Appendix B Toxicity Summaries

Transcription

1 Appendix B Toxicity Summaries

2 Table of Contents B1 Introduction... B-1 B2 Carbon Tetrachloride... B-2 B3 Chloroform... B-8 B4 Dichloromethane... B-14 B5 1,1,2,2-Tetrachloroethane... B-20 B6 1,1,2-Trichloroethane... B-25 B7 1,2-Dichloroethane (EDC)... B-29 B8 Tetrachloroethene (PCE)... B-34 B9 Trichloroethene (TCE)... B-40 B10 1,1-Dichloroethane... B-46 B11 1,1-Dichloroethene... B-49 B12 cis- and trans-1,2-dichloroethene... B-53 B13 Vinyl Chloride... B-58 B14 Hexachlorobenzene (HCB)... B-63 B15 Hexachlorobutadiene (HCBD)... B-68 B16 Hexachloroethane (HCE)... B-73 B17 Mercury... B-77

3 Glossary of Terms ADI ADWG ANZECC ATDS ATSDR BMD BTEX CCME CICAD CNS EHC EPA FSANZ HEC HED HIL HSDB HSL IARC IRIS JECFA JMPR LOAEL LOEL MF MOA NEPC NEPM NHMRC NOAEL NOEL NSW DECCW OCS PAH PTDI PTWI RAIS RfC RfD SF Acceptable Daily Intake Australian Drinking Water Guidelines Australia and New Zealand Environment and Conservation Council Australian Total Diet Survey Agency for Toxic Substances and Disease Registry Benchmark Dose Benzene, toluene, ethylbenzene and total xylenes Canadian Council of Ministers of the Environment Concise International Chemicals Assessment Document Central Nervous System Environmental Health Criteria Environment Protection Authority Food Standards Australia New Zealand Human Equivalent Concentration Human Equivalent Dose Health Investigation Level Hazardous Substances Data Bank Health Screening Level International Agency for Research on Cancer Integrated Risk Information System Joint FAO/WHO Expert Committee on Food Additives WHO/FAO Joint Meeting on Pesticide Residues Lowest-Observed-Adverse-Effect Level Lowest-Observed-Effect Level Modifying Factor Mode (or Mechanism) of Action National Environment Protection Council National Environment Protection Measure National Health and Medical Research Council No-Observed-Adverse-Effect Level No-Observed-Effect Level New South Wales Department of Environment, Climate Change and Water Office of Chemical Safety Polycyclic aromatic hydrocarbon Provisional Tolerable Daily Intake Provisional Tolerable Weekly Intake Risk Assessment Information System Reference Concentration Reference Dose Slope Factor

4 TC TCE TDI TPH TPHCWG UF UR USEPA VC VOC WHO WHO DWG Tolerable Concentration Trichloroethene Tolerable Daily Intake Total petroleum hydrocarbons Total Petroleum Hydrocarbon Criteria Working Group Uncertainty Factor Unit Risk United States Environmental Protection Agency Vinyl chloride Volatile Organic Compound World Health Organisation World Health Organisation Drinking Water Guidelines

5 B1 Introduction This appendix presents toxicity summaries relevant to the CoPC identified in the 2017 CHHRA. The CoPC identified and considered in the 2017 CHHRA are the same as considered in the 2010 CHHRA. It is noted that while much of the general chemical information remains the same, the review has considered all available toxicity data, including more recent information (where relevant) and ensured that the assessment of toxicity is consistent with guidance available in the NEPM (NEPC 1999 amended 2013a) and enhealth (enhealth 2012). B-1 P age

6 B2 Carbon Tetrachloride B2.1 General Carbon Tetrachloride (also known as carbona, carbon chloride, tetrachloromethane, carbon tet, methane tetrachloride, perchloromethane, tetrachlorocarbon and CTC) is predominantly a manmade compound, however, it has been detected in volcanic emission gases. It has also been suggested that carbon tetrachloride can be formed in the troposphere by solar induced photochemical reactions of chlorinated alkenes (WHO 1999a). Production of carbon tetrachloride began in about 1907 in the US. Since 1990 the production of carbon tetrachloride has dropped due to the Montreal protocol which established a phase-out by 1996 of the production of carbon tetrachloride and chloroflurocarbons (CFCs) by major manufacturing countries. Most of the carbon tetrachloride produced is used in the production of CFCs, which were primarily used as refrigerants, propellants, foam-blowing agents and solvents and in the production of other chlorinated hydrocarbons. Carbon tetrachloride has also been used as a grain fumigant, pesticide, solvent for oils and fats, metal degreaser, fire extinguisher and flame retardant, and in the production of paint, ink, plastics, semi-conductors and petrol additives. It was previously also widely used as a cleaning agent. All these uses have tended to be phased-out as production has dropped (WHO 1999a). B2.2 Properties Carbon tetrachloride is a clear, colourless, volatile liquid with a characteristic, sweet odour. It is miscible with most aliphatic solvents and is itself a solvent. The solubility in water is low. Carbon tetrachloride is non-flammable and is stable in the presence of air and light. Decomposition may produce phosgene, carbon dioxide and hydrochloric acid. Key properties are presented below (ATSDR 2005; RAIS): CAS No Chemical Formula CCl 4 Molecular Weight Vapour Pressure 115 mmhg at 20 o C Vapour Density 5.32 Density 1.59 g/ml at 25 o C Solubility 793 mg/l at 20 o C Air Diffusion Coefficient cm 2 /s Water Diffusion Coefficient x 10-6 cm 2 /s Henry s Law Coefficient 0.03 atm.m 3 /mol = 1.13 at 25 o C (unitless) Koc 43.9 cm 3 /g Log Kow 2.83 Odour Threshold 10-71,000 mg/m 3 Permeability Constant cm/hr Conversion Factors 1 ppm = 6.39 mg/m 3 in air (25 o C) B-2 P age

7 B2.3 Exposure Exposure of the general population to carbon tetrachloride maybe by inhalation, oral or dermal routes. Inhalation is expected to be the major route of exposure, particularly in occupational environment, but also in the general population. Dermal contact has not been shown to be a significant route of exposure to carbon tetrachloride (ATSDR 2005). NHMRC indicate that concentrations of carbon tetrachloride in major Australian reticulated supplies are significantly less than mg/l (NHMRC 2011 Updated 2016). In relation to the assessment of dermal absorption, dermal absorption of highly volatile chemicals is expected to be negligible as it is not expected to remain on the skin long enough for absorption to be significant (USEPA 2004). Region III guidance (USEPA 1995a) of dermal absorption for volatile compounds suggests that a value of 0.05% be adopted for benzene and other volatiles with a vapour pressure similar to or greater than benzene (VP = 95.2 mmhg). No data is available specifically for the dermal absorption of CTC and it has a vapour pressure similar to that of benzene; hence a value of 0.05% is considered relevant. If released into the environment the following can be noted with respect to carbon tetrachloride (WHO 1999a): Air: Nearly all carbon tetrachloride released to the environment will ultimately be present in the atmosphere, due to its volatility. Since the atmospheric residence time of carbon tetrachloride is long, it is widely distributed. Estimates of atmospheric lifetime are variable, but years is accepted as the most reasonable value. Carbon tetrachloride contributes both to ozone depletion and to global warming. Soil and Water: Following releases to soil, most carbon tetrachloride is expected to evaporate rapidly due to its high vapour pressure. A small fraction of carbon tetrachloride may adsorb to organic matter. Carbon tetrachloride is expected to be moderately mobile in most soils, depending on organic carbon content, and leaching to groundwater may occur. Carbon tetrachloride introduced into water resources is transported by movement of surface water and groundwater. Because of its volatility, evaporation is considered to be the main process for the removal of carbon tetrachloride from aquatic systems. The amount of carbon tetrachloride dissolved in the oceans is reported to be less than 1-3% of that in the atmosphere. Biodegradation: Carbon tetrachloride is very stable in the troposphere primarily because carbon tetrachloride, in contrast to most other volatile halocarbons, has low reactivity towards hydroxyl radicals. The principal degradation process for carbon tetrachloride occurs in the stratosphere, where it is dissociated by short wave length ( nm) UV radiation to form the trichloromethyl radical and chlorine atoms with an estimated a half-life of years for this photo dissociation process. Carbon tetrachloride dissolved in water does not photodegrade or oxidize in any measurable amounts with the rate of hydrolysis calculated with a half-life of 7000 years (concentration of 1 ppm). Carbon tetrachloride has been shown to be resistant to aerobic biodegradation, however biodegradation may occur within 16 days under anaerobic conditions. Carbon tetrachloride may undergo reductive dechlorination to form chloroform and other products in the presence of free sulphide and ferrous ions B-3 P age

8 Carbon tetrachloride has a low tendency to bioconcentrate in aquatic or marine organisms. Most animals readily metabolise and excrete carbon tetrachloride following exposure and hence biomagnification is not expected. B2.4 Background Exposures/Intake Intake of carbon tetrachloride from soil, water and food can be considered to be insignificant. Intakes from air can be calculated from urban air concentrations from a light industrial area in Brisbane (Hawas et al. 2001) which indicate a background concentration of mg/m 3 (average) to mg/m 3 (max) which is approximately 40% to 65% of the tolerable concentration in air (equivalent to an ADI) as adopted from the WHO air quality guidelines (WHO 2000c). As the data from the Brisbane study is derived from an industrial area, it is considered relevant to use the average value measured rather than the maximum. However, if an area of interest is in an industrial area where background levels of carbon tetrachloride are expected to be elevated a higher background intake may be relevant. On the basis of average concentrations of carbon tetrachloride in air from this study, background intake can be assumed to be up to 40% of the TC (WHO 2000). As other sources of emission on the BIP have been included in the assessment separately, the average background intake is considered appropriate for other sources. B2.5 Health Effects General The following information is available from (ATSDR 2005; WHO 1999a). There is no clinical disease which is unique to carbon tetrachloride toxicity. Carbon tetrachloride is well absorbed from the gastrointestinal and respiratory tract in animals and humans. Dermal absorption of liquid carbon tetrachloride is possible, but dermal absorption of the vapour is slow. Carbon tetrachloride is distributed throughout the whole body, with highest concentrations in liver, brain, kidney, muscle, fat and blood. The parent compound is eliminated primarily in exhaled air, while minimal amounts are excreted in the faeces and urine. Carbon tetrachloride has depressant effects on the central nervous system particularly following high levels of exposure. It can also produce irritation effects on the gastrointestinal tract and skin. Most other toxic effects associated with exposure to carbon tetrachloride are associated with it metabolism by mixed function cytochrome P-450 oxygenases. The liver and kidney are target organs for carbon tetrachloride toxicity via oral and inhalation exposures. The severity of the effects on the liver depends on a number of factors such as species susceptibility, route and mode of exposure, diet or co-exposure to other compounds, in particular ethanol. Furthermore, it appears that pre-treatment with various compounds, such as phenobarbital and vitamin A, enhances hepatotoxicity, while other compounds, such as vitamin E, reduce the hepatotoxic action of carbon tetrachloride. In humans, acute symptoms after carbon tetrachloride exposure are independent of the route of intake and are characterized by gastrointestinal and neurological symptoms, such as nausea, vomiting, headache, dizziness, dyspnoea and death. Liver damage appears after 24 h or more. Kidney damage is evident often only 2 to 3 weeks following the poisoning. B-4 P age

9 Epidemiological studies have not established an association between carbon tetrachloride exposure and increased risk of mortality, neoplasia or liver disease. Some studies have suggested an association with increased risk of non-hodgkin's lymphoma and, in one study, with mortality and liver cirrhosis. However, not all of these studies pinpointed specific exposure to carbon tetrachloride, and the statistical associations were not strong. Carcinogenicity and Genotoxicity Human data on the carcinogenic potential of carbon tetrachloride are limited and there have been no conclusive associated between carbon tetrachloride exposure and cancer in humans. In experiments with mice and rats, carbon tetrachloride proved to be capable of inducing hepatomas and hepatocellular carcinomas. The doses inducing hepatic tumours were higher than those inducing cell toxicity. It is considered likely that the carcinogenicity of carbon tetrachloride is secondary to its hepatotoxic effects (WHO 1999a) and may be related to its metabolism (ATSDR 2005). Carbon tetrachloride can induce embryotoxic and embryolethal effects, but only at doses that are maternally toxic, as observed in inhalation studies in rats and mice. In addition carbon tetrachloride is not teratogenic (WHO 1999a). (Baars et al. 2001) indicates that the available data show that carbon tetrachloride has no mutagenic end points, however, it does bind covalently to DNA in vitro. The data also indicate that the carcinogenic potency of carbon tetrachloride can only be noticed at dose levels with apparent hepatotoxicity. Many genotoxicity assays have been conducted with carbon tetrachloride. On the basis of available data, carbon tetrachloride can be considered as a non-genotoxic compound (WHO 1999a). A detailed review of genotoxicity associated with carbon tetrachloride in the Stage 2 assessment (Woodward-Clyde 1996) supported this outcome. Recent studies (Nagano, Kasuke et al. 2007; Nagano, K. et al. 2007), however, suggest clear evidence of carcinogenicity for carbon tetrachloride in rats and mice and suggest a cytotoxicproliferative and genotoxic mode of action. However, these studies has not identified relevant approaches for quantifying such effects or the relationship with hepatotoxicty (noted previously). Hence it is considered relevant to assess exposures to carbon tetrachloride on the basis of threshold values derived to be protective of the most sensitive end-point, hepatotoxicity. Sensitive Populations Potential issues associated with exposures to CTC and susceptible population have been reviewed by the (USEPA 2010b). This review identified that the events involved in CTC liver toxicity and carcinogenicity involve metabolic and cellular processes common to cells at all life stages. Because metabolism is a hypothesised key event, heterogeneity in the human population in the microsomal enzymes responsible for CTC toxicity could affect susceptibility to CTC. There is no direct evidence for increased or decreased susceptibility to carbon tetrachloride in children. However, based on the level of hepatic enzymes in young children (lower) compared with adults, it is hypothesised that infants and children would be less susceptible to liver injury from CTC. No increased susceptibility has been identified for the developing foetus. B-5 P age

10 Fasting or food deprivation has been shown to increase the toxicity of carbon tetrachloride. Carbon tetrachloride toxicity is also affected by the level of antioxidants in the diet (USEPA 2010b). Based on experimental findings from rodent studies, there is some reason to suspect that people with diabetes may have altered susceptibility to hepatotoxic effects from carbon tetrachloride (USEPA 2010b). Factors that increase the expression of CYP2E1 or CYP3A are likely to increase susceptibility to carbon tetrachloride exposure (all other things being the same) because the relatively higher rate of metabolism on a per cell basis would significantly increase the rate of generation of trichloromethyl radicals in the liver and kidney. This includes heavy consumers of ethanol and co-exposure to other chemical inducers of CYP450 (such as acetone, methanol and aliphatic alcohols, MEK, MIBK, ketones, PCBs, DDT and some pesticides) (USEPA 2010b). Classification Carbon tetrachloride has been classified as a "probable" human carcinogen (Category B2) by the USEPA based on carcinogenicity in rats, mice and hamsters (USEPA 2010b). IARC has classified carbon tetrachloride in Group 2B (possibly carcinogenic to humans) based on inadequate evidence in humans and sufficient evidence in experimental animals for carcinogenicity (IARC 1999b). The National Occupational Health and Safety Commission (NOHSC) as Category 2 carcinogen (probable human carcinogen) (Safe Work Australia). NICNAS has not classified carbon tetrachloride. B2.6 Quantitative Toxicity Reference Values On the basis of the weight of evidence, CTC does not appear to have significant genotoxic potential so it is considered reasonable that a threshold approach is adopted for the characterisation of all health effects including carcinogenicity. The following quantitative values are available for CTC appropriate Australian and International sources: B-6 P age

11 Table B1 Summary of Published Toxicity Reference Values: Carbon Tetrachloride Source Value Basis/Comments Australian ADWG (NHMRC 2011 Updated 2016) TDI = mg/kg/day The current ADWG have derived a guideline of mg/l for CTC based on a no effect level of 1.2 mg/kg/day based on a 90-day gavage study on mice and the application of 1000 safety factor and a 5/7 study duration adjustment factor. The NOEL adopted was consistent with that in the old WHO DWG (prior to revision to the values noted below). Hence the quantitative approach adopted in these guidelines is considered dated. International WHO (WHO 1999a) WHO DWG (WHO 2011) RIVM (Baars et al. 2001) ATSDR (ATSDR 2005) USEPA (USEPA 2010b) TDI = mg/kg/day TC = mg/m 3 TDI based on a 12 week oral rat study (NOAEL of 1 mg/kg), 500 uncertainty factor and a 5/7 conversion. TC based on 90-day inhalation study on rats (NOAEL 6.1 mg/m 3 ) and 100 uncertainty factor. Value is also published in the Air Quality Guidelines (WHO 2000a). TDI = mg/kg/day The WHO derives a guideline of mg/l based on a TDI of mg/kg/day derived from a 12-week oral study in rats (as per (WHO 1999a)). It is noted that the guideline derived is lower than values calculated using linear extrapolation and a lifetime excess cancer risk of 10-4 to 10-6 and is considered to be protective of all health endpoints. TDI = mg/kg/day TC = 0.06 mg/m 3 No chronic oral MRL Inhalation MRL =0.19 mg/m 3 RfD = mg/kg/day RfC = 0.1 mg/m 3 TDI derived based on a NOAEL of 1 mg/kg/day for hepatotoxic effects for semi-chronic oral exposures in rats and an uncertainty factor of 250. TC derived based on a NOAEL of hepatic effects for an inhalation exposure study over 200 days in rats and uncertainty factor of 100. No chronic oral MRL has been established. The chronic inhalation MRL has been derived on the basis of a NOAEL of (adjusted) of 5.8 mg/m 3 associated with liver effects in rats and an uncertainty factor of 30. Oral reference dose (RfD) (revised in 2010) derived on the basis of a benchmark dose (adjusted) of 3.9 mg/kg/day associated with elevated serum SDH activity in rats and an uncertainty factor of The uncertainty factor includes a factor of 10 to protect sensitive individuals. Inhalation RfC (revised 2010) derived on the basis of a benchmark dose (human equivalent concentrations) of 14.3 mg/m 3 associated with liver effects in a rat study and a 100 fold uncertainty factor. The uncertainty factor includes a factor of 10 to protect sensitive individuals. Non-threshold values are also available from the USEPA. While most of the evaluations conducted have considered similar critical endpoints there are a wide range of toxicity reference values that have been derived, particularly for the assessment of inhalation exposures. While the USEPA values are based on the most recent review, the threshold values available from the WHO (WHO 1999a) are considered the most relevant for the assessment of both non-carcinogenic and carcinogenic endpoints. B-7 P age

12 B3 Chloroform B3.1 General Chloroform (also known as trichloromethane, methenyl chloride, methane trichloride, methyl trichloride and formyl trichloride, CFM) is both a synthetic and naturally occurring compound, with anthropogenic sources responsible for most of the chloroform in the environment. Chloroform is mainly used in the production of other materials, principally fluorocarbons, used in the synthesis of tetrafluoroethylene and polytetrafluoroethylene, and as a refrigerant and propellant. Chloroform is also widely employed as an organic solvent in industry and in analytical laboratories. It has also been used as an ingredient of pharmaceuticals, drugs, cosmetics, grain fumigants, dyes and pesticides. In the past, chloroform has been extensively used as a surgical anaesthetic, but this use was discontinued because exposure to narcotic concentrations resulted in adverse side effects. The US Food and Drug Administration banned the use of chloroform as an ingredient in human drug and cosmetic products in B3.2 Properties It is a colourless liquid with a pleasant, non-irritating odour and a slightly sweet taste. It is only slightly soluble in water, but is miscible with alcohol, benzene, ether, petroleum ether, carbon tetrachloride, carbon disulfide, and oils. Decomposition may produce phosgene, carbon dioxide and hydrogen chloride. Key properties are presented below (ATSDR 1997b; HSDB; RAIS): CAS No Chemical Formula CHCl 3 Molecular Weight Vapour Pressure 197 mmhg at 20 o C Vapour Density 4.1 Density 1.48 g/ml at 25 o C Solubility 7950 mg/l at 25 o C Air Diffusion Coefficient cm 2 /s Water Diffusion Coefficient 1.09 x 10-5 cm 2 /s Henry s Law Coefficient atm.m 3 /mol = 0.15 at 25 o C (unitless) Koc 31.8 cm 3 /g Log Kow 1.97 Odour Threshold 85 ppm (421 mg/m 3 ) Permeability Constant cm/hr Conversion factor 1 mg/m 3 = ppm at 20 o C and 101.3Pa B3.3 Exposure Human exposure to chloroform can occur orally, dermally, or by inhalation. Chloroform is the principal trihalomethane generated as by-products during the chlorination of drinking water. The primary sources of chloroform in the environment are chlorinated drinking water and wastewater, pulp and paper mills, and chemical and pharmaceutical manufacturing plants. The general population is exposed to chloroform mainly in food, drinking-water and indoor air. Most of the chloroform released to the environment eventually enters the atmosphere, while much smaller amounts enter groundwater as a result of filtration through the soil. NHMRC indicate that B-8 P age

13 concentrations of total trihalomethanes (including chloroform) in major Australian reticulated supplies range up to 0.6 mg/l (NHMRC 2011 Updated 2016). In relation to the assessment of dermal absorption, as noted in USEPA (2004), dermal absorption of highly volatile chemicals is expected to be negligible as it is not expected to remain on the skin long enough for absorption to be significant (USEPA 2004). Region III guidance (USEPA 1995a) of dermal absorption for volatile compounds suggests that a value of 0.05% be adopted for benzene and other volatiles with a vapour pressure similar to or greater than benzene (VP = 95.2 mmhg). No data is available specifically for the dermal absorption of chloroform and it has a vapour pressure similar to that of benzene; hence a value of 0.05% is considered relevant. If released into the environment the following can be noted with respect to chloroform (WHO 1994a, 2004b): Air: Nearly all chloroform released to the environment will ultimately be present in the atmosphere due to its volatility. In the atmosphere, chloroform may be transported long distances before degrading via indirection photochemicals reactions with free radicals such as hydroxyl (which form low levels of phosgene and hydrogen chloride). Half-lives vary from 55 to 20 days. Soil and Water: Following releases to soil, most chloroform is expected to evaporate rapidly due to its high volatility and low soil adsorption. Most of the remaining chloroform will travel through the soil because of its low adsorption onto soils with leaching of chloroform to groundwater considered to be a significant pathway. Because of its volatility, evaporation is considered to be the main process for the removal of chloroform from aquatic systems. Chloroform is not expected to adsorb significantly to sediment or suspended organic matter in surface water. Biodegradation: Hydrolysis or direct photolysis are not considered to be significant degradation processes in water for chloroform. Chloroform is generally considered persistent in water and soils with a low potential for degradation. Under correct condition, chloroform may undergo anaerobic biodegradation. Concentrations of chloroform in soil or water above a certain threshold levels results in toxic conditions which inhibits bacteria, methanefermenting bacteria under anaerobic conditions. Chloroform is unlikely to bioaccumulate to any significant extent in aquatic biota. B3.4 Background Exposures/Intake With respect to chloroform the average intake from food, water and air has been estimated (WHO 2004) to be between 0.6 to 10 μg/kg/day (WHO 2004b). Data available from Australia indicate a similar range of potential intakes from water and air as those considered by the WHO. Given the available TDI levels adopted, it is considered relevant to assume a 50% intake from background. On this basis, the suggested threshold values should be adjusted to account for background intakes. B-9 P age

14 B3.5 Health Effects General The following information is available from WHO and ATSDR (ATSDR 1997b; WHO 2004b). There is no clinical disease which is unique to chloroform toxicity. Chloroform is rapidly absorbed through the lungs and the gastrointestinal tract, and to some extent through the skin. In humans, the respiratory absorption of chloroform ranges from 49 to 77% and absorption from the gastrointestinal tract approximates 100%, with peak blood levels being reached within 1 hour (ATSDR 1997b; WHO 2004b). Following its absorption, chloroform is distributed to all organs. The distribution of chloroform in the body does not differ qualitatively between the various routes of exposure. A number of studies have shown that chloroform distributes to fat tissue. It is lipid soluble, readily passes through cell membranes, reaching relatively high concentrations in nervous tissue. Chloroform concentrations in tissues are dose-related and occur in the following order: adipose > brain > liver > kidney > blood. Chloroform passes through the placenta and has been detected in fresh cow s milk and foetal blood at levels equal to or greater than that in maternal blood (ATSDR 1997b; WHO 2004b). Both oxidative and reductive pathways of chloroform metabolism have been identified. Chloroform is metabolised by oxidative dehydrochlorination of its carbon-hydrogen bond to form phosgene (CCl 2O), while the reductive pathway generates the dichloromethylcarbene free radical. Both oxidative and reductive metabolism proceeds through a cytochrome P450 (CYP)-dependant enzymatic activation step that occurs in both the liver and the kidney. The balance between oxidative and reductive pathways depends on species, tissue, dose and oxygen tension. The major end product of chloroform metabolism is carbon dioxide (CO 2), most of which is eliminated via the lungs, but some is incorporated into endogenous metabolites and may be excreted as bicarbonate, urea, methionine and other amino acids, inorganic chloride ion, and carbon monoxide. Elimination of chloroform is not affected by the route of exposure. About 60-70% is eliminated unchanged in expired air; 30-40% is metabolised and excreted in urine and faeces. The extent of metabolism is dose-dependent (ATSDR 1997b; WHO 2004b). Target organs for chloroform toxicity are the liver, kidneys, and central nervous system. The most universally observed toxic effect of chloroform is damage to the liver. Liver effects (hepatomegaly, fatty liver, and hepatitis) were observed in individuals occupationally exposed to chloroform. Several subchronic and chronic studies by the oral or inhalation routes of exposure documented hepatotoxic effects in rats, mice, and dogs. Renal effects have been reported in rats and mice following oral and inhalation exposures, but evidence for chloroform-induced renal toxicity in humans is sparse (ATSDR 1997b; WHO 2004b). Chloroform is a central nervous system depressant, inducing narcosis and anaesthesia at high concentrations. Lower concentrations may cause irritability, lassitude, depression, gastrointestinal symptoms, and frequent and burning urination (ATSDR 1997b; WHO 2004b). B-10 P age

15 Carcinogenicity and Genotoxicity Human data on the carcinogenic potential of chloroform are limited and there have been no conclusive associated between chloroform exposure and cancer in humans. In experiments with mice and rats, chloroform induced liver and kidney tumours. The carcinogenic effects of chloroform on the mouse liver appear to be closely related to cytotoxic and cell replicative effects. Liver tumours in rat and mice studies have only occurred where signs of hepatoxicity have been seen. In the rat and mice studies, the development of renal tumours in males is a consequence of nephrototoxicity of chloroform (ATSDR 1997b; WHO 2004b). The pattern of development of tumours following chloroform treatment in animals is consistent with a tumour promoting mechanism rather than a genotoxic one. On the basis of available evidence, a dose threshold for the development of liver tumours is considered appropriate. It was considered plausible by the WHO that kidney tumours in rats may be associated with a threshold mechanism; however there are some limitations of the database (ATSDR 1997b; WHO 2004b). Review of chloroform by the USEPA indicates that it is considered likely to be carcinogenic to humans by all routes of exposure under high-dose conditions that lead to cytotoxicity and regenerative hyperplasia. Chloroform is not likely to be carcinogenic to humans by any routes of exposure at doses that do not cause cytotoxicity and cell regeneration. Hence the USEPA has concluded that the threshold effects value established is also protective against increased risk of cancer (USEPA 2001). Similarly a review of the mode of action by the WHO has identified that mechanism for induction of tumours is consistent with a non-linear (or threshold) dose-response relationship for induction of tumours (WHO 2004b). The weight of the available evidence indicates that chloroform has little, if any, capability to induce gene mutation, chromosomal damage and DNA repair (WHO 1994a, 2004b). However, there is some evidence of low-level binding to DNA. Chloroform does not appear capable of inducing unscheduled DNA synthesis in vivo. Review of chloroform by USEPA indicates that chloroform is not a mutagen and is not likely to cause cancer through a genotoxic mode of action (USEPA 2001). Sensitive Populations Based on the review conducted by ATSDR (ATSDR 1997b), the following is noted: Since the liver and kidney are the two main organs responsible for chloroform metabolism, individuals who have hepatic or renal impairment may be more susceptible to chloroform toxicity; one such population would be those who abuse alcohol. Also, exhaustion and starvation may potentiate chloroform hepatotoxicity, as indicated in some human clinical reports and in animal studies. Animal studies indicate that male mice and rats may be more susceptible to the lethal and renal effects of chloroform than female mice and rats. The greater susceptibility of adult male animals is associated with testosterone levels in the animals. B-11 P age

16 Evidence also exists for age-related effects; young male mice were less susceptible to the lethal effects of chloroform compared to adult males. Classification Chloroform has been classified as a "probable" human carcinogen (Category B2) by the USEPA based on carcinogenicity in animals. The USEPA review considered that chloroform is likely to be carcinogenic to humans by all routes of exposure under high-exposure conditions that lead to cytotoxicity and regenerative hyperplasia in susceptible tissues. Chloroform is not likely to be carcinogenic to humans by any route of exposure under exposure conditions that do not cause cytotoxicity and cell regeneration (USEPA 2001). In addition, the weight-of-evidence of the genotoxicity data on chloroform supports a conclusion that chloroform is not strongly mutagenic, and that genotoxicity is not likely to be the predominant mode of action underlying the carcinogenic potential of chloroform. Although no cancer data exist for exposures via the dermal pathway, the weight-of-evidence conclusion is considered to be applicable to this pathway as well, because chloroform absorbed through the skin and into the blood is expected to be metabolized and to cause toxicity in much the same way as chloroform absorbed by other exposure routes. IARC has classified chloroform in Group 2B (possibly carcinogenic to humans) based on inadequate evidence in humans and sufficient evidence in experimental animals for carcinogenicity (IARC 1999c). The National Occupational Health and Safety Commission (NOHSC) as Category 3 carcinogen (possible human carcinogen) (Safe Work Australia). NICNAS has not classified chloroform. B3.6 Quantitative Toxicity Reference Values On the basis of the weight of evidence, it is appropriate that chloroform is assessed on the basis of a threshold. The following quantitative values are available for chloroform from relevant Australian and International sources: B-12 P age

17 Table B2 Summary of Published Toxicity Reference Values: Chloroform Source Value Basis/Comments Australian ADWG (NHMRC 2011 Updated 2016) TDI = 0.07 mg/kg/day The current ADWG have derived a drinking water guideline for total trihalomethanes, which included chloroform (as well as bromodichloromethane, dibromochloromethane and bromoform) of 0.25 mg/l as a total or individually using a TDI of 0.07 mg/kg/day derived from a no effect level based on a 90-day gavage study on rats and the application of 100 safety factor. International WHO (WHO 1994a) WHO DWG (WHO 2011) WHO (WHO 2004b) RIVM (Baars et al. 2001) ATSDR (ATSDR 1997b) USEPA (USEPA 2001) TDI = mg/kg/day for non-neoplastic effects TDI = 0.01 mg/kg/day for neoplastic effects TDI = mg/kg/day TDI = mg/kg/day TC = 0.14 mg/m 3 TDI = 0.03 mg/kg/day TC = 0.1 mg/m 3 Oral MRL = 0.01 mg/kg/day Inhalation MRL =0.1 mg/m 3 RfD = 0.01 mg/kg/day TDI = mg/kg/day based on non-neoplastic effects (hepatoxicity) in a 7.5 year study on dogs (lowest identified effects level of 15 mg/kg), 1000 uncertainty factor. TDI = 0.01 mg/kg/day for neoplastic effects (liver tumours) based on a 3 week study in mice (NOAEL of 10 mg/kg), 1000 uncertainty factor. Based on induction of renal tumours in male rats a total daily intake associated with a 10-5 excess cancer risk (linearised multistage model) is mg/kg/day. This review has been superseded by more recent reviews below. Based on hepatoxicity in dogs (derived in 1994 from oral studies) generated using PBPK modelling and an uncertainty factor of 25. TDI and TC derived on the same basis as noted above from the DWG. The TDI and TC were considered to be protective against possible human carcinogenic risk from chloroform exposure as well as possible kidney damage that likely precede tumour development. TDI derived based on a LOAEL of 30 mg/kg/day for hepatotoxic effects in mice and an uncertainty factor of TC derived based on a NOAEL of 110 mg/m 3 for hepatic effects in rats and an uncertainty factor of MRL derived based on a LOAEL of 12.9 (adusted) mg/kg/day for hepatotoxic effects in dogs and an uncertainty factor of The chronic inhalation MRL has been derived on the basis of a LOAEL of 9.9 mg/m 3 associated with liver effects in humans and an uncertainty factor of 100. Oral reference dose (RfD) (updated in 2001) has been derived for the assessment of both carcinogenic and non-carcinogenic effects of chloroform. The RfD is based on a BMD approach based on a study associated with liver effects in dogs (the same study considered by the WHO (WHO 2004b)) and application of a 100 fold uncertainty factor. The value has been derived following consideration of the mode of action where a non-linear dose response was considered relevant. The assessment of cancer risk from chloroform inhalation is noted on IRIS to be dated (from 1987) and has not incorporated newer data or the revised cancer guidelines. The old approach of considering a linear dose response for carcinogens regardless of the mode of action remains on the data base, however this is under review. The threshold values available from the WHO are the most current and relevant values that are considered adequately protective of human carcinogenic risk from chloroform exposure as well as possible kidney damage that likely precede tumour development (WHO 2004b). B-13 P age

18 B4 Dichloromethane B4.1 General Dichloromethane (also commonly known as methylene chloride as well as methane dichloride, methylene bichloride, methylene dichloride or DCM) is a synthetic compound, which is not known to occur naturally in the environment. DCM is primarily used as a solvent, especially for grease, plastics and various paint-binding agents. Among its uses are: as a component of paint and varnish strippers, and adhesive formulations; solvent in aerosol formulations; extractant in food and pharmaceutical industries; process solvent in cellulose ester production and fibre and film forming; process solvent in polycarbonate production; blowing agent in flexible polyurethane foams; the extraction of fats and paraffins; plastics processing, and metal and textile treatment; a vapour degreasing solvent in metal-working industries. The main use in consumer products is in paint strippers, where DCM is the main constituent (70-75%). The second important use is in hairspray aerosols, where it acts as a solvent and vapour pressure modifier. Other types of DCM-containing products are household cleaning products and lubricating, degreasing and automotive products, some of which may be in aerosol form. DCM is produced by the reaction of methanol with hydrogen chloride which is then reacted with chlorine. Chloroform and, to a lesser extent, carbon tetrachloride are also produced (ATSDR 2000). B4.2 Properties DCM is a non-flammable, colourless liquid with a penetrating ether-like odour. It is soluble in alcohol, ether, acetone, chloroform and carbon tetrachloride. The pure dry compound is very stable. DCM hydrolyses slowly in the presence of moisture, producing small quantities of hydrogen chloride. Commercial DCM normally contains small quantities of stabilisers to prevent decomposition. Key properties are presented below (ATSDR 2000; RAIS): CAS No Chemical Formula CH 2Cl 2 Molecular Weight Vapour Pressure 435 mmhg at 20 o C Vapour Density 2.9 Density 1.32 g/ml at 25 o C Solubility mg/l at 20 o C Air Diffusion Coefficient cm 2 /s Water Diffusion Coefficient 1.25 x 10-5 cm 2 /s Henry s Law Coefficient atm.m 3 /mol = at 25 o C (unitless) Koc 21.7 cm 3 /g Log Kow 1.25 Odour Threshold 540 to 2160 mg/m 3 Permeability Constant cm/hr B-14 P age

19 B4.3 Exposure Human exposure to DCM occurs principally through inhalation. However exposure may also occur via oral and dermal routes particularly during occupational or consumer use of DCM containing products. The chlorination of drinking water also produces DCM. NHMRC indicate that DCM has not been found in Australian drinking waters (NHMRC 2011 Updated 2016). In relation to the assessment of dermal absorption, dermal absorption of highly volatile chemicals is expected to be negligible as it is not expected to remain on the skin long enough for absorption to be significant (USEPA 2004). Region III guidance (USEPA 1995a) of dermal absorption for volatile compounds suggests that a value of 0.05% be adopted for benzene and other volatiles with a vapour pressure similar to or greater than benzene (VP = 95.2 mmhg). No data is available specifically for the dermal absorption of DCM and it has a vapour pressure greater than benzene; hence a value of 0.05% is considered relevant. If released into the environment the following can be noted with respect to DCM (ATSDR 2000; WHO 1996): Air: Nearly all DCM released to the environment will ultimately be present in the atmosphere due to its volatility, where it will degrade by reaction with photochemically produced hydroxyl radicals with a lifetime of 6 months. Transport can occur to regions far removed from the emission source. DCM is expected to have no significant impact on stratospheric ozone depletion nor will it contribute significantly to photochemical smog formation. Soil and Water: Following releases to soil, most DCM is expected to volatilise and low soil adsorption. Most of the remaining DCM will travel through the soil because of its low adsorption onto soils (and hence high mobility) with leaching to groundwater considered to be a significant pathway. Volatilisation is considered to be the main process for the removal of DCM from aquatic systems. DCM is not expected to adsorb significantly to sediment or suspended organic matter in surface water. Biodegradation: DCM undergoes slow hydrolysis in water and hence it is not considered to be a significant degradation process in water. Both aerobic and anaerobic biodegradation may be important for DCM in water. Degradation of DCM in soils was found to occur with the rate of degradation dependant on the soil type, concentration and redox state of the soil with degradation observed under both aerobic and anaerobic conditions. Biodegradation of DCM appears to be accelerated by the presence of elevated levels of organic carbon. Bioaccumulation of DCM is not expected to be significant. B4.4 Background Exposures/Intake With respect to DCM, intakes from soil, water and food can be considered to be insignificant. Based on data available from urban air in Brisbane and Perth (Hawas et al. 2001; WA DEP 2000) DCM intakes from air may contribute to approximately 20% of the TDI. Hence, the suggested TDI values presented for the evaluation of DCM should be adjusted to account for 20% intake from background. B-15 P age

20 B4.5 Health Effects General The following information is available from WHO and ATSDR (ATSDR 2000; WHO 1996). There is no clinical disease which is unique to DCM toxicity. Humans and animals readily absorb DCM from the lungs and the gastrointestinal tract into systemic circulation. The compound is also absorbed to some extent through intact skin. Following absorption, DCM concentrations rapidly increase in the blood to reach equilibrium levels that depend primarily on exposure concentrations. A fairly uniform distribution to heart, liver, and brain is reported with increased concentrations also reported in adipose tissue. DCM is quite rapidly excreted, mostly via the lungs in the exhaled air. It can cross the blood-brain barrier and be transferred across the placenta, and small amounts can be excreted in urine or in milk (ATSDR 2000; WHO 1996). Extensive toxicokinetic studies have shown that DCM is metabolised by two pathways: (1) a mixed function oxidase (MFO) pathway mediated by the P-450 system yielding CO and CO 2 and (2) a glutathione-dependent (GST) pathway yielding only CO 2. Other metabolites of DCM include formaldehyde and formic acid (ATSDR 2000; WHO 1996). Tests involving acute exposure of animals have shown DCM to have moderate acute toxicity from oral and inhalation exposure. Case studies of DCM poisoning during paint stripping operations have demonstrated that inhalation exposure to extremely high levels can be fatal to humans. Acute inhalation exposure to high levels of DCM in humans has resulted in effects on the central nervous system (CNS) including decreased visual, auditory, and psychomotor functions, but these effects are reversible once exposure ceases. DCM also irritates the nose and throat at high concentrations (ATSDR 2000; WHO 1996). The major effects from chronic inhalation exposure to DCM in humans are effects on the CNS, such as headaches, dizziness, nausea, and memory loss. Animal studies indicate that the inhalation of DCM causes effects on the liver, kidney, CNS, and cardiovascular system (ATSDR 2000; WHO 1996). Animal studies have demonstrated that DCM crosses the placental barrier, however in the studies available DCM is not a reproductive toxicant nor is it a developmental toxicant via inhalation or oral pathways (ATSDR 2000; WHO 1996). Carcinogenicity and Genotoxicity Review of carcinogenicity indicates that DCM has been found to be carcinogenic in mice, causing both lung and liver tumours, following exposure to high concentrations in air. These tumours were not seen in the rat or the hamster (WHO 1996). Metabolism and biochemical studies, and mutagenicity assays in bacteria and B6C3F 1 mice have provided a plausible explanation for the mechanism of action and the species differences in the carcinogenicity of DCM to the lung and liver. This explanation is based on the existence of an isoenzyme of glutathione-s-transferase which specifically metabolises DCM to the reactive intermediates responsible for tumour induction in the mouse. This is an important pathway only in B-16 P age

21 mice and then only at high doses. It is not a major pathway for rats, hamsters or humans. The mouse appears to be unique in its response to DCM and is not an appropriate model for humans. It is noted that the USEPA review has not dismissed these studies and considers them in their evaluation. Evaluation of the relevance of the mice studies notes their limitations but does not preclude them (USEPA 2011c). Benign mammary tumours observed in rats exposed at high doses to DCM are the result of high serum prolactin levels which is not expected to occur at low levels of exposure and has not been observed in humans exposed to DCM (USEPA 2011c; WHO 1996). On the basis of the available information, the carcinogenic potency of DCM in humans is expected to be low. This evaluation is considered to remain current despite the USEPA review which considers that there is sufficient data (primarily from the mice studies) to consider that DCM is likely to be carcinogenic in humans (USEPA 2011c; WHO 1996). Review of genotoxicity indicates that the available data indicate that DCM or its metabolites are capable of interacting with DNA (WHO 1996). However, with the exception of mouse studies, in vivo studies using high levels of DCM exposure have not provided clear evidence of genotoxicity. The evidence suggests that DCM genotoxicity in the mouse results from the metabolism of DCM to genotoxic metabolites and this is a species-specific phenomenon which does not appear to occur in other species including humans. Therefore, the relevance of the genotoxicity in mice to humans is considered limited and there is no conclusive evidence that DCM in genotoxic (USEPA 2011c; WHO 1996). The USEPA review has considered that the mode of action for DCM induced tumours in the lung and liver in mice) involves mutagenicity via reactive metabolites. As these endpoints are not considered relevant to humans, and no additional data is presented in the review, there is no strong evidence that DCM is genotoxic or mutagenic. However, if further data/peer-reviewed evaluations are available that supports this outcome then the assessment of DCM will need to be revised (USEPA 2011c; WHO 1996). Sensitive Populations Insufficient information is available regarding potentially susceptible populations. The review conducted by the USEPA assumes a mutagenic mode of action base on mice data which does not appear to be supported by other reviews (USEPA 2011c; WHO 1996). Classification DCM has been classified as a "probable" human carcinogen (Category B2) by the USEPA based on increased incidence of hepatocellular neoplasms and alveolar/bronchiolar neoplasms in mice and benign mammary tumours in rats. It is noted that the USEPA review considered that DCM is likely to be carcinogenic to humans by all routes of exposure (USEPA 2011c). IARC has classified DCM in Group 2A (probably carcinogenic to humans) based on inadequate evidence in humans and sufficient evidence in experimental animals for carcinogenicity (Benbrahim- Tallaa et al. 2014). B-17 P age

22 The National Occupational Health and Safety Commission (NOHSC) has classified DCM as Category 3 carcinogen (possible human carcinogen) (Safe Work Australia). NICNAS has not classified DCM B4.6 Quantitative Toxicity Reference Values On the basis of the weight of evidence, it is appropriate that DCM is assessed on the basis of a threshold. The following quantitative values are available for DCM from relevant Australian and International sources: Table B3 Summary of Published Toxicity Reference Values: Dichloromethane Source Value Basis/Comments Australian ADWG (NHMRC 2011 Updated 2016) TDI = mg/kg/day The current ADWG have derived a drinking water guideline for DCM of mg/l using a TDI of mg/kg/day derived from a lowest effect level based on a 2 year drinking water study on rats and the application of 5000 safety factor. The 5000 fold safety factor included a 10 fold factor for potential genotoxicity. International WHO DWG (WHO 2011) WHO (WHO 2000c) EU (CSTEE 2000; TNO 1999) RIVM (Baars et al. 2001) TCEQ (TCEQ 2011) ATSDR (ATSDR 2000) USEPA (USEPA 2011c) TDI = mg/kg/day TC = 0.45 mg/m 3 (1 week) TC = 1.25 mg/m 3 TDI = 0.06 mg/kg/day TC = 3 mg/m 3 Chronic ESL = 0.35 mg/m 3 Oral MRL = 0.06 mg/kg/day Inhalation MRL =1.1 mg/m 3 RfD = mg/kg/day RfC = 0.6 mg/m 3 Based on hepatotoxic effects in a 2-year drinking water study in rats and an uncertainty factor of 1000 including a factor of 10 to address concern about the carcinogenic potential. The WHO (2000) review of DCM has identified that carcinogenicity is not the critical end point for risk assessment purposes. The formation of carbon monoxide in blood (COHb is a more direct indication of a toxic effect, it can be monitored and is a more suitable basis for the derivation of a guideline. A guideline value of 3 mg/m 3 has been derived for the assessment of 24-hour exposures based on a 0.1% increase in COHb. In addition, it is noted that the weekly average concentration should not exceed one-seventh of this guideline (0.45 mg/m 3 ). Chronic inhalation exposures have been evaluated on the basis of liver effects in the rat, leading to a NOAEL of 125 mg/m 3 continuous exposure, which, with a MOS of 100, reduces to a limit of 1.25 mg/m 3. A chronic standard of 0.2 mg/m 3 has been derived based on 1x10-4 incremental risk level, however the acceptable risk level adopted was is not considered to be acceptable by the EU. The review committee considered that the acceptable limit for long-term exposure of the general population should be based on consideration of the carcinogenic risk. TDI derived based on a NOAEL of 6 mg/kg/day for hepatotoxic effects in rats and an uncertainty factor of 100. TC derived based on a LOAEL (adjusted) of 28 mg/m 3 for CNS effects and increases in blood COHb levels in humans and an uncertainty factor of 10. Same as that derived by WHO for 24-hour exposures. Development of air criteria resulted in the derivation of a threshold criteria of 1.3 mg/m 3 associated with hepatotoxic effects from a 2 year inhalation study in rats, and an uncertainty factor of 100. A lower criteria of 0.35 mg/m 3 was derived on the basis of linear effects for liver and lung tumours in mice and a risk level of 1x10-5. The lower value from these evaluations listed in this table. MRL derived based on a NOAEL of 6 mg/kg/day for hepatotoxic effects in rats and an uncertainty factor of 100. The chronic inhalation MRL has been derived on the basis of a NOAEL (adjusted) of 31 mg/m 3 associated with liver effects in rats and an uncertainty factor of 30. Oral RfD based on a BMD from study associated with hepatotoxic effects in a rat study, use of a rat physiologically based PBPK model to estimate internal doses and an uncertainty factor of 30. B-18 P age