabolites via feces is only a minor route, independent of applied dose ( WHO, 1999a). 19 Buchter et al. ( 1980) exposed rhesus monkeys with 100  800 ppm VC and measured the time 20 dependent disappearance of VC from the atmosphere. The maximum metabolic rate was determined at 45 21 µ mol/ kg hr; this turnover is obtained at 400 ppm VC; no attempt was made to identify the metabolites 22 formed. From the decrease in atmospheric VC concentration metabolic clearance rates were calculated in 23 liter air/ hour/ kg body weight. Clearance rates for monkeys, rabbit and humans are 2.0  3.55 l/ hr kg, for 24 gerbils and rats 11.0 to 12.5, and 25.6 l/ hr kg for mice, indicating major species differences, which are in 25 accordance with allometric scaling. 26 After oral ingestion of 0.05, 1.0 or 100 mg/ kg body weight, male rats metabolize VC to the epoxide 27 which is further metabolized ( e. g. to thiodiglycolic acid: about 25% of the 14C containing urinary 28 metabolites). Of the total dose, 9, 13.3 and 2.5% are excreted as CO2 or 1.4, 2.1 or 66.6% VC, respectively 29 at the low, mid and high dose ( Watanabe et al., 1976b). At 100 mg/ kg bw pulmonary elimination showed a 30 biphasic clearance with an initial half life of 15 min and a terminal half life of 41 min. After 0.05 and 1 31 mg/ kg VC only monophasic pulmonary clearance could be observed with half life values of 53  58 min 32 ( Watanabe et al., 1976b). Initial urinary excretion of metabolites followed first order kinetics with half life 33 values of 4.5  4.6 hours, followed by a slow terminal phase ( Watanabe et al., 1976b). Thus, the 34 equilibrium concentration for metabolites will not be reached within 8 hours or less. The ratio of the 35 metabolites excreted in the urine does not vary in dependence on dose. 36 Vinyl chloride metabolism is saturated at concentrations exceeding 380 ppm in Rhesus monkeys 37 ( Buchter et al., 1980) ( see table 6). In humans, 24 ppm appears to be below the threshold of saturation 38 ( Krajewski et al., 1980) since no difference in pulmonary retention could be observed between 3, 6, 12 and 39 24 ppm VC. When exposing rats in a closed system with 50  1,000 ppm VC metabolic clearance was 40 slowed at concentrations above 220 ppm as evidenced by longer half lives ( Hefner et al., 1975). Bolt et al. 41 ( 1977) exposed rats in a similar system and found metabolic saturation to occur at 250 ppm ( see table 6). 42 These data are in accordance with the data from Watanabe et al. ( 1976a): after inhalation of 1,000 ppm in 43 Vinyl chloride PROPOSED 1: 3/ 2004 32 rats metabolism was saturated, whereas at 100 ppm VC saturation was not evident ( no intermediate 1 concentration was tested). 2 Saturation of the metabolism has also been observed after oral application: at high doses ( 100 3 mg/ kg) metabolism was saturated as is evident from the increase in VC expiration from 2.1% at 1 mg/ kg to 4 66,6% at 100 mg/ kg ( Watanabe et al., 1976b). 5 TABLE 6: METABOLIC SATURATION CONCENTRATIONS OF VC IN RATS AND MONKEYS 6 Rhesus Monkey 7 about 380 ppm ( Buchter et al., 1980)

Rat 8 250 ppm ( Bolt et al., 1977)

VC metabolites are assumed to destroy cytochrome P450 enzymes responsible for its epoxidation 9 ( Du et al., 1982; Pessayre et al., 1979). On the other hand activity of glutathione S transferase and 10 glutathione reductase is elevated after VC exposure of rats ( glutathione content is reduced) representing an 11 early hepatocellular adaption to VC exposure ( Du et al., 1982). 12 4.2. Mechanism of Toxicity 13 Acute neurotoxicity by inhalation of high VC concentrations is likely dependent upon VC 14 concentrations and independent of VC metabolism. This assumption is supported by comparison of narcotic 15 concentrations which are similar for the four species guinea pig, mouse, rabbit and rat ( Prodan et al., 1975; 16 Mastromatteo et al., 1960). Vinyl chloride has been investigated as a possible human anesthetic ( Oster et 17 al., 1947; Peoples and Leake, 1933) but was abandoned because of its induction of cardiac arrhythmia. 18 Acute toxicity/ lethality is mainly accompanied by congestion of all internal organs, pulmonary 19 edema, liver and kidney changes ( up to necrosis) ( Prodan et al., 1975). The mechanism of action is not 20 evident, toxic effects are possible mediated by reactive metabolites. 21 VC genotoxicity and carcinogenicity has been attributed to formation of reactive metabolites, 22 especially 2 chloroethylene oxide and 2 chloroacetaldehyde ( see WHO, 1999a). 2 Chloroethylene oxide 23 interacts directly with DNA and produces alkylation products ( Fedtke et al., 1990). This alkylation results 24 in a highly efficient base pair substitution that leads to neoplastic transformation ( ATSDR, 1997). VC 25 DNA ethenobases are shown to lead to miscoding and are found in VC induced tumors in animals and 26 humans ( Barbin, 2000). Despite relevant repair, no full reduction to background was observed for these 27 adducts two weeks after a 5 day exposure ( 4 hours/ day) to 600 ppm ( Swenberg et al., 1999). For vinyl 28 fluoride, when all of the data for rats and mice on  G and hemangiosarcomas were compared by regression 29 analysis, a high correlation was seen ( r2= 0.88) ( Swenberg et al., 1999). However, in case of VC there is a 30 close correlation in the occurrence of  A,  C,  G and there are indications that also  A might be related to 31 tumor formation ( Barbin, 1999; Barbin, 2000). In adults, nonparenchymal cells have a higher rate of 32 proliferation than hepatocytes. Thus, this cell population is more likely to convert promutagenic DNA 33 adducts into mutations ( Swenberg et al., 1999). During rapid growth of the liver this relationship may be 34 changed: Young animals demonstrate a high rate of etheno adducts in the liver and a high rate of 35 preneoplastic foci of the liver. These foci persisted over several month even after short durations of 36 exposure ( Laib et al., 1989). In young animals a high rate of hepatoma and hepatocellular carcinoma have 37 been found after short term exposure to VC ( Maltoni et al., 1981; 1984; Froment et al., 1994). 38 Vinyl chloride PROPOSED 1: 3/ 2004 33 In humans occupationally exposed to VC   vinyl chloride disease" ( characterized by Raynaud` s 1 phenomena and scleroderma) is a common finding after prolonged exposure. No similar observations have 2 been made in experimental animals after single exposition experiments. These effects are probably due to 3 immunological abnormalities ( caused by interaction of reactive VC metabolites with proteins) as has been 4 proposed by Grainger et al. ( 1980) and Ward et al. ( 1976), however, no definitive mechanism has been 5 elucidated to date. 6 4.3. Other Relevant Information 7 4.3.1 PBPK Modeling 8 Physiology based pharmacokinetic ( PBPK) models have been proposed to predict VC metabolism 9 and cancer risk ( Reitz et al., 1996; Clewell et al., 1995 and Clewell et al., 2001). PBPK models have been 10 developed to account for physiological differences among species relevant to VC uptake, distribution, 11 metabolism and excretion and should allow a better comparison across species. 12 Current models use four compartments ( liver, fat, slowly perfused tissues, richly perfused tissues) 13 and partition coefficients determined in vitro. Metabolism is modeled by one ( Reitz et al., 1996) or two 14 ( Clewell et al., 1995) saturable pathways. The model of Clewell et al. ( 1995, 2001) uses one high affinity, 15 low capacity pathway likely pertaining to cytochrome P450 2E1, and one low affinity, high capacity 16 pathway tentatively assigned to cytochromes P450 2C11/ 6 and 1A1/ 2). Since VC readily reacts with 17 glutathione ( GSH) and is known to deplete hepatic GSH stores, description of the GSH kinetics was also 18 included. 19 4.3.2. Interspecies Variability 20 A comparison of the metabolic activity across species indicates mice to be the metabolically most 21 active species with a first order metabolic clearance rate for VC of 25.6 l/ h per kg bw at VC concentrations 22 below metabolic saturation ( Buchter et al., 1980). Clearance of rats, rhesus monkey, rabbits and men is 23 lower ( 11.0, 3.55, 2.74 and 2.02 l/ h per kg bw, respectively). Because the metabolism of VC is perfusion 24 limited ( Filser and Bolt, 1979), comparison of clearance rates on body weight basis is not satisfying. If 25 clearance is compared on a body surface area basis these mammalian species exhibit similar clearance rates 26 ( WHO, 1999a). 27 Comparison of lethal concentrations ( lethality occurring in the context of narcosis) in mice, rats, 28 rabbits and guinea pigs point to certain interspecies variations with the guinea pig and rabbit being less 29 sensitive than mice and rats. Comparing the most sensitive species ( mouse) with the at least sensitive 30 species ( rabbit and guinea pig) point to a factor of 2. 31 Vinyl chloride PROPOSED 1: 3/ 2004 34 LC50 mouse; exposure time 2 h: 117,500 ppm ( Prodan et al., 1975) 1 LC50 rat; exposure time 2 h: 150,000 ppm ( Prodan et al., 1975; Lester et al., 1963) 2 LC50 rabbit; exposure time 2 h: 240,000 ppm ( Prodan et al., 1975) 3 LC50 guinea pig; exposure time 2 h: 240,000 ppm ( Prodan et al., 1975) 4 Concerning non lethal, pre narcotic effects marginal interspecies differences are observed 5 indicating that rats and mice are a little bit more sensitive than guinea pigs: e. g. thirty minutes exposure of 6 guinea pigs, rats and mice to 100,000 ppm VC resulted in the same symptoms: unconsciousness ( in all rats 7 and mice but only in one of five guinea pigs) and a lung hyperaemia persisting for more than 2 weeks, rats 8 and mice fell aside after 20 min exposure and guinea pigs showed side position after 30 min exposure 9 ( Mastromatteo et al., 1960). No comparable data on humans are available. Concerning hepatic effects mice 10 seem to be more sensitive than rats and rabbits: Exposure of mice to 1,500 ppm VC for 2 h caused severe 11 liver effects, resulting in shock liver and death of the mice. But no hepatic and lethal effects were observed 12 in rats and rabbits treated identically for 24 h ( Tátrai and Ungvary, 1981). The reasons for these 13 interspecies differences are not known. Data on acute hepatic effects of VC in humans are not available. 14 Concerning the similar clearance rates of VC on a body surface area there does not seem to be a 15 large toxicokinetic difference between various species. Due to these findings we suggest to use a reduced 16 interspecies factor of 3, accounting for toxicodynamic differences, in cases where the toxicity of VC is 17 mediated by VC metabolites. 18 With respect to lethality and VC induced ( pre) narcotic symptoms there seem to be only minimal 19 interspecies differences. Use of a reduced extrapolation factor of 3 is recommended in this context. 20 4.3.3. Intraspecies Variability 21 Cytochrome P450 isoenzyme 2E1 is the key enzyme converting VC to 2 chloroethylene oxide. 22 CYP2E1 activity in human liver microsomes may vary up to 12 fold between individuals ( substrate: p 23 nitrophenol; Seaton et al., 1994). These data indicate a potential interindividual variability in VC 24 metabolism. 25 Investigation of VC retention in the lung of human volunteers revealed large interindividual 26 differences in VC retention ( minimum 20.2% of the exposure concentration; maximum 79% of the 27 exposure concentration; Krajewski et al., 1980). 28 Interindividual differences in the response of human subjects to varying concentrations of VC were 29 observed by Lester et al. ( 1963): 8,000 ppm VC did not cause any response in 5 individuals, but one person 30 felt   slightly heady". Other subjects complained about adverse health effects at concentrations of  12,000 31 ppm, indicating that there are only small interindividual differences in the response to neurotoxic effects of 32 VC. 33 Relevant interindividual differences were not described in animal experiments. 34 Due to these observations a factor of 3 is used for the characterization of intraspecies variabilities 35 in the context with neurotoxic effects or cardiac sensitization. A factor of 10 is used to describe intraspecies 36 differences which are mediated by metabolites of VC. 37 Vinyl chloride PROPOSED 1: 3/ 2004 35 4.3.4. Concurrent Exposure Issues 1 Concurrent administration of ethanol and VC leads to an increase of liver angiosarcoma in rats in 2 comparison to animals exposed only to VC. This effect may be due to the interaction of ethanol ( a known 3 CYP2E1 inducer) with VC metabolism ( WHO, 1999a). 4 Induction of certain enzymes of the mixed function oxidase system by pretreatment with 5 phenobarbital or the mixture of polychlorinated biphenyls enhanced acute hepatotoxicity in rats as 6 measured by increased activity of hepatic enzymes and / or focal hepatic necrosis. On the other hand, 7 inhibitors of the mixed function oxidase system like SKF 525A have an opposite effect ( WHO, 1999a). 8 5. RATIONALE AND PROPOSED AEGL 1 9 5.1. Human Data Relevant to AEGL 1 10 Detection of 261 ppm VC by entering the exposure chamber was reported by Baretta et al. ( 1969). 11 The authors also described that 5 of 7 persons detected the odor of VC entering a chamber with 491 ppm 12 VC, but after 5 minutes of exposure detection was not any longer possible. 13 Amoore and Hautala ( 1983) reported an odor threshold of 3,000 ppm for VC. This value 14 represents the geometric average of three studies, extreme points and duplicate quotations were omitted. It 15 was not stated whether it is the detection or recognition threshold. 16 A " fairly pleasant odor" was reported by two persons exposed to 25,000 ppm for 3 minutes. At 17 these concentrations dizziness and slight disorientation occurred ( Patty et al., 1930). 18 Hori et al. ( 1972) reported an odor threshold for VC of 10  20 ppm ( 20 ppm in production 19 workers and 10 ppm in workers from other sites). This value was reviewed by the AIHA and the value has 20 been rejected because of several shortcomings of the experimental procedure ( e. g. no calibration of panel 21 odor sensitivity, not stated whether the given limit was due to recognition or detection, number of trials not 22 stated). 23 Irritating effects of VC are only observed at very high concentrations: accidental exposure to lethal 24 concentrations was accompanied by lesions of the eyes ( Danziger, 1960). 25 Baretta et al. ( 1969) exposed 4  6 volunteers to 59, 261, 491 ppm VC ( analytical concentrations) 26 for 7.5 h ( including a 0.5 h lunch period; corresponding to time weighted average concentrations of 48, 248 27 or 459 ppm over a period of 7.5 h), seven persons were exposed to 491 ppm for only 3.5 hours. The only 28 complaints were those of two subjects who reported mild headache and some dryness of their eyes and nose 29 during exposure to the highest concentration ( the time of onset of headaches is not specified and is assumed 30 to have occurred after 3.5 hours of exposure). 31 5.2. Animal Data Relevant to AEGL 1 32 Lacrimation occurred shortly after onset of exposure in animals exposed to VC ( exposure of mice, 33 rats, guinea pigs, and rabbits to concentrations between 42,900 ppm to 280,000 ppm, no differentiated 34 evaluation according to lacrimation). Lethal effects have been observed in mice and rats even in the lowest 35 Vinyl chloride PROPOSED 1: 3/ 2004 36 exposure concentrations ( 42,900 ppm without ventilation in mice and 150,000 ppm with ventilation in rats) 1 ( Prodan et al., 1975). Mastromatteo et al. ( 1960) described that irritation ( no further details) was occurring 2 immediately after onset of exposure to 100,000, 200,000 or 300,000 ppm VC in rats and mice; in guinea 3 pigs irritation was not described in concentrations below 400,000 ppm VC. However, 100,000 ppm VC 4 already resulted in unconsciousness of the animals. No other data on irritation of VC in animals are 5 available from literature. 6 5.3. Derivation of AEGL 1 7 Vinyl chloride is a compound with poor odor warning properties. Reports on odor threshold vary 8 over a wide range ( 10 to 25,000 ppm). There is no qualified study determining the detection or recognition 9 threshold. According to the report of Baretta et al. ( 1969) people seem to get used to the odor of VC. In 10 humans and animals irritation is only reported in the context of exposure to very high concentrations which 11 are lethal or cause unconsciousness. So, derivation of AEGL 1 values on base of the odor detection or 12 irritation is not possible. 13 Occurrence of headache has been reported by Baretta et al. ( 1969) in two subjects after acute 14 exposure ( the time of onset of headaches is not specified and is assumed to have occurred after 3.5 hours of 15 exposure) . These findings are supported by data from occupationally exposed persons who developed 16 headache after VC exposure ( Lilis et al., 1975; Suciu et al., 1975). The endpoint " mild headache" in the 17 study from Baretta et al. ( 1969) can be regarded as a no effect level for notable discomfort ( 491 ppm for 18 3.5 h). An intraspecies factor of 3 is employed: it is assumed that the effects are due to VC itself and not 19 due to a metabolite, so only small interindividual differences are expected. The relationship between 20 concentration and duration of exposure as related to lethality was examined by Ten Berge et al. ( 1986) for 21 approximately 20 irritant or systemically acting vapors and gases. The authors subjected the individual 22 animal data sets to Probit analysis with exposure duration and exposure concentration as independent 23 variables. An exponential function ( Cn x t = k), where the value of n ranged from 0.8 to 3.5 for different 24 chemicals was found to be an accurate quantitative descriptor for the chemicals evaluated. Approximately 25 90 percent of the values of n range between n= 1 and n= 3. Consequently, these values were selected as the 26 reasonable lower and upper bounds of n to use when data are not available to derive a value of n. A value 27 of n= 1 is used when extrapolating from shorter to longer time periods because the extrapolated values are 28 conservative and therefore, reasonable in the absence of any data to the contrary. Conversely, a value of 29 n= 3 is used when extrapolating from longer to shorter time periods because the extrapolated values are 30 conservative and therefore reasonable in the absence of any data to the contrary. The default values for " n" 31 are used, as the mechanism for the induction of headache is not well understood. The extrapolation to 10 32 minutes from a 3.5 hour exposure is justified because exposure of human at 4,000 ppm for 5 minutes did 33 not result in headache ( Lester et al., 1963). 34 TABLE 7: AEGL 1 VALUES FOR VINYL CHLORIDE 35 AEGL Level 36 10 minute 30 minute 1 hour 4 hour 8 hour AEGL 1 37 450 ppm 1200 mg/ m3 310 ppm 800 mg/ m3 250 ppm 650 mg/ m3 140 ppm 360 mg/ m3 70 ppm 180 mg/ m3 6. RATIONALE AND PROPOSED AEGL 2 38 6.1. Human Data Relevant to AEGL 2 39 Vinyl chloride PROPOSED 1: 3/ 2004 37 Lester et al. ( 1963) reported that 5 min exposure to 8,000 ppm caused dizziness in 1/ 6 subjects ( the 1 same subject reported slight dizziness at sham exposure and no effect at 12,000 ppm). No complaints were 2 made by any volunteer at 4,000 ppm. At 12,000 ppm one subject reported clear signs of discomfort 3 ( reeling, swimming head) and another subject another was unsure of some effect; he had a " somewhat 4 dizzy" feeling in the middle of exposure. At 16,000 ppm ( 5/ 6) and 20,000 ppm ( 6/ 6) persons complained 5 about dizziness, nausea, headache, dulling of visual and auditory cues. All symptoms disappeared shortly 6 after termination; headache persisted for 30 minutes in one subject after exposure to 20,000 ppm. 7 Three minutes exposure to 25,000 ppm resulted in dizziness and slight disorientation as to space 8 and size of surrounding objects and a burning sensation in the feet in two persons. They immediately 9 recovered on leaving the chamber and complained only of a slight headache which persisted for 30 minutes 10 ( Patty et al., 1930). 11 Baretta et al. ( 1969) exposed 4  6 volunteers to 59, 261, 491 ppm VC ( analytical concentrations) 12 for 7.5 h ( including a 0.5 h lunch period; corresponding to time weighted average concentrations of 48, 248 13 or 459 ppm over a period of 7.5 h), seven persons were exposed to 491 ppm for only 3.5 hours. The only 14 complaints were those of two subjects who reported mild headache and some dryness of their eyes and nose 15 during exposure to the highest concentration ( the time of onset of headaches is not specified and is assumed 16 to have occurred after 3.5 hours of exposure) . 17 6.2. Animal Data Relevant to AEGL 2 18 Animal toxicity after short term exposure is characterized by cardiac sensitization, ( pre) narcotic 19 and hepatic effects. Short term exposure ( 5 min) of dogs to VC induced cardiac sensitization towards 20 epinephrine ( EC50: 50,000 or 71,000 ppm in two independent experiments) ( Clark and Tinston, 1973; 21 1982). This observation is confirmed in higher concentrations by additional experimental data ). 22 Hehir et al. ( 1981) reported that single exposure of mice to 50,000 ppm VC caused twitching, 23 ataxia, hyperventilation and hyperactivity, beginning 40 min after start of exposure. Consistent with these 24 data Mastromatteo et al. ( 1960) reported that 100,000 ppm VC induced pronounced tremor, unsteady gait 25 and muscular incoordination in mice 15 min after onset of exposure. Exposure of mice to 1,500 ppm VC 26 for 2 h resulted in stasis of blood flow, decreasing enzyme activities in the liver, subcellular liver damage, 27 and shock liver after 24 h of exposure ( Tátrai and Ungváry, 1981). 28 Viola et al. ( 1970) reported that rats exposed to 30,000 ppm for 4 h/ d were slightly soporific ( no 29 further details). At higher concentrations ( 50,000 ppm for 2 h) moderate intoxication and loss of righting 30 reflex and intense intoxication at 60,000 ppm for 2 h ( but righting reflex still present) have been reported 31 by Lester et al. ( 1963). Intoxication was not further characterized. Higher VC concentrations ( 100,000 32 ppm) resulted in a loss of the corneal reflex ( exposure for 2 h) ( Lester et al., 1963). Already 15 min after 33 onset of exposure to 100,000 ppm tremor and ataxia were observed by Mastromatteo et al. ( 1960). Guinea 34 pigs exposed to 25,000 ppm for 5 min showed motor ataxia, unsteadiness on feet, after 90 min the animals 35 were unconscious ( NOAEL 10,000 ppm) ( Patty et al., 1930). Mastromatteo et al. ( 1960) reported the 36 unsteady gait and muscular incoordination in guinea pigs exposed for 15 min to 100,000 ppm. 37 Vinyl chloride PROPOSED 1: 3/ 2004 38 Single inhalation exposure of rats for 6 hours to 100,000 ppm VC resulted in histopathological 1 changes of the liver ( vacuolization), but was not observed in lower concentrations ( 50,000 ppm) ( Jaeger et 2 al., 1974). However, in mice Tátrai and Ungváry ( 1981) reported that stasis of the liver developed 2 and 4 3 h after the beginning of inhalation. The authors observed decreasing enzyme activities in liver and 4 subcellular liver damage at exposure concentrations of 1,500 ppm VC for 2 h; after 24 h shock liver 5 developed. Repeated exposure of rats to 1,500 ppm VC for up to 9 days during pregnancy caused increased 6 relative and absolute liver weights without light microscopic visible changes. Also, no histopathological 7 effects were observed in rabbits treated identically ( Ungváry et al., 1978). In another developmental study 8 increased absolute and relative liver weights have been observed in rats exposed intermittently to 2,500 9 ppm from day 6  15 of pregnancy, the NOAEL was 500 ppm ( John et al., 1977; 1981). 10 11 6.3. Derivation of AEGL 2 12 Short term exposure ( 5 min) of dogs to VC induced cardiac sensitization towards epinephrine 13 ( EC50: 50,000 or 71,000 ppm in two independent experiments) ( Clark and Tinston, 1973; 1982). A 14 NOAEL for this effect can be reasonably estimated by using a factor of 3 on EC50 ( 50,000 ppm) resulting 15 in a concentration of about 17,000 ppm. This concentration already leads to CNS effects in humans after 5 16 minutes exposure ( Lester et al., 1963). Thus, the endpoint of cardiac sensitization would not be the critical 17 effect for AEGL 2 derivation. However, the AEGL 2 derived below is supported by the data on cardiac 18 sensitization. 19 Liver toxicity is a major endpoint after long term exposure to VC and may possibly be linked to 20 tumor development in young animals ( see section 4.2. for further discussion). The NOAEL for irreversible 21 effects to the liver after single exposure is 50,000 ppm ( 6h, rat data). The effects seen in lower 22 concentrations ( liver weight changes) may not be regarded as key studies for AEGL 2 derivation. 23 Narcotic effects seem to predominate in rats, mice and guinea pigs acutely exposed to high 24 concentrations of VC. These effects are relevant AEGL 2 endpoints as they impair the possibility to escape. 25 Although guinea pigs seem to be less sensitive than rats and mice concerning lethality ( see 7.2) they are 26 more sensitive than rats and mice with regard to early signs of narcotic effects: exposure of guinea pigs for 27 5 min to 25,000 ppm resulted in early signs of narcotic effects ( motor ataxia, unsteadiness on feet), after 90 28 minutes animals were unconscious ( NOAEL 10,000 ppm) ( Patty et al., 1930). Rats exposed to 30,000 ppm 29 VC for 4 h were only slightly soporific ( Viola et al., 1970), and single exposure of mice to 50,000 ppm VC 30 caused twitching, ataxia, hyperventilation and hyperactivity, beginning 40 min after start of exposure 31 ( Hehir et al., 1981) . 32 The observations in animals are in good accordance with the effects observed in humans: dizziness, 33 reeling, swimming head, nausea etc., which can be regarded as early signs of narcosis, have been reported 34 in humans exposed to VC in concentrations  12,000 ppm for 5 min. No effects were reported at 4,000 ppm 35 ( Lester et al., 1963). The effects observed at 12,000 ppm ( dizziness, reeling, swimming head) were only 36 seen in 1 or 2 of 6 persons ( one person was unsure of an effect) and do not yet impair the capability to 37 escape, whereas, the effects observed at concentrations  16,000 ppm ( dizziness, nausea, headache, dulling 38 of visual and auditory cues) might possibly impair escape. Therefore, 12,000 ppm is interpreted as the no 39 effect level for impaired ability to escape and is used to derived the AEGL 2 values. 40 Vinyl chloride PROPOSED 1: 3/ 2004 39 By analogy to other anaesthetics the effects are assumed to be solely concentration dependent. 1 Thus, after reaching steady state at about 2 hours of exposure, no increase in effect is expected. The other 2 exposure duration specific values were derived by time scaling according to the dose response regression 3 equation Cn x t = k, using a factor of n= 2, based on data from Mastromatteo et al. ( 1960). Mastromatteo et 4 al. observed various time dependent prenarcotic effects in mice and guinea pigs after less than steady state 5 exposure conditions ( For details see Appendix B). With this, time extrapolation was performed from 5 to 6 10, 30, 60 minutes and 2 hours, where the steady state concentration was calculated. However, the resulting 7 AEGL 2 values may not provide a sufficient margin safety to avoid mutational events or malignancies after 8 short term exposure to VC. 9 The calculations of exposure concentrations scaled to AEGL 2 time points are shown in Appendix 10 A. The data are listed in the table below. 11 TABLE 8: AEGL 2 VALUES FOR VINYL CHLORIDE 12 AEGL Level 13 10 minute 30 minute 1 hour 4 hour 8 hour AEGL 2 14 2,800 ppm ( 7300 mg/ m ³ ) 1,600 ppm ( 4100 mg/ m ³ ) 1,200 ppm ( 3100 mg/ m ³ ) 820 ppm ( 2100 mg/ m ³ ) 820 ppm ( 2100 mg/ m ³ )

7. RATIONALE AND PROPOSED AEGL 3 15 7.1. Human Data Relevant to AEGL 3 16 Only two cases of accidental death due to VC exposure are described in literature. Exposure 17 concentrations and exposure time are unknown, but circumstances suggest inhalation of very high 18 concentrations. At autopsy cyanosis, congestion of lung and kidneys and blood coagulation failure were 19 observed ( Danziger, 1960). 20 7.2. Animal Data Relevant to AEGL 3 21 LC50 values reported for mice, rats, rabbits and guinea pigs indicate similar sensitivity of mice and 22 rats and of rabbits and guinea pigs. According to the data presented by Prodan et al. ( 1975) the following 23 LC50 values were obtained: 24 mice 117,500 ppm 25 rats 150,000 ppm 26 rabbits 240,000 ppm 27 guinea pigs 240,000 ppm 28 The findings in rats are supported by the data of Lester et al. ( 1963) who described that exposure 29 of 2 rats to 150,000 ppm for 2 hours resulted in the death of one rat whereas the other rat recovered on 30 removal to air. 31 The following LC00 values have been reported for these species. 32 Vinyl chloride PROPOSED 1: 3/ 2004 40 mice 100,000 ppm ( 2 h, Prodan et al., 1975) 1 rats 100,000 ppm ( 8 h, Lester et al., 1963) 2 200,000 ppm ( 0,5 h, Mastromatteo et al., 1960) 3 rabbits 200,000 ppm ( 2 h, Prodan et al., 1975) 4 guinea pigs 100,000 ppm ( 6 h, Patty et al., 1930) 5 200,000 ppm ( 2 h, Prodan et al., 1975) 6 In addition, relevant data on cardiac sensitization exist: Short term exposure ( 5 min) of dogs to VC 7 induced cardiac sensitization towards epinephrine ( EC50: 50,000 or 71,000 ppm in two independent 8 experiments) ( Clark and Tinston, 1973; 1982). These effects were also seen in mice at higher 9 concentrations ( Aviado and Belej, 1974). In monkeys, only myocardial depression after inhalation of 2.5 10 10% VC was observed. It is not clearly stated whether an addition challenge with epinephrine was applied 11 or not ( Belej et al., 1974). 12 7.3. Derivation of AEGL 3 13 Lethality data provide AEGL 3 values that are marginally higher than those derived based on 14 cardiac sensitization. Thus, animal data ( Clark and Tinston, 1973; 1982) on cardiac sensitization after 15 exposure for 5 minutes were used to derive AEGL 3. Severe cardiac sensitization is a life threatening 16 effect, but at 50,000 ppm no animal died in the reported study and is used to derive AEGL 3 values. A total 17 uncertainty factor of 3 is used to account for toxicodynamic differences among individuals. As the 18 challenge with epinephrine and the doses of epinephrine used represent a conservative scenario, no 19 interspecies uncertainty factor was used. As the unmetabolized VC is responsible for the effect, no relevant 20 differences in toxicokinetics are assumed. In analogy to other halocarbons ( e. g., Halon 1211, HFC 134a) 21 which lead to cardiac sensitization the effects are assumed to be solely concentration dependent. Thus, after 22 reaching steady state at about 2 hours of exposure, no increase in effect is expected. The other exposure 23 duration specific values were derived by time scaling according to the dose response regression equation Cn 24 x t = k, using an n of 2, based on data from Mastromatteo et al. ( 1960). Mastromatteo et al. observed 25 various time dependent prenarcotic effects ( muscular incoordination, side position and unconsciousness, 26 effects which occur immediately before lethality) in mice and guinea pigs after less than steady state 27 exposure conditions. With this, time extrapolation was performed from 5 to 10, 30, 60 minutes and 2 hours, 28 where the steady state concentration was calculated. 29 The values are listed in the table below. 30 TABLE 9: AEGL 3 VALUES FOR VINYL CHLORIDE 31 AEGL Level 32 10 minute 30 minute 1 hour 4 hour 8 hour AEGL 3 33 12,000 ppm ( 31,000 mg/ m ³ ) 6,800 ppm ( 18,000 mg/ m ³ ) 4,800 ppm ( 12,000 mg/ m ³ ) 3,400 ppm ( 8,800 mg/ m ³ ) 3,400 ppm ( 8,800 mg/ m ³ )

8. SUMMARY OF PROPOSED AEGLs 34 8.1. AEGL Values and Toxicity Endpoints 35 Vinyl chloride PROPOSED 1: 3/ 2004 41 The derived AEGL values for various levels of effects and durations of exposure are summarized 1 in Table 10. AEGL 1 values have been derived based on mild headaches observed in volunteers ( Baretta et 2 al., 1969); odor threshold was not determined in a validated manner and seems to vary over a wide range. 3 AEGL 2 values are based on CNS effects, which may impair escape capacity ( Lester et al., 1963). Data on 4 cardiac sensitization ( Clark and Tinston, 1982; 1973) are supported by lethality concentrations ( LC00) in 5 slightly higher concentrations ( Prodan et al., 1975) and are used for AEGL 3 derivation. 6 7 TABLE 10: SUMMARY/ RELATIONSHIP OF PROPOSED AEGL VALUES 8 Classification 9 10 minute 30 minute 1 hour 4 hour 8 hour AEGL 1 10 ( Non disabling) 11 450 ppm 1200 mg/ m3 310 ppm 800 mg/ m3 250 ppm 650 mg/ m3 140 ppm 360 mg/ m3 70 ppm 180 mg/ m3 AEGL 2 12 ( Disabling) 13 2,800 ppm 7,300 mg/ m3 1,600 ppm 4,100 mg/ m3 1,200 ppm 3,100 mg/ m3 820 ppm 2,100 mg/ m3 820 ppm 2,100 mg/ m3 AEGL 3 14 ( Lethal) 15 12,000 ppm ( 31,000 mg/ m3) 6,800 ppm ( 18,000 mg/ m3) 4,800 ppm ( 12,000 mg/ m3) 3,400 ppm ( 8,800 mg/ m3) 3,400 ppm ( 8,800 mg/ m3)

Inhalation data are summarized in Figure 1 below. The data were classified into severity categories 16 chosen to fit into definitions of the AEGL level health effects. The category severity definitions are " No 17 effect"; " Disabling"; " Lethal" and " AEGL". 18 Vinyl chloride PROPOSED 1: 3/ 2004 42 10 100 1000 10000 100000 1000000 ppm 0 60 120 180 240 300 360 420 480 Minutes Human  No Effect Human  Discomfort Human  Disabling Animal  No Effect Animal  Discomfort Animal  Disabling Animal  Partially Lethal Animal  Lethal AEGL Chemical Toxicity  TSD All Data Vinyl chloride AEGL 3 AEGL 1 AEGL 2 FIGURE 1: CATEGORICAL REPRESENTATION OF VINYL CHLORIDE INHALATION 1 DATA ( data where the exposure time exceeded 500 min are not included) 2 8.2. Comparison with Other Standards and Criteria 3 Other standards and guidance levels for workplace and community exposures are listed in Table 4 11. 5 Vinyl chloride PROPOSED 1: 3/ 2004 43 TABLE 11: EXISTENT STANDARDS AND GUIDELINES FOR VINYL CHLORIDE 1 Guideline 2 Exposure Duration 10 minute 30 minute 1 hour 4 hour 8 hour AEGL 1 3 310 ppm 310 ppm 250 ppm 140 ppm 70 ppm AEGL 2 4 2,800 ppm 1,600 ppm 1,200 ppm 820 ppm 820 ppm AEGL 3 5 12,000 ppm 6,800 ppm 4,800 ppm 3,400 ppm 3,400 ppm PEL TWA ( OSHA) a 6 1 ppm STEL ( OSHA) b 7 5 ppm [ for 15 min]

TLV TWA 8 ( ACGIH) c 9 5 ppm TEEL 0 ( CSP) d 10 1 ppm TEEL 1 ( CSP) e 11 5 ppm TEEL 2 ( CSP) f 12 5 ppm TEEL 3 ( CSP) g 13 75 ppm TRK ( Germany) h 14 2 ( 3) ppm Einsatztoleranzwerte ( Greim, 15 Germany) i 16 100 ppm Störfallbeurtei lungswert ( VCI) j 17 1,000 ppm a OSHA PEL TWA ( Occupational Health and Safety Administration, Permissible Exposure Limits  Time 18 Weighted Average) ( OSHA, 2002) is the time weighted average concentration for a normal 8 hour 19 workday and a 40 hour work week, to which nearly all workers may be repeatedly exposed, day after day, 20 without adverse effect. 21 b OSHA PEL STEL ( Permissible Exposure Limits  Short Term Exposure Limit) ( OSHA, 2002) is defined as a 22 15 minute TWA exposure which should not be exceeded at any time during the workday even if the 8 23 hour TWA is within the PEL TWA. Exposures above the PEL TWA up to the STEL should not be longer 24 than 15 minutes and should not occur more than 4 times per day. There should be at least 60 minutes 25 between successive exposures in this range. 26 C ACGIH TLV TWA ( American Conference of Governmental Industrial Hygienists, Threshold Limit Value 27  Time Weighted Average) ( ACGIH, 1998). The time weighted average concentration for a normal 8 28 hour workday and a 40 hour work week, to which nearly all workers may be repeatedly exposed, day after 29 day, without adverse effect. The value was based on a calculation of the carcinogenic potency of vinyl 30 chloride by Gehring and coworkers. The TLV Committee concluded that a TLV TWA of 5 ppm should 31 not result in a detectable increase in the incidence of occupational cancers, specifically angiosarcoma of 32 the liver. 33 Vinyl chloride PROPOSED 1: 3/ 2004 44 d TEEL 0 ( U. S. department of Energy` s Chemical safety Program, Temporary Emergency Exposure Limit) 1 ( CSP, 2002). The threshold concentration below which most people will experience no appreciable risk of 2 health effects. 3 e TEEL 1 ( U. S. department of Energy` s Chemical safety Program, Temporary Emergency Exposure Limit) 4 ( CSP, 2002). The maximum concentration in air below which it is believed nearly all individuals could be 5 exposed without experiencing other than mild transient adverse health effects or perceiving a clearly 6 defined objectionable odor. 7 f TEEL 2 ( U. S. department of Energy` s Chemical safety Program, Temporary Emergency Exposure Limit) 8 ( CSP, 2002). The maximum concentration in air below which it is believed nearly all individuals could be 9 exposed without experiencing or developing irreversible or other serious health effects or symptoms that 10 could impair their abilities to take protective action. 11 g TEEL 3 ( U. S. department of Energy` s Chemical safety Program, Temporary Emergency Exposure Limit) 12 ( CSP, 2002). The maximum concentration in air below which it is believed nearly all individuals could be 13 exposed without experiencing or developing life threatening health effects. 14 h TRK ( Technische Richtkonzentrationen [ Technical Guidance Concentration], Deutsche 15 Forschungsgemeinschaft [ German Research Association], Germany) ( DFG, 2001). TRK is defined as 16 the air concentration of a substance which can be achieved with the current technical standards. TRK 17 values are given for those substances for which no maximum workplace concentration can be established. 18 Compliance of the TRK should minimize the risk of health effects, but health effects cannot be excluded 19 even at this concentration. ( A value of 3 ppm is given for existing plants and the production of VC and 20 PVC, in all other cases 2 ppm should not be exceeded.) 21 i Einsatztoleranzwert [ Action Tolerance Levels] ( Vereinigung zur Förderung des deutschen Brandschutzes 22 e. V. [ Federation for the Advancement of German Fire Prevention]) ( Greim, 1995/ 1996) constitutes a 23 concentration to which unprotected firemen and the general population can be exposed to for up to 4 hours 24 without any health risks. The value is based on the observation that no acute toxic effects or irritating 25 effects have been observed during exposure to 500 ppm for 4 hours. 26 j Störfallbeurteilungswert [ Emergency Assessment Value] ( VCI, Verband der Chemischen Industrie, 27 Deutschland [ Association of the Chemical Industry in Germany]) ( VCI, 1990). These values have been 28 set for an exposure time of up to 1 h. Considering that VC leads to anaesthesia in concentrations of 7%, to 29 pre narcotic syndroms at 0.5%, and to respiratory arrest the Emergency Assessment Value has been set at 30 1,000 ppm. 31 8.3. Data Adequacy and Research Needs 32 As VC has only poor warning properties there is only a very limited data base to derive AEGL 1. 33 Additional studies with volunteers may not be performed due to ethical reasons. AEGL 2 values are based 34 on animal experiments regarding CNS effects. The respective concentration range is well established but 35 excludes potential mutagenic or carcinogenic effects after short term exposure, which might occur in lower 36 concentrations. However, quantitative estimates of the respective risk are highly uncertain. For derivation 37 of AEGL 3 values, the dogs studies on cardiac sensitization are in good accordance with lethality data in 38 slightly higher concentrations. 39 Vinyl chloride PROPOSED 1: 3/ 2004 45 9. REFERENCES 1 ACGIH ( American Conference of Governmental Industrial Hygienists). 1998. Documentation of the 2 Threshold Limit Values and Biological Exposure Indices. Cincinnati, OH. 3 AIHA ( American Industrial Hygiene Association). 1997. 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Biomonitoring and Risk Assessment, 17 Oxford University Press, London, 421 428. 18 Weber, H., W. Reinl, and E. Greiser. 1981. German investigations on morbidity and mortality of workers 19 exposed to vinyl chloride. Environ. Health Perspect. 41: 95 99. 20 WHO, World Health Organization. 1987. Air Quality Guidelines for Europe. WHO Regional Publications. 21 European Series, No. 23. Kopenhagen, 1987. 22 WHO, World Health Organization. 1999a. Environmental Health Criteria 215, Vinyl Chloride. IPCS, 23 International Programme on Chemical Safety. World Health Organization, Geneva, 1999. 24 WHO, World Health Organization. 1999b. Update and Revision of WHO Air Quality Guidelines for 25 Europe. http:// www. who. dk/ envhlth/ airqual. htm ( accessed: 29/ 10/ 1999). 26 Vinyl chloride PROPOSED 1: 3/ 2004 55 APPENDIX A  Derivation of AEGL values 1 Vinyl chloride PROPOSED 1: 3/ 2004 56 AEGL 1 1 Key study: Baretta et al. ( 1969) 2 Toxicity endpoint: Mild headache in 2 subjects during exposure to highest concentration ( i. e. 491 3 ppm for 3.5 h) 4 Uncertainty/ Total uncertainty factor of 3 for intraspecies variability 5 modifying factors: 6 Time Scaling: C3 x t = k for extrapolation to 1 hour and 30 minute ( 10 minute = 30 minute 7 value); C1 x t = k for extrapolation to 4 and 8 hour 8 k = ( 491 ppm) 3 x 210 min = 2.49 x 10E+ 10 ppm3 min 9 k = ( 491 ppm) 1 x 210 min = 103110 ppm min 10 Calculations: 11 10 minute AEGL 1 C3 x 10 min = 2.49 x 10E+ 10 ppm3 min 12 C = 1355 ppm 13 10 min AEGL 1 = 1355 ppm/ 3 = 450 ppm (= 1170 mg/ m3) 14 15 30 minute AEGL 1 C3 x 30 min = 2.49 x 10E+ 10 ppm3 min 16 C = 939.25 ppm 17 30 min AEGL 1 = 939 ppm/ 3 = 310 ppm (= 810 mg/ m3) 18 1 hour AEGL 1 C3 x 60 min = 2.49 x 10E+ 10 ppm3 min 19 C = 745.48 ppm 20 1 h AEGL 1 = 745 ppm/ 3 = 250 ppm (= 640 mg/ m3) 21 4 hour AEGL 1 C x 240 min = 103110 ppm min 22 C = 429.63 ppm 23 4 h AEGL 1 = 430 ppm/ 3 = 140 ppm (= 370 mg/ m3) 24 8 hour AEGL 1 C x 480 min = 103110 ppm min 25 C = 214.81 ppm 26 8 h AEGL 1 = 214 ppm/ 3 = 70 ppm (= 190 mg/ m3) 27 Vinyl chloride PROPOSED 1: 3/ 2004 57 AEGL 2 1 Key study: Lester et al. ( 1963) 2 Toxicity endpoint: Prenarcotic effects were observed in human volunteers. After 5 minute exposure to 3 16,000 ppm VC 5 of 6 persons showed dizziness, lightheadedness, nausea, visual 4 and auditory dulling. At concentrations of 12,000 ppm one of six persons showed 5 " swimming head, reeling". Another individual was unsure of some effect and was 6 somewhat dizzy. A single person reported slight effects (" slightly heady") of 7 questionable meaning at 8,000 ppm ( this volunteer felt also slightly heady at sham 8 exposure and reported no response at 12,000 ppm). No effects were observed at 9 4,000 ppm. ( Lester et al., 1963). 12,000 ppm was regarded as a concentration 10 below AEGL 2 level and taken as NOAEL. 11 Uncertainty/ Total uncertainty factor of 3 for intraspecies variability 12 modifying factors: 13 Time Scaling: C2 x t = k for extrapolation 2 hour, 1 hour, 30 minute, and 10 minute, flatlining 14 from 4h to 8 h ( based on 2 hours steady state concentration) 15 k = ( 12,000 ppm) 2 x 5 min = 7.2 x 10E+ 8 ppm2 min 16 Calculations: 17 10 minute AEGL 2 C2 x 10 min = 7.2 x 10E+ 8 ppm2 min 18 C = 8485.28 ppm 19 10 min AEGL 2 = 8485 ppm/ 3 = 2800 ppm (= 7300 mg/ m3) 20 21 30 minute AEGL 2 C2 x 30 min = 7.2 x 10E+ 8 ppm2 min 22 C = 4898.98 ppm 23 30 min AEGL 2 = 4899 ppm/ 3 = 1600 ppm (= 4100 mg/ m3) 24 1 hour AEGL 2 C2 x 60 min = 7.2 x 10E+ 8 ppm2 min 25 C = 3464.11 ppm 26 1 h AEGL 2 = 3464 ppm/ 3 = 1200 ppm (= 3100 mg/ m3) 27 2 hour steady state C2 x 120 min = 7.2 x 10E+ 8 ppm2 min 28 C = 2449.49 ppm 29 2 h steady state= 2450/ 3 ppm/ 3 = 820 ppm (= 2100 mg/ m3) 30 4 hour AEGL 2 = 2 hour steady state/ 3 = 820 ppm (= 2100 mg/ m3) 31 8 hour AEGL 2 = 4 hour AEGL 2 = 820 ppm (= 2100 mg/ m3) 32 Vinyl chloride PROPOSED 1: 3/ 2004 58 AEGL 3 1 Key study: Clark and Tinston, 1973; 1982 2 Toxicity endpoint: Short term exposure ( 5 min) of dogs to VC induced cardiac sensitization towards 3 epinephrine ( EC50: 50,000 or 71,000 ppm in two independent experiments) ( Clark 4 and Tinston, 1973; 1982). These effects were also seen in mice at higher 5 concentrations ( Aviado and Belej, 1974). 50,000 ppm was used as NOAEL for life 6 threatening effects 7 Uncertainty/ Combined uncertainty factor of 3 8 modifying factors: 1 for interspecies variability 9 3 for intraspecies variability 10 Time Scaling: C2 x t = k for extrapolation to 2 hour, 1 hour, and 30 minute and 10 minutes; 11 flatlining from 4h to 8 h ( based on 2 hours steady state concentration) 12 k = ( 50,000 ppm) 2 x 5 min = 1,25 10E+ 10 ppm2 min 13 14 Calculations: 15 10 minute AEGL 3 C2 x 10 min = 1,25 10E+ 10 ppm2 min 16 C = 35,355.34 ppm 17 30 min AEGL 2 = 35,355 ppm/ 3 = 12,000 ppm (= 31,000 mg/ m3) 18 30 minute AEGL 3 C2 x 30 min = 1,25 10E+ 10 ppm2 min 19 C = 20,412.41 ppm 20 30 min AEGL 2 = 20,412 ppm/ 3 = 6,800 ppm (= 18,000 mg/ m3) 21 1 hour AEGL 3 C2 x 60 min = 1,25 10E+ 10 ppm2 min 22 C = 14433.76 ppm 23 1 h AEGL 2 = 14434 ppm/ 10 = 4,800 ppm (= 12,000 mg/ m3) 24 2 hour steady state C2 x 120 min = 1,25 10E+ 10 ppm2 min 25 C = 10,206.21 ppm 26 2 h steady state = 10,206 ppm/ 3 = 3,400 ppm (= 8,800 mg/ m3) 27 4 hour AEGL 3 = 2 h steady state/ 3 = 3,400 ppm (= 8,800 mg/ m3) 28 29 8 hour AEGL 3 = 4 h AEGL 3 = 3,400 ppm (= 8,800 mg/ m3) 30 Vinyl chloride PROPOSED 1: 3/ 2004 59 APPENDIX B  Time Scaling Calculations for Vinyl Chloride AEGLs 1 Vinyl chloride PROPOSED 1: 3/ 2004 60 Time Scaling for Vinyl Chloride AEGLs 1 The relationship between dose and exposure time to produce a toxic effect for any given chemical 2 is a function of the physical and chemical properties of the substance and the unique toxicologic and 3 pharmacologic properties of the individual substance. Historically, the relationship according to Haber 4 ( 1924), commonly called Haber` s rule ( i. e., C x t = k, where C = exposure concentration, t = exposure 5 duration, and k = a constant) has been used to relate exposure concentration and duration to a toxic effect 6 ( Rinehart and Hatch, 1964). This concept states that exposure concentration and exposure duration may be 7 reciprocally adjusted to maintain a cumulative exposure constant ( k) and that this cumulative exposure 8 constant will always reflect a specific quantitative and qualitative response. This inverse relationship of 9 concentration and time may be valid when the toxic response to a chemical is equally dependent upon the 10 concentration and the exposure duration. However, an assessment by ten Berge et al. ( 1986) of LC50 data 11 for certain chemicals revealed chemical specific relationships between exposure concentration and exposure 12 duration that were often exponential. This relationship can be expressed by the equation Cn x t = k, where n 13 represents a chemical specific and even a toxic endpoint specific exponent. The relationship described by 14 this equation is basically the form of a linear regression analysis of the log log transformation of a plot of C 15 vs. t ( NRC, 2001). 16 Acute CNS toxicity and lethality of VC are dominated by its narcotic effects characterized by a 17 typical sequence of effects ( increased motor activity, tremor, muscular incoordination, side position, 18 unconsciousness, resulting in deep narcosis). The occurrence and time sequence of these effects in rats, 19 mice and guinea pigs has been described by Mastromatteo et al. ( 1960). These experimental data are used 20 for the derivation of values of n by linear regression analysis of the log log transformed plot of C vs. t. 21 Three data sets of toxic effects in mice and rats or guinea pigs described by Mastromatteo et al. 22 ( 1960) were analyzed. As the time concentration relationships for mice and rats were identical the following 23 evaluation concentrates on the data obtained in mice and guinea pigs. Regression analysis has been 24 performed for the endpoints unconsciousness, muscular incoordination, and side position. The time 25 concentration relation ships are described below. 26 Time dependency is only true as long as no steady state is reached. Similar to other inhalation 27 anesthetics, maximal blood concentration of VC after inhalation exposure depends on the partial pressure 28 of VC in the air. Blood respectively brain concentration, which directly correlates with the depth of narcosis 29 ( see below) and  presumably  with cardiac sensitization level, can be controlled by changing the 30 concentration of VC in the air, i. e. by changing the partial pressure of VC in the air. If equilibrium is 31 reached between the partial pressure of VC in the air and in the blood ( steady state), no further increase of 32 VC concentration in the blood is possible, even if the exposure time is prolonged ( Forth et al., 1987). The 33 time necessary to set up steady state mainly depends on the blood/ air partition coefficient of a substance. 34 The blood/ air partition coefficient of VC in humans is 1.2 ( Csanady and Filser, 2001), similar to that of the 35 inhalation anesthetic isoflurane ( 1.4; Forth et al., 1987). For this substance the equilibrium is reached after 36 about 2 hours, derived by graphical extrapolation of the data on isoflurane ( Goodman and Gilman, 1975). 37 For VC, in much lower concentrations an elimination half time of VC of 20.5 minutes has been derived 38 ( Buchter, 1979; Bolt et al., 1981). From that, for low concentrations a steady state concentration for VC in 39 blood of about 5 x 20.5 = 102.5 minutes can be calculated by standard estimation rules. Thus, in high or 40 low concentrations a relevant increase of internal concentrations of VC is not to be expected after more 41 Vinyl chloride PROPOSED 1: 3/ 2004 61 than 2 hours of exposure. However, for shorter periods of exposure a relevant influence of time on the 1 built up of VC on internal concentrations has to be taken into account: 2 Unconsciousness: 3 The time after which unconsciousness was observed in mice after exposure to 100,000, 200,000 or 4 300,000 ppm VC was 25 min, 10 min, and 5 min, respectively: 5 Time min 6 Concentration ppm Log time Log Concentration 5 7 300000 0.699 5.477 10 8 200000 1 5.301 25 9 100000 1.398 5 The time after which unconsciousness was observed in guinea pigs after exposure to 100,000, 200, 10 000, 300,000, and 400,000 ppm VC was 30 min, 10 min, 5 min and 5 min, respectively: 11 Time min 12 Concentration ppm Log time Log Concentration 5 13 400000 0.699 5.602 5 14 300000 0.699 5.477 10 15 200000 1 5.301 30 16 100000 1.477 5 Regression analysis of the data is shown in figure 2: 17 Vinyl chloride PROPOSED 1: 3/ 2004 62 y =  0.6865x + 5.968 R2 = 0.9951 y =  0.6957x + 6.019 R2 = 0.9586 4.9 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 log time [ min] log concentration [ ppm] Unconsciousness gpg Unconsciousness mouse FIGURE 2: REGRESSION ANALYSIS OF THE LOG LOG TRANSFORMED 1 CONCENTRATION TIME CURVE REGARDING UNCONSCIOUSNESS IN MICE AND 2 GUINEA PIGS ( DATA FROM MASTROMATTEO ET AL., 1960) 3 The slope of the regression line was  0.6865 and  0.6957 in mice and guinea pigs, respectively, 4 corresponding to a value of 1.46 and 1.44 for n. 5 Vinyl chloride PROPOSED 1: 3/ 2004 63 Muscular incoordination: 1 The time after which muscular incoordination was observed in mice after exposure to 100,000, 2 200,000 or 300,000 ppm VC was 15 min, 2 min, and 1 min, respectively: 3 Time min 4 Concentration ppm Log time Log Concentration 1 5 300000 0 5.477 2 6 200000 0.301 5.301 15 7 100000 1.176 5 The time after which muscular incoordination was observed in guinea pigs after exposure to 8 100,000, 200,000, 300,000, or 400,000 ppm VC was 15 min, 5 min, 2 min, and few seconds, respectively: 9 Time min 10 Concentration ppm Log time Log Concentration few seconds* 11 400000  5.602 2 12 300000 0.301 5.477 5 13 200000 0.699 5.301 15 14 100000 1.176 5 *: this value was not regarded in regression analysis 15 Regression analysis of the data is shown in figure 3: 16 Vinyl chloride PROPOSED 1: 3/ 2004 64 y =  0.3919x + 5.4523 R2 = 0.9845 y =  0.5481x + 5.6569 R2 = 0.9905 4.9 5 5.1 5.2 5.3 5.4 5.5 5.6 5.7 0 0.2 0.4 0.6 0.8 1 1.2 1.4 log time [ min] log concentration [ ppm] Muscular incoordination gpg Muscular incoordination mouse FIGURE 3: REGRESSION ANALYSIS OF THE LOG LOG TRANSFORMED 1 CONCENTRATION TIME CURVE REGARDING MUSCULAR INCOORDINATION IN MICE 2 AND GUINEA PIGS ( DATA FROM MASTROMATTEO ET AL., 1960) 3 The slope of the regression line was  0.3919 and  0.5481 in mice and guinea pigs, respectively, 4 corresponding to a value of 2.6 and 1.8 for n. 5 Vinyl chloride PROPOSED 1: 3/ 2004 65 Side position: 1 The time after which side position was observed in mice after exposure to 100,000, 200,000 or 2 300,000 ppm VC was 20 min, 5 min, and 2 min, respectively: 3 Time min 4 Concentration ppm Log time Log Concentration 2 5 300000 0.301 5.477 5 6 200000 0.699 5.301 20 7 100000 1.301 5 The time after which side position was observed in guinea pigs after exposure to 100,000, 200,000, 8 or 300,000 ppm VC was 30 min, 10 min, 2 5 min ( set to 3.5), respectively: 9 Time min 10 Concentration ppm Log time Log Concentration 35 11 300000 0.544 5.477 10 12 200000 1 5.301 30 13 100000 1.477 5 Regression analysis of the data is shown in figure 4: 14 Vinyl chloride PROPOSED 1: 3/ 2004 66 y =  0.479x + 5.6268 R2 = 0.9989 y =  0.5123x + 5.7753 R2 = 0.9814 4.9 5 5.1 5.2 5.3 5.4 5.5 5.6 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 log time [ min] log concentration [ ppm] Side position gpg Side position mouse FIGURE 4: REGRESSION ANALYSIS OF THE LOG LOG TRANSFORMED 1 CONCENTRATION TIME CURVE REGARDING SIDE POSITION IN MICE AND GUINEA 2 PIGS ( DATA FROM MASTROMATTEO ET AL., 1960) 3 The slope of the regression line was  0.479 and  0.5123 in mice and guinea pigs, respectively, 4 corresponding to a value of 2.1 and 2.0 for n. 5 Regarding the three different endpoints and the data obtained for mice and guinea pigs values for n 6 were in the range of 1.44 to 2.6 ( 1.44; 1.46; 1.8; 2.0; 2.1; 2.6; arithmetic mean: 1.9 +/ 0.4). Based on 7 these data it is justified to use a value of n= 2 for the time extrapolation for AEGL 2 ( CNS effects) and 8 AEGL 3 ( cardiac sensitization) values up to two hours. Concentrations for these " less than steady state" 9 durations ( i. e. 10, 30, 60 and 120 minutes) should be calculated according to 10 C2 * t = const. 11 Vinyl chloride PROPOSED 1: 3/ 2004 67 APPENDIX C  Cancer Assessment of Vinyl Chloride 1 Vinyl chloride PROPOSED 1: 3/ 2004 68 Cancer Assessment of Vinyl Chloride 1 2 The most recently published risk estimate from the US EPA seems to be the best unit risk estimate 3 currently available ( US EPA 2000 a, b). The values are 8.8 x 10 6 (

g/ m3) 1 for continuous lifetime 4 exposure, including childhood, and 4.4 x 10 6 (

g/ m3) 1 for continuous exposure as an adult. These risk 5 values indicate that exposure during childhood results in a similar tumor incidence as exposure as an adult. 6 The EPA unit risk calculation was derived by using the PBPK model of Clewell et al. ( 1995, 2002). These 7 risk values are based on model derived estimates of internal dose of the active metabolite in animals and the 8 continuous external exposure in humans that would result in these same internal dose of the active 9 metabolite. 10 Several calculations for cancer risk are presented below. These are: 11 Calculation A: based on the unit risk for continuous lifetime exposure from EPA ( 2002 a, b), transformed 12 to a single 24 hour exposure estimate by the default procedure recommended in the SOP on 13 AEGL development ( that is, linear transformation, correction by a factor of 6 to account 14 for the relevance of sensitive stages in development). Exposures of less than 24 hours are 15 derived using the PBPK model of Clewell et al. ( 1995, 2002). 16 Calculation B: based on the unit risk for childhood exposure only ( possibly the first 10 years of age) as 17 estimated by US EPA ( 2002 a, b), transformed to a single 24 hour exposure estimate by 18 the default procedure recommended in the SOP on AEGL development ( that is, linear 19 transformation, correction by a factor of 6 to account for the relevance of sensitive stages 20 in development). Exposures of less than 24 hours are derived using the PBPK model of 21 Clewell et al. ( 1995, 2002). 22 Calculation C: based on the cancer incidence as evident from a five weeks animal study from Maltoni et 23 al. ( 1981), assuming that 5 weeks of exposure of animal is equivalent to about 150 weeks 24 exposure of humans, with linear transformation to a single 24 hour exposure without 25 further correction for potential sensitive stages of tumor development. Exposures of less 26 than 24 hours are derived using the PBPK model of Clewell et al. ( 1995, 2002). 27 Calculation D: based on the NOAEL for DNA adducts after single in vivo exposure of adult animals and 28 the application of an uncertainty factor for intraspecies variability. 29 Calculation C is judged to be the best basis for estimation of the risk for carcinogenic effects after single 30 exposure and is included into the main part of the TSD. However, substantial uncertainties on risk 31 quantification exist. 32 Calculation A: based on the unit risk for continuous lifetime exposure from EPA ( 2002 a, b), transformed 33 to a single 24 hour exposure estimate by the default procedure recommended in the SOP on 34 AEGL development ( that is, linear transformation, correction by a factor of 6 to account 35 for the relevance of sensitive stages in development). Exposures of less than 24 hours are 36 derived using the PBPK model of Clewell et al. ( 1995, 2002). 37 Vinyl chloride PROPOSED 1: 3/ 2004 69 AEGL SOP Calculation 1 The US EPA's unit risk estimate for continuous lifetime exposure ( inclusive of childhood) is 8.8 x 2 10 6 (

g/ m3) 1. This unit risk was derived using the PBPK model of Clewell et al ( 1995, 2002) which 3 relates liver tumor incidence in animals with the lifetime average daily dose of the vinyl chloride metabolite 4 in the liver believed responsible for the tumor response ( that is, the internal dose of the metabolite). The 5 model then uses human parameters to transform that internal dose to an external exposure concentration for 6 humans. 7 Unit risk for continuous lifetime exposure: 8.8 x 10 6 per

g/ m3 8 Exposure at a risk of 1 in 10,000: 11.36

g/ m3 9 To convert a 70 year exposure to a 24 hour exposure, the exposure is multiplied by the number of days in 10 70 years. Under this strict c x t assumption, these exposures are considered equipotent. 11 11.36

g/ m3 x 25,600 = 291 mg/ m3 12 To account for uncertainty regarding the variability in the stage of the cancer process at which VC or its 13 metabolites may act, a multistage factor of 6 is applied ( NRC, 2001). 14 291 mg/ m3 x 1/ 6 = 48.5 mg/ m3 ( 18.4 ppm) 15 Based on this transformation, a 24 hour VC exposure at this concentration would result in a 10 4 risk. For 16 10 5 and 10 6 risk, the 10 4 value is reduced by 10 and 100 fold, respectively. This estimate is based on the 17 assumption of a strict c x t relationship. 18 PBPK model calculations for an exposure less than 24 hours 19 As mentioned above, the basis of US EPA's risk estimate is the internal dose, the lifetime average 20 daily dose( LADD) of VC metabolite in the liver. For numerous reasons this metric may be quite different 21 after a single exposure of less than 24 hours. Rather than make any assumption about the extent to which c 22 x t may or may not be operative, the PBPK model was used to estimate directly the internal dose to the liver 23 under different external exposure regimes. These data are shown in the table and figure below. 24 From above, the external exposure corresponding to a 10 4 risk with a 24 hour exposure is 48.5 25 mg/ m3. Values for less than 24 hour exposure are determined by interpolation using Table 1. The internal 26 dose metric ( mg/ L Liver) corresponding to a 10 4 risk with a 24 hour exposure is 51.4 mg/ L ( 48.5 mg/ m3 27 divided by 100 mg/ m3 times 106 mg/ L. The external exposure necessary to give 51.4 mg/ L Liver after an 28 8 hour exposure is 147 mg/ m3 ( 51.4 mg/ L divided by 35.0 mg/ L times 100 mg/ m3). A corresponding 29 calculation was made for each exposure duration ( 0.5 hours, 1 hr, 4 hrs, and 8 hrs) and each risk level ( 10 30 4, 10 5, and 10 6). 31 Dose to the liver ( mg/ L) of active metabolite at 24 hours after exposure to VC 32 mg/ m3 0.5 hr 1 hr 4 hr 8 hr 24 hr/ 70 yrs 33 1 0.022 0.044 0.176 0.352 1.07 34 10 0.220 0.441 1.76 3.52 10.7 35 Vinyl chloride PROPOSED 1: 3/ 2004 70 100 2.19 4.38 17.5 35.0 106 1 200 4.36 8.72 34.8 69.4 211 2 300 6.50 13.0 51.8 103 313 3 400 8.61 17.2 68.4 136 413 4 500 10.7 21.3 84.5 169 510 5 600 12.7 25.2 100 199 604 6 700 14.6 29.1 115 229 692 7 800 16.5 32.7 129 256 775 8 900 18.2 36.1 142 282 850 9 1000 19.9 39.3 153 304 917 10 2000 30.4 57.7 211 412 1220 11 3000 35.7 65.8 231 442 1300 12 4000 39.7 71.9 243 461 1350 13 5000 43.3 77.2 254 476 1390 14 6000 46.6 82.1 264 490 1420 15 7000 49.7 86.7 273 502 1460 16 8000 52.3 91.1 279 513 1490 17 9000 54.7 95.3 284 523 1520 18 10000 57.0 99.3 289 533 1540 19 Figure 5 shows the PBPK modeling results graphically ( with a cut off for the external concentration at 20 2000 mg/ m3). 21 Vinyl chloride PROPOSED 1: 3/ 2004 71 FIGURE 5: EXTERNAL CONCENTRATION ( mg/ m3) AND DOSE TO LIVER ( mg/ L) AS 1 CALCULATED BY PBPK MODELING BY EPA ( Personal Communication, Gary Foureman, US 2 EPA, NCEA RTP, June 2003) 3 If the exposure is limited to a fraction of a 24 hour period, the exposure corresponding to the various risk 4 levels are presented in the table below. 5 Exposure Duration 6 10 4 risk 10 5 risk 10 6 risk 8 hours 7 147 mg/ m3 ( 55.9 ppm) 14.6 mg/ m3 ( 5.55 ppm) 1.46 mg/ m3 ( 0.555 ppm)

4 hours 8 298 mg/ m3 ( 113 ppm) 29.2 mg/ m3 ( 11.1 ppm) 2.92 mg/ m3 ( 1.11 ppm)

1 hour 9 1780 mg/ m3 ( 676 ppm) 117 mg/ m3 ( 44.5 ppm) 11.6 mg/ m3 ( 4.45 ppm)

30 minutes 10 7870 mg/ m3 ( 2990 ppm) 236 mg/ m3 ( 89.7 ppm) 23.3 mg/ m3 ( 8.97 ppm) Vinyl chloride PROPOSED 1: 3/ 2004 72 Calculation B: based on the unit risk for childhood ( possibly first 10 years of age) as estimated by EPA 1 ( 2000 a, b), transformed to a single exposure estimate by the default procedure, 2 recommended in the SOP on AEGL development ( i. e. linear transformation, correction by 3 a factor of 6 to account for the relevance of sensitive stages in development). Exposures of 4 less than 24 hours derived using the PBPK model of Clewell et al. ( 1995, 2002). 5 The unit risk calculation of EPA is based on the occurrence of angiosarcoma in newborn rats ( 5 weeks 6 exposure) which were observed with similar incidences as in adult female rats ( 52 weeks exposure 7 beginning at 13 weeks of age; see Table C1). Thus, the unit risk for adults ( long term study) was directly 8 calculated and was assumed to be roughly identical for childhood ( first 10 years of exposure). 9 unit risk for continuous childhood exposure: 4.4 x 10 6 per µ g/ m3 ( first 10 years) 10 dose at risk 1 : 10,000: 22.73 µ g/ m3 11 To convert a 10 year exposure (= 10 x 365.7 = 3657) to a 24 hours exposure, the dose is multiplied by the 12 number of days in 10 years: 13 22.73 µ g/ m3 x 3657 = 83.1 mg/ m3 14 To account for uncertainty regarding the variability in the stage of the cancer process at which VC or its 15 metabolites may act, a multistage factor of 6 is applied ( NRC, 2001): 16 83.1 mg/ m3 x 1/ 6 = 13.85 mg/ m3 17 Therefore, based upon the potential carcinogenicity of VC during early life, a 24 h exposure corresponding 18 to a 10 4 risk would be 13.85 mg/ m3 ( 5.26 ppm). For 10 5 and 10 6 risk levels, the 10 4 values are reduced by 19 10 fold and 100 fold, respectively. 20 If the exposure is limited to a fraction of a 24 hour period, the exposure corresponding to the various risk 21 levels are presented in the table below. These values were calculated using the PBPK model for vinyl 22 chloride as described above for calculation A. 23 Exposure Duration 24 10 4 risk 10 5 risk 10 6 risk 8 hours 25 42.1 mg/ m3 ( 16.0 ppm) 4.21 mg/ m3 ( 1.60 ppm) 0.421 mg/ m3 ( 0.160 ppm)

4 hours 26 84.5 mg/ m3 ( 32.1 ppm) 8.41 mg/ m3 ( 3.20 ppm) 0.840 mg/ m3 ( 0.329 ppm)

1 hour 27 342 mg/ m3 ( 130 ppm) 33.6 mg/ m3 ( 12.8 ppm) 3.36 mg/ m3 ( 1.28 ppm)

30 minutes 28 709 mg/ m3 ( 269 ppm) 67.5 mg/ m3 ( 25.7 ppm) 6.72 mg/ m3 ( 2.55 ppm)

Calculation C: based on the cancer incidence as evident from a five weeks animal study from Maltoni et 29 al. ( 1981), assuming that 5 weeks of exposure of animal is equivalent to about 150 weeks 30 Vinyl chloride PROPOSED 1: 3/ 2004 73 exposure of humans, with linear transformation to a single 24 hour exposure without 1 further correction for potential sensitive stages of tumor development. Exposures of less 2 than 24 hours are derived using the PBPK model of Clewell et al. ( 1995, 2002). 3 The study seems to be relevant, as 4 ° investigations were performed with newborn rats which represent a sensitive subgroup for the 5 endpoint carcinogenesis 6 ° exposure was over a short period of time 7 ° endpoints ( incidence of liver angiosarcoma) are relevant for humans. 8 Data are shown in table C1: 9 TABLE C1: INCIDENCE OF TUMORS IN THE STUDIES FROM MALTONI ET AL., 1981, 10 ( EXPERIMENTS BT 14 AND BT 1), CITED FROM EPA, 2000a 11 Administered concentration ( ppm) 12 Angiosarcoma Hepatoma 4 hours/ day, 5 days/ week for 5 weeks starting at day 1 ( BT 14) 13 6000 14 20/ 42 ( 48%), all* 17/ 42 ( 40.5%) , LAS* 20/ 42 ( 47,6 %)

10000 15 18/ 44 ( 41%), all* 15/ 44 ( 34.1%), LAS* 20/ 44 ( 45,4 %)

4 hours/ day, 5 days/ week for 52 weeks starting at age 13 weeks ( BT 1) 16 6000 17 22/ 42 ( 52%), all* 13/ 42 ( 31%), LAS* 1/ 27 ( 3,7%)

10000 18 13/ 46 ( 28 %), all* 7/ 46 ( 15%), LAS* 1/ 24 ( 4,2%)

* Angiosarcoma, all sites include extra liver angiosarcoma, including angioma; LAS: liver angiosarcoma ( only 19 those were taken for further risk quantifications) 20 Derivation on the Inhalation Unit Risk 21 Exposure concentration: 6,000 ppm 22 liver angiosarcoma 40.5 % 23 6,000 ppm corresponds to a human equivalent concentration of 51 ppm ( 132 mg/ m3), based on the PBPK 24 model published by Clewell et al. ( 1995). Corresponding data are shown in table C2 ( note that rats 25 exposure is intermittent ( 4hours/ day; 5 days/ week) compared to HEC ( human equivalent exposure) which 26 is given for continuous exposure ( 24 hours/ day)). Note further that saturation in rats leads to only minor 27 increases of metabolite concentrations, when exposure exceeds 250 ppm ( intermittent exposure). The 28 derivation of the Inhalation Unit Risk is based on the assumption that the tumor response is a linear 29 function of the concentration of the active metabolite in the liver ( HEC). See Table C2. 30 Vinyl chloride PROPOSED 1: 3/ 2004 74 132 mg/ m3 = 40.5%; 1 => 3.3 mg/ m3 = 1%; 2 => 33 µ g/ m3 = 0.01% = 1: 10,000 3 dose at risk ( 1: 10,000): 33.0 µ g/ m3 4 conversion from 5 weeks to 24 h exposure: 5 Newborn rats grow about 30 times faster than newborn humans ( NRC, 1993), which is similar to the ratio 6 of lifetime 75 years ( human): 2.5 years ( rat) = 30. 5 x 7 x 30 = 1050 7 33,0 µ g/ m3 x 1050 days = 34.7 mg/ m3 ( 14 ppm) 8 An additional factor to adjust for uncertainties in assessing potential cancer risks under short term 9 exposures is not applied, as exposure was short term in the underlying study. 10 Therefore, based upon the potential carcinogenicity of VC during early life, a 24 h exposure corresponding 11 to a 10 4 risk would be 34.7 mg/ m3 ( 13.2 ppm). For 10 5 and 10 6 risk levels, the 10 4 values are reduced by 12 10 fold and 100 fold, respectively. 13 If the exposure is limited to a fraction of a 24 hour period, the exposure corresponding to the various risk 14 levels are presented in the table below. These values were calculated using the PBPK model for vinyl 15 chloride as described above for calculation A. 16 Exposure Duration 17 10 4 risk 10 5 risk 10 6 risk 8 hours 18 106 mg/ m3 ( 40.3 ppm) 10.5 mg/ m3 ( 3.99 ppm) 1.05 mg/ m3 ( 0.399 ppm)

4 hours 19 213 mg/ m3 ( 80.9 ppm) 21.0 mg/ m3 ( 7.98 ppm) 2.10 mg/ m3 ( 0.798 ppm)

1 hour 20 922 mg/ m3 ( 350 ppm) 84.4 mg/ m3 ( 32.1 ppm) 8.40 mg/ m3 ( 3.19 ppm)

30 minutes 21 3110 mg/ m3 ( 1180 ppm) 170 mg/ m3 ( 64.6 ppm) 16.8 mg/ m3 ( 6.38 ppm)

A similar result is obtained if the tumor data from Froment et al. ( 1994) are used. Froment et al. exposed 22 the newborn animals to only 500 ppm. Hence, fewer extrapolations were needed compared to the Maltoni et 23 al. data. ( Data and calculation not shown). For both calculations, relevant uncertainty on the influence of 24 the oral uptake of mothers ´ milk has to be stated. Because of metabolic saturation at high level inhalation 25 exposure, this influence may have been limited. However, no estimate of the quantitative consequences of 26 this multi pathway exposure may be given. 27 TABLE C2: CONVERSION OF ADMINISTERED VC DOSE TO A HUMAN EQUIVALENT 28 CONCENTRATION ( data from EPA, 2000a, b) 29 Admin. conc. ( ppm) a 30 Metabolite ( mg/ L liver) b HEC ( ppm) c Vinyl chloride PROPOSED 1: 3/ 2004 75 0 1 0 0 1 2 0.59 0.2 5 3 2.96 1 10 4 5.9 2 25 5 14.61 4.6 50 6 31.27 10.1 100 7 55.95 19 150 8 76.67 26 200 9 90 31 250 10 103.45 35 500 11 116.94 40 2500 12 134.37 48 6000 13 143.72 51 a Animals exposed 4 hours/ day, 5 days/ week for 52 weeks. 14 b Dose metric ( lifetime average delivered dose in female rats) calculated from PBPK modeling of the 15 administered animal concentration. 16 c Continuous human exposure concentration over a lifetime required to produce an equivalent mg 17 metabolite/ L of liver. 18 Calculation D: based on the NOAEL for DNA adducts after single in vivo exposure of adult 19 animals and the application of an uncertainty factor for intraspecies variability. 20 DNA adducts seem to be relevant and quantitatively linked to carcinogenic potency of VC: 21 ° ethenobases were shown to possess miscoding properties ( Barbin, 2000) and are slowly repaired 22 ( Morinello et al., 2002a) 23 ° ethenobases generate mainly base pair substitution mutations ( Barbin, 2000) 24 ° ethenobases assumed to be initiating lesions in carcinogenesis ( Barbin, 2000) 25 ° high correlation between DNA adducts formation (  G) and incidence of haemangiosarcoma in mice 26 after exposure to vinyl fluoride ( Swenberg et al., 1999) 27 Elevated DNA adducts were seen after single 5 hour exposure of adult rats to 250 ppm VC ( Bolt et 28 al.  1980). Watson et al. ( 1991) exposed adult male Fisher 344 rats for 6 hours to atmospheres containing 1, 29 10, or 45 ppm VC. The alkylation frequencies of 7( 2' oxoethyl) guanine ( OEG) in liver DNA were 0.026, 30 0.28 and 1.28 residues OEG per 106 nucleotides respectively. With these air concentrations, there was no 31 evidence to indicate the formation of the cyclic adducts 1, N6 ethenoadenine (  A) or 3, N4 ethenocytosine 32 (  C). The threshold for detection of these adducts were about 1 adduct per 1 x 108 nucleotides. Swenberg et 33 Vinyl chloride PROPOSED 1: 3/ 2004 76 al. ( 1999) reported a factor 1/ 10  1/ 100 to calculate the amount of N2,3 ethenoguanine (  G) in relation to 1 OEG. Thus,  G would be lower than 0.1  0.01 per 106 nucleotides at 45 ppm. This would equal the 2 reported background of  G ( Swenberg et al., 1999). It may be concluded that single exposure to 45 ppm 3 VC ( 6 hours) would not lead to an increase of relevant cyclic adducts (  A,  C,  G) in adult rats. 4 5 With higher DNA adduct levels ( at higher single exposure, or in young rats, or after repeated short 6 term exposure) there apparently is a relevant correlation to mutations, foci or carcinogenicity: Adult rats 7 repeatedly ( 5 days) exposed to 10 ppm VC for 6 hours/ day showed slightly elevated etheno adducts (  G) 8 compared to control ( Swenberg et al., 2000). Higher adduct levels were seen in young animals than in adult 9 animals after identical treatment ( Fedtke et al., 1990; Laib et al., 1989; Ciroussel et al., 1990, Morinello et 10 al., 2002a). Respective mutations ( e. g., G> A transitions, A> T transitions) were observed in VC induced 11 tumors ( Barbin, 2000). Despite relevant repair, no full reduction to background was observed for these 12 adducts two weeks after a 5 day exposure ( 4 hours/ day) to 600 ppm ( Swenberg et al., 1999). DNA adducts 13 formation (  G) in whole liver DNA or hepatocytes increased linearly from 5 days to 8 weeks after exposure 14 of rats to 500 ppm or 10 ppm VC ( Morinello et al., 2002a). Table C3 presents the data for relevant DNA 15 adducts after short term exposure to VC for different concentrations and exposure durations and gives an 16 indication about the reversibility. 17 TABLE C3: DNA ADDUCTS AFTER SINGLE AND SHORT TERM VC EXPOSURE 18 VC inhalation ( ppm) 19 0 1 10 45 100 600 7( 2' oxoethyl) guanine ( OEG) 20 [ adducts/ nucleotides] 1 21 0.026/ 106 0.28/ 106 1.28/ 106 1, N6 ethenoadenine (  A) 1 22 < 1/ 108 3, N4 ethenocytosine (  C) 1 23 < 1/ 108 N2,3 ethenoguanine (  G)* 24  1/ 108 for comparison2: 25  G Background ( rat) 26 0.9/ 107  G, 5 days 27 2/ 107 6.8/ 107  G, 20 days 28 5.3/ 107 2.3/ 106  G, 4h/ d, 5d, immed. after exposure 29 3.8/ 106  G, 4h/ d, 5d, 14 days after exposure 30 4.7/ 107  G Background ( human) 31 6/ 108  7/ 107 * estimated (  G) by the authors of the TSD from ratio

1/ 100 OEG/  G in other VC experiments 32 1 data from Watson et al., 1991; 2 data from Swenberg et al., 1999 33 Vinyl chloride PROPOSED 1: 3/ 2004 77 TABLE C4: ADDUCTS RATIO NEONATE: ADULT FOR VINYL CHLORIDE 1 Swenberg et al., 1999 2 ( OEG) 3 600 ppm 4 5d, 4h/ d, rat 5 Swenberg et al., 1999 (  G) 600 ppm 5d, 4h/ d, rat Ciroussel et al., 1990 (  dAdo/ dAdo) 500 ppm 2 weeks, 7h/ d, rat Ciroussel et al., 1990 (  dCyd/ dCyd) 500 ppm 2 weeks, 7h/ d, rat 162/ 43  3.8 6 1.81/ 0.47  3.9 1.3/ 0.19  6.8 4.92/ 0.8  6.15 7 calculation of an practical threshold (" NAEL") for short term exposure: 8 Intraspecies: Because of the high sensitivity of young animals an intraspecies factor of 10 is 9 regarded as necessary. This is supported by comparisons between effects at different ages based on tumors, 10 foci or DNA adducts. For DNA adducts a comparison is shown in table C4. 11 Interspecies: There is no apparent higher sensitivity of men compared to rats, which is supported 12 by the comparison of unit risks derived from animal data respectively human data ( Clewell et al., 2001). 13 This leads to an uncertainty factor for interspecies differences of 1 ( EPA, 2000a). 14 Exponent for time extrapolation: Steady state is not reached within 8 hours as evidenced by the 15 longer halftime of metabolites. Thus, default time extrapolation should be performed based on the observed 16 NOAEL at 6 hours exposure. This leads to an estimated close to background level as quantified by the 17 calculations below: 18 Key study: Watson et al., 1991; Swenberg et al., 1999; Barbin, 2000 19 Toxicity endpoint: DNA adducts; background adduct levels at single 45 ppm exposure of rats is 20 taken as practical " NAEL" ( 6 hours) 21 Uncertainty/ Combined uncertainty factor of 10 22 modifying factors: 1 for interspecies variability 23 10 for intraspecies variability 24 Time Scaling: C3 x t = k for extrapolation to 4 hour, 1 hour, and 30 minute; 25 k = ( 45 ppm) 3 x 360 min = 3,2 x 10E+ 7 ppm3 min 26 C1 x t = k for extrapolation to 8 hours; 27 k = 45 ppm x 360 min = 16,200 ppm1 min 28 29 30 minute: C3 x 30 min = 3,2 x 10E+ 7 ppm3 min 30 C = 103 ppm 31 30 min NAEL = 103 ppm/ 10 = 10 ppm (= 26 mg/ m3) 32 1 hour: C3 x 60 min = 3,2 x 10E+ 7 ppm3 min 33 C = 81.8 ppm 34 1 h NAEL = 81.8 ppm/ 10 = 8.2 ppm (= 21 mg/ m3) 35 Vinyl chloride PROPOSED 1: 3/ 2004 78 4 hour: C3 x 240 min = 3,2 x 10E+ 7 ppm3 min 1 C = 51.5 ppm 2 4 h NAEL = 51.5 ppm/ 10 = 5.1 ppm (= 13 mg/ m3) 3 8 hour: C x 480 min = 16200 ppm min 4 C = 33.75 ppm 5 8 h NAEL = 34 ppm/ 10 = 3.4 ppm (= 8.8 mg/ m3) 6 Concluding remark: 7 Table C5 provides an overview of the calculations on carcinogenic potency after single exposure as derived 8 above compared to the AEGL values derived based on nonmalignant effects. 9 TABLE C5: COMPARISON OF AEGL VALUES ( VC) BASED ON NONMALIGNANT 10 EFFECTS AND DIFFERENT ESTIMATIONS OF CARCINOGENIC RISK AFTER SINGLE 11 EXPOSURE 12 [ ppm] 13 10 minute 30 minute 1 hour 4 hour 8 hour AEGL 1( Baretta et al., UF: 3; n= 3,1) 14 450 310 250 140 70 AEGL 2 ( Lester et al., UF: 3; n= 2 to 2h; 2h= 4h= 8h) 15 2800 1600 1200 820 820 AEGL 3 ( Clark & Tinston; UF: 3; n= 2 to 2h; 16 2h= 4h= 8h) 17 12000 6800 4800 3400 3400 Estimation of carcinogenic potency ( 10 4 risk): 18 CALCULATION A ( unit risk) default SOP; linear 19 transformation 20 lifetime unit risk x 6 21 2990 676 113 55.9 CALCULATION B ( unit risk) linear 22 transformation, early life= 10 years, x 6 23 269 130 32.1 16 CALCULATION C ( Maltoni et al., 1981, risk direct 24 from 5w study); Human equivalent dose to 6000 ppm; 25 growth rate rat/ hum: 30 26 1180 350 80.9 40.3 CALCULATION D ( Watson et al., ( DNA)), UF: 3; 27 n= 3: 30,60, 120,480 min; n= 1: 8h; 10 min= 30min. 28 10 8.2 5.1 3.4 Calculation C is judged to be the best basis for estimation of the risk for carcinogenic effects after single 29 exposure and is included into the main part of the TSD. However, substantial uncertainties on risk 30 quantification persists. 31 Vinyl chloride PROPOSED 1: 3/ 2004 79 APPENDIX D  Occupational epidemiological studies on carcinogenicity ( focus: limited exposure 1 time) 2 Vinyl chloride PROPOSED 1: 3/ 2004 80 Two large studies of workers employed in the VCM/ PVC industry prior to 1974 were completed. 1 Both studies were retrospective cohort mortality studies. The first study was done in Europe and included 2 study populations in Italy, Norway, Sweden and United Kingdom. The second study included plants in the 3 United States and Canada. Each study has been updated multiple times and has been the subject of 4 numerous papers. Only the results from the most recent updates are discussed here. The focus is to review 5 the liver cancer incidence in workers exposed to VCM for relatively short time periods or where the 6 cumulative dose ( ppm years) was known to have been low. Both studies have more deaths than expected 7 from ASLs among workers with high and/ or long exposure to VCM ( Ward et al., ( 2000) and Mundt et al., 8 ( 1999)). A third study from Weber et al. ( 1981) with epidemiologic data from Germany shows 9 conflicting results to the above cited large studies. 10 European Study 11 The European study includes approximately 12,700 men with at least one year of employment in 12 the VCM/ PVC industry from 1955 to 1974 ( Ward et al., 2000). Three of the 19 plants had incomplete 13 records and thus the starting date for these three plants ranged from 1961 to 1974. The vital status follow 14 up was complete through 1997. Age and calendar period specific mortality rates for males from Italy, 15 Norway, Sweden and United Kingdom were used to calculate the Standardized Mortality Ratios ( SMR) and 16 Confidence Intervals ( CI). Typical exposure scenarios were estimated by industrial hygienists based on job 17 exposure matrices. These job exposure matrices were based primarily on job title and were reviewed by two 18 other industrial hygienists with several years of experience in the VC industry. Information provided in the 19 job exposure matrix was used to develop a ranked level of exposure index. Quantitative estimates of 20 exposure were obtained for 82% of the cohort. 21 The total number of person years at risk by the cohort is 324,701. The work force was classified 22 by duration of employment, < 3, 3 6, 7 11, 12 18 and 19+ ppm years. The SMR ( CI) for liver cancer for 23 workers with less than 3 years experience was 62 ( 2 345), below the expected value ( Table D1). For 24 workers exposed to VCM/ PVC for a longer time period, the incidence of liver cancer was higher than 25 expected. In general, the incidence of liver cancer increased with years of employment in the VCM/ PVC 26 industry. 27 In addition, Ward et al., ( 2000), examined cumulative exposure for the cohort ( Table D2). Again, 28 the work force was subdivided into 0 734, 735 2379, 2380 5188, 5189 7531 and 7532+ ppm years. The 29 SMR ( CI) was 107 ( 54 192) based on 11 observed liver cancers and 10.26 expected. Assuming workers 30 are employed in the industry for up to 30 years, to be included in this first category, the highest average 31 concentration the worker would have been exposed to was ~ 25 ppm. Workers with shorter work histories 32 may have been exposed to much higher concentrations. Under this scenario there was no increase in the 33 incidence of liver cancer. As previously noted, the incidence of liver cancer increased with cumulative 34 exposure with an SMR ( CI) of 1140 ( 571 2050) for those workers with a cumulative exposure of 7532+ 35 ppm years. However, of the 11 liver cancers observed in the 0 734 ppm year cumulative exposure 36 group, fours were angiosarcomas. These four angiosarcomas occurred in individuals with 287 37 734 ppm years cumulative exposure ( Ward et al., 2001). There were no angiosarcomas reported 38 in workers with less than 287 ppm years cumulative exposure. 39 Vinyl chloride PROPOSED 1: 3/ 2004 81 North American Study 1 The North American study consists of approximately 10,100 men employed for at least one year in 2 the VCM/ PVC industry from 1942 1974 ( Mundt et al., 1999). This group was followed through December 3 31, 1995. Thus, most workers have been followed for at least twenty one years. Since the VCM/ PVC 4 industry was located in 16 states and one Province of Canada, mortality rates for 16 states were used to 5 calculate SMR's. For the Province of Canada, mortality rate data from the state of Michigan was used since 6 it was geographically the closest to the plant. As of December 31, 1995, 30% of the study group were 7 deceased Although the authors of previous studies had attempted to categorize individuals by exposures, 8 no consistent criteria had been used and thus no attempt was made to estimate exposure levels in this study. 9 The age at first exposure, duration of exposure and year of first exposure appeared to be related to 10 cancer of the liver and biliary tract ( data not shown). Of these, duration of exposure had the greatest 11 significance and appeared to be independent of age at first exposure and year of first exposure ( Table D3). 12 Mundt categorized the cohort into groups working 1 4, 5 9, 10 19 or 20+ years in the VCM/ PVC industry. 13 Nearly half of the cohort worked for less than 5 years in the VCM/ PVC industry with fewer workers in 14 each of the subsequent groups. This data shows that working in the VCM/ PVC industry for 1 4 years 15 resulted in a slightly lower liver cancer rate than expected. Working in this industry for longer periods of 16 time resulted in higher death rates than expected for liver and biliary tract cancer. Mundt et al. ( 2000) also 17 examined the incidence of angiosarcomas based on duration of exposure. Three individuals working in the 18 VCM/ PVC industry for 1 4 years have ASLs. No further information on exposure or job classification 19 was provided. 20 Both of these studies have shown that working in the VCM/ PVC industry for < 3 years or to a low, 21 but still relevant, estimated concentration of VCM resulted in liver cancer rates very close to expected 22 values. A low incidence of ASLs was reported by both Ward et al. ( 2000) and Mundt et al. ( 2000) but 23 based on the Ward study appeared to be related to higher ppm years exposure. 24 TABLE D1: LIVER CANCER INCIDENCE FOR ALL EUROPEAN COUNTRIES BY 25 DURATION OF EMPLOYMENTA 26 Duration of Incidence 27 Employment ( years) 28 Number of Individualsb Number of person years ( Observed/ Expected) SMR ( 95% CI) c < 3 29 10961 91970 1/ 1.61 62 ( 2 345)

3 6 30 8999 79747 3/ 1.44 208 ( 43 609)

7 11 31 6919 65789 7/ 1.35 517 ( 208 1060)

12 18 32 4610 55149 5/ 1.42 352 ( 114 821)

19+ 33 2006 32050 13/ 1.46 893 ( 475 1530)

Total 34 12700 324706 29/ 7.29 398 ( 267 572)

a From Tables T1.7 and D7 of Ward et al., ( 2000). 35 b Number of individuals cited for various employment intervals add up to greater than 12,700 since 36 individuals can meet more than one criteria as defined by the author. 37 c SMR = Observed/ Expected * 100. CI = Confidence Intervals. 38 Vinyl chloride PROPOSED 1: 3/ 2004 82 TABLE D2: LIVER CANCER INCIDENCE FOR ALL EUROPEAN COUNTRIES BY 1 CUMULATIVE EXPOSUREA 2 Cumulative Exposure 3 ( ppm years) 4 Number of Individualsb Number of person years Incidence ( Observed/ Expected) SMR ( 95% CI) c Unknown 5 2243 52300 2/ 3.19 63 ( 8 227)

0 734 6 9552 188204 11/ 10.26 107 ( 54 192)

735 2379 7 2772 43174 9/ 3.32 271 ( 124 515)

2380 5188 8 1463 26480 10/ 2.62 382 ( 183 703)

5189 7531 9 515 9274 10/ 1.77 566 ( 271 1040)

7532+ 10 215 5274 11/ 0.96 1140 ( 571 2050 Total 11 12700 324706 53/ 22.11 240 ( 1800 3140)

a From Tables 12 and D7 of Ward et al., ( 2000). 12 b Number of individuals cited for various employment intervals add up to greater than 12,700 since 13 individuals can meet more than one criteria 14 c SMR = Observed/ Expected * 100. CI = Confidence Intervals. 15 TABLE D3: LIVER AND BILIARY TRACT CANCER INCIDENCE FOR THE UNITED 16 STATES BY DURATION OF EMPLOYMENTA 17 Duration of Employment 18 ( years) 19 Number of Individuals Number of person years Incidence ( Observed/ Expected) SMR ( 95% CI) b 1 4 20 4774 136200 7/ 8.43 83 ( 33 171)

5 9 21 2383 71806 10/ 4.65 215 ( 103 396)

10 19 22 1992 69015 39/ 5.74 679 ( 483 929)

20+ 23 960 39524 24/ 3.49 688 ( 440 1023)