Reproduction in Fischer-344 rats exposed to methyl chloride by inhalation for two generation*1, *2

This chapter reviews the one‐carbon compounds with chlorinated, brominated, or iodinated substituted side groups. At ambient temperatures, methyl chloride and methyl bromide are gases; iodoform and methylene chlorobromide are solids; and the remaining seven chemicals in this chapter are volatile, nonflammable liquids. The nonflammability has been an important property for the uses of these chemicals as solvents. Most, if not all, of the chemicals in this chapter are produced in closed‐system facilities. Three of the chemicals (methyl bromide, carbon tetrachloride, and methylene chlorobromide) are ozone‐depleting substances and are tightly regulated under the Montreal Protocol on Substances that Deplete the Ozone Layer. Thus, these chemicals are restricted to feedstock or intermediate uses where, by definition, it is used and entirely consumed, except for trace quantities, and certain exempt applications. For the other chemicals in this chapter, the primary, if not exclusive, uses are as feedstocks or intermediates in the production of other chemicals, the exception being methyl iodide.

Halogenated One‐Carbon Compounds

Bevan

2023

Saturated Methyl Halogenated Aliphatic Hydrocarbons

Reid¹

2001

It is impossible to generalize on the saturated methyl halogenated aliphatic hydrocarbons discussed in this chapter. Physical properties and toxicological manifestations differ over a broad range depending on the particular halogen and the number of halogen atoms involved. As mentioned in the previous edition, the usefulness of these compounds has been significantly reduced because of the concern over stratospheric ozone depletion. On the other hand, toxicological interest in these compounds has increased because of concern over their production in chlorinated water systems. The USEPA (National Center for Environmental Assessment) and others are actively investigating the possible relationship between chlorination of drinking water sources and human cancer through many avenues, including sophisticated epidemiologic tools. Many of the compounds have been shown to produce cancer in animals, but their potency for humans is still under consideration, and the complex interactions with regard to human health are challenging. The other area of biochemistry that is of relevance to some of these materials is in regard to lipid peroxidation and its role in disease and in extrapolation from animal species to humans. As in the previous editions, this review relies extensively on information provided in earlier editions. Several online databases were utilized in searching for the most recent information in preparing the chapter. These included NTP (National Toxicology Program), IRIS (Integrated Risk Information Service), and the ATSDR (Agency for Toxic Substances and Disease Registry) websites. Most recent information was sought through MEDLINE, and, when possible, the original articles were reviewed. Debatably, IRIS was considered to be the last word with regard to cancer. Many of the compounds have been recently reviewed by the ATSDR and are reported in their toxicological profiles. Recent reviews were utilized in preparing this chapter. In addition, the Pocket Guide to Chemical Hazards and the ACGIH's TLV's and Other Occupational Exposure Values‐1999 were utilized.

Halogenated One‐Carbon Compounds

Reid¹,

Muianga²

2012

Chlorinated methanes (also ethanes) are among the most widely used and useful chemical compounds. There are potentially 26 compounds with other multiple halogen substitutions. Eleven important or representative compounds were selected to discuss in this chapter. The physical states vary from colorless gases: methyl chloride and methyl bromide; colorless liquids: methyl iodide, methylene chloride, methylene bromide, chloroform, bromoform (heavy), and carbon tetrachloride; and a yellow solid, iodoform, and colorless solid; carbon tetrabromide. The main use of methyl chloride is in the manufacture of silicone while methylene chloride, chloroform, and carbon tetrachloride have been used as solvents, paint removers, degreasers, cleaning compounds, and chemical intermediates. The following table provides toxicity information (reference doses, RfD; reference concentrations, RfC; oral slope factors (carcinogen), OSF; and inhalation unit risks (carcinogen), IUR) from Integrated Risk Information Service (IRIS). It can be seen that the RfDs (oral exposure for lifetime) for the chemicals that have been evaluated are in the order of 10 −2 to 10 −3 mg/kg/day. The inhalation RfCs (inhalation exposure) for chemicals that have been evaluated are 10 −2 to 10 −3 mg/m 3 . For the chemicals indicated as either probable human carcinogens or methylene chloride, chloroform, bromoform, and likely to be a human carcinogen, carbon tetrachloride, the OSF (per mg/kg/day) are in the order of 10 −2 to 10 −3 . The IURs for the chemicals evaluated are of the order of 10 −5 to 10 −6 per μg/m 3 . Fluorene compounds are not included in this chapter as they represent a very special case of halogenated compounds. Chemical RfD (mg/kg/day RfC (mg/m 3 ) Cancer Description OSF (Per mg/kg/day) IUR (Per μg/m 3 ) References Methyl chloride None 9E−2 Brain Not classified None None Toxicological Review (2001) Methyl bromide 1.4E−3 5E−3 Nasal Not classified None None No Toxicological Review Methyl iodide None None None None None No Toxicological Review Methylene chloride 6E−2 Liver None Probable human 7.5E−3 4.7E−7 No Toxicological Review Methylene bromide None None None None None None Chloroform 1E−2 Liver None Probable human RfD 1E−2 2.3E−5 Toxicological Review (2001) Bromoform 2E−2 Liver None Probable human 7.9E−3 1.1E−6 No Toxicological Review Iodoform None None None None None No Toxicological Review Carbon tetrachloride 4E−3 Serum SDH 1E−1 Likely human 7E−2 6E−6 Toxicological Review (2010) Carbon tetrabromide None None None None None No Toxicological Review Methylene chlorobromide None None None None None No Toxicological Review Several of the compounds listed in the above table are receiving attention because of their presence as disinfection by‐products (DBPs): products formed in reaction with chlorine, ozone, chlorine dioxide, or chloramines with naturally occurring organic matter in drinking water. A comprehensive review was provided in Mutation Research in conjunction with the IARC review. The trihalomethanes (THMs)—chloroform, bromoform, bromodichloromethane, and chlorodibromomethane—are regulated by the U.S. EPA at a level of 80 μg/L (for total halomethanes) and are included in 600 drinking water DBPs. Together, the THMs and haloacetic acids (HHAs) are the two most prevalent classes of DBPs formed in chlorinated drinking water, accounting for approximately 25% of the halogenated DBPs. Of concern is the demonstrated human carcinogenicity of many of the DBPs. The WHO in Trihalomethanes in Drinking‐Water (background document for development of WHO Guidelines for Drinking‐Water Quality ) provides a thorough discussion of four compounds considered the most common forms of halomethanes present in drinking water. These are chloroform, bromodichloromethane, dibromochloromethane, and bromoform. These compounds are liquids at room temperature, relatively to extremely volatile, and only slightly soluble in water. As in the previous editions, this chapter includes relevant information provided in earlier editions along with updated information from several sources including National Toxicology Program (NTP), IRIS, and the Agency for Toxic Substances and Disease Registry (ATSDR) websites.