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Chemical-Induced Atrial Thrombosis in NTP Rodent Studies—Supplementary Data
Katsuhiko Yoshizawa*,
Grace E. Kissling ,
Jo Anne Johnson*,
Natasha P. Clayton*,
Norris D. Flagler* and
Abraham Nyska*
* Laboratory of Experimental Pathology
Biostatistics Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina, 27709, USA
Figure 1 presents the chemical names and structures of these 13 compounds. We summarize below the information concerning usages and effects in humans of these chemicals. Table 1 shows data from rats indicating the relationship between the severity of myocardial lesions and atrial thrombosis which were induced by bis(2-chloroethoxy)methane.
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Figure 1 Chemical structure of compounds from the NTP rodent studies that might induce atrial thrombosis.
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Bis(2-chloroethoxy)methane (CEM)
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The majority is used for the production of polysulfide polymers, which are used in a variety of sealant applications because of their resistance to high temperatures and solvent degradation. No specific data for human toxicity are available, except those implicating it as an irritant of the skin and eye (NTP, 2003a, 2003b).
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2-Butoxyethanol (2-BE)
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This substance is used extensively as a solvent in surface coatings, such as lacquers, enamels, varnishes, and latex paint; paint thinners and paint stripping formulations; inks; and degreasers and industrial and household cleaners. In humans, the chemical can induce hemolytic anemia and hemoglobinurea (ATSDR, 1998; Burkhart and Donovan, 1998; Gualtieri et al., 2003; NTP, 1998a). Only a few human cases involving hypotension, ventricular tachycardia, and/or arrhythmia exhibited cardiovascular effects (ATSDR, 1998; Gualtieri et al., 2003).
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C.I. Acid Red 114 (Red 114)
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This chemical is a benzidine congener-based dye, used to color textiles, paper, plastic, rubber, and leather. No epidemiological studies or reports of human health effects related to exposure to this chemical were found in the literature (NTP, 1991).
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C.I. Direct Blue 15 (Blue 15)
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A benzidine congener-based dye, this chemical is used as a dye to color textiles, paper, plastic, rubber, and leather. No epidemiological studies or reports of adverse health effects in humans related to exposure to this chemical were discovered in the literature (NTP, 1992a).
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C. I. Pigment Red 23 (Red 23)
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This chemical, a bluish-red dye used as a coloring agent in paints, inks, rubber, plastics, lacquers, and papers, is considered a genotoxic compound (Moller, 2000). No epidemiological studies or reports of human health effects related to exposure were found in the literature (NTP, 1992b).
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Diazoaminobenzene (DAB)
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Used as an intermediate, complexing agent and polymer additive, this chemical also occurs as an impurity in certain color additives used in cosmetics, food products, and pharmaceuticals. No information related to the toxicity of this compound in humans was found in a review of the available literature (NTP, 2002b).
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Diethanolamine (DEL)
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This compound is widely used in the preparation of diethanolamides and diethanolamine salts that are formulated into soaps and surfactants used in liquid laundry and dishwashing detergents, cosmetics, shampoos, and hair conditioners. No references to human side effects caused by this chemical were found in a review of the literature (NTP, 1992c, 1999).
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3,3'-Dimethoxybenzidine dihydrochloride
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Used principally as an intermediate in the production of commercial bisazobiphenyl dyes, this compound is used to color textiles, paper, plastic, rubber, and leather. No epidemiological studies or reports of effects, especially hematological, upon human health related to exposure were discovered in the literature (NTP, 1990).
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Hexachloroethane (HCE)
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This chemical is used in organic synthesis as a retarding agent in fermentation and camphor substitute in nitrocellulose, in pyrotechnics and smoke devices, in explosives, and as a solvent. No epidemiological studies or reports of human health effects, including cardiovascular, related to exposure were found in the literature (ATSDR, 1997; NTP, 1989, 2002a).
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Isobutene (IBT)
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This compound, which has been detected in the urban atmosphere, is used primarily to produce diisobutylene, trimers of butyl rubber, and other polymers. During halothane anesthesia, a 10-fold increase over normal occurs in the concentration of isobutene in the breath of patients; the source was speculated to be terpenes or ubiquinones (Hempel et al., 1980). No epidemiological studies or reports of human health effects related to exposure were discovered in the literature (NTP, 1998b).
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Methyleugenol (MEG)
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The chemical acts as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish, and ice cream and is also used as a fragrance in perfumes, creams, lotions, detergents, and soaps. In addition, it occurs as a natural constituent of many essential plant oils (Lahlou et al., 2004; Smith et al., 2002). No information related to the toxicity of this compound in humans was found in a review of the literature (NTP, 2000).
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Oxazepam (OZP)
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This drug is one of a number of benzodiazepines used therapeutically as a sedative-hypnotic and antianxiety agent. Overdoses of this drug in humans commonly cause drowsiness, blurred vision, ataxia, and coma (Buckley et al., 1995; NTP, 1993). No references to adverse effects in humans, especially hematological, were found in the literature.
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4,4'-Thiobis(6-t-butyl-m-cresol) (TBBC)
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Used in the rubber and plastics industries as an antioxidant and incorporated as a stabilizer into polyethylene and polyolefin packaging materials for foodstuffs, this chemical may cause allergic contact dermatitis. No other references to human side effects were found in the literature (NTP, 1994).
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References
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- Agency for Toxic Substances and Disease Registry (ATSDR). (1997). Toxicological profile for hexachloroethane. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service
- Agency for Toxic Substances and Disease Registry (ATSDR). (1998). Toxicological profile for 2-butoxyethanol and 2-butoxyethanol acetate. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service
- Buckley, NA, Dawson, AH, Whyte, IM, & O’Connell, DL. (1995). Relative toxicity of benzodiazepines in overdose. BMJ, 310, 219-21[Abstract/Free Full Text]
- Burkhart, KK, & Donovan, JW. (1998). Hemodialysis following butoxyethanol ingestion. J Toxicol Clin Toxicol, 36, 723-5[Web of Science][Medline]
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- Dunnick, JK, Lieuallen, W, Moyer, C, Orzech, D, & Nyska, A. (2004). Cardiac damage in rodents after exposure to bis(2-chloroethoxy)methane. Toxicol Pathol, 32, 309-17[CrossRef][Web of Science][Medline]
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- Gualtieri, JF, DeBoer, L, Harris, CR, & Corley, R. (2003). Repeated ingestion of 2-butoxyethanol: case report and literature review. J Toxicol Clin Toxicol, 41, 57-62[CrossRef][Web of Science][Medline]
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- Hempel, V, May, R, Frank, H, Remmer, H, & Koster, U. (1980). Isobutene formation during halothane anaesthesia in man. Br J Anaesth, 52, 989-92[Abstract/Free Full Text]
- Lahlou, S, Figueiredo, AF, Magalhaes, PJC, Leal-Cardoso, JH, & Gloria, PD. (2004). Cardiovascular effects of methyleugenol, a natural constituent of many plant essential oils, in normotensive rats. Life Sci, 74, 2401-12[CrossRef][Web of Science][Medline]
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- Moller, P, & Wallin, H. (2000). Genotoxic hazards of azo pigments and other colorants related to 1-phenylazo-2-hydroxynaphthalene. Mutat Res, 462, 13-30[CrossRef][Web of Science][Medline]
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- National Toxicology Program. (1989). NTP technical report on the toxicology and carcinogenesis studies of hexachloroethane (CAS No. 67-72-1) in F344/N rats (gavage studies). TR 361, Research Triangle Park, NC.
 http://ntp-server.niehs.nih.gov/index . - National Toxicology Program. (1990). NTP technical report on the toxicology and carcinogenesis studies of 3,3'-dimethoxybenzidine dihydrochloride (CAS No. 20325-40-0) in F344/N rats and B6C3F1 mice (drinking water studies). TR 487, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1991). NTP technical report on the toxicology and carcinogenesis studies of C.I. Acid Red 114 (CAS No. 6459-94-5) in F344/N rats and B6C3F1 mice (drinking water studies). TR 405, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1992a). NTP technical report on the toxicology and carcinogenesis studies of C.I. Direct Blue 15 (CAS No. 2429-74-5) in F344/N rats and B6C3F1 mice (drinking water studies). TR 397, Research Triangle Park, NC, http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1992b). NTP technical report on the toxicology and carcinogenesis studies of C.I. Pigment Red 23 (CAS No. 6471-49-4) in F344/N rats and B6C3F1 mice (feed studies). TR 411, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1992c). NTP technical report on toxicology studies of diethanolamine (CAS No. 111-42-2) administered topically and drinking water to F344/N rats and B6C3F1 mice (inhalation studies). TOX20, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1993). NTP technical report on the toxicology and carcinogenesis studies of oxazepam (CAS No. 604-75-1) in Swiss-Webster and B6C3F1 mice (feed studies). TR 443, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1994). NTP technical report on the toxicology and carcinogenesis studies of 4,4'-thiobis(6-t-butyl-m-cresol) (CAS No. 96-69-5) in F344/N rats and B6C3F1 mice (feed studies). TR 435, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1998a). NTP technical report on the toxicology and carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). TR 484, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1998b). NTP technical report on the toxicology and carcinogenesis studies of isobutene (CAS No. 115-11-7) in F344/N rats and B6C3F1 mice (inhalation studies). TR 487, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (1999). NTP technical report on the toxicology and carcinogenesis studies of diethanolamine (CAS No. 111-42-2) in F344/N rats and B6C3F1 mice (dermal studies). TR 478, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (2000). NTP technical report on the toxicology and carcinogenesis studies of methyleugenol (CAS No. 93-15-2) in F344/N rats and B6C3F1 mice (gavage studies). TR 491, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (2002a). Hexachloroethane. Rep Carcinog, 10, 135-7[Medline]
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- National Toxicology Program. (2002b). NTP report on the metabolism, toxicity, and predicted carcinogenicity of diazoaminobenzene (CAS No. 136-35-6). TOX 73, Research Triangle Park, NC. http://ntp-server.niehs.nih.gov/index.
- National Toxicology Program. (2003a). The 14-day cardiac toxicity study of bis(2-chloroethoxy)methane (CEM) (CAS No. 111-91-1) dermally administered to Fischer 344 rats. Battelle Columbus reports submitted to NTP-G004164-AH. Research Triangle Park, NC
- National Toxicology Program. (2003b). The 90-day dermal toxicity study of bis(2-chloroethoxy)methane (CEM) (CAS No. 111-91-1) in Fischer 344 rats. Battelle Columbus reports submitted to NTP-G004164-AD. Research Triangle Park, NC
- Smith, RL, Adams, TB, Doull, J, Feron, VJ, Goodmen, LJ, Marnett, LJ, Portoghese, PS, Waddell, WJ, Wagner, BM, Rogers, AE, Caldwell, J, & Sipes, IG. (2002). Safety assessment of allylalkoxy-benzene derivatives used as flavouring substances—methyl eugenol and estragole. Food Chem Toxicol, 40, 851-70[CrossRef][Web of Science][Medline]
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Toxicologic Pathology, Vol. 33, No. 5,
1-3 (2005)
DOI: 10.1080/725272397
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Bis(2-chloroethoxy)methane (CEM)
2-Butoxyethanol (2-BE)