Benzotrichloride

Benzotrichloride is a poorly water-soluble, clear to yellowish liquid with a penetrating odor. It hydrolyzes rapidly to benzoic acid and hydrochloric acid with a half life of about 2.4 minutes, thus making the compound unstable in the presence of water. In other chemical reactions, benzotrichloride reacts at the chlorinated α-carbon, for example in substitution reactions. It is used as an intermediate in the synthesis of benzoyl chloride, benzotrifluoride and 2,4-dihydroxybenzophenone which in turn are also intermediates in other reactions: : C6H5CCl3 + H2O → C6H5C(O)Cl + 2 HCl : C6H5CCl3 + 3 KF → C6H5CF3 + 3 KCl These compounds are further used to synthesize chemicals needed in the pharmaceutical industry (benzoyl peroxide), the synthesis of pesticides, dyes and UV-absorbing compounds which are often used in paint and plastics to prevent degradation by sunlight. ==Production==

Production capacity of benzotrichloride was estimated at 80,000 tonnes for the year 2000. It is produced by the free radical chlorination of toluene, catalysed by light or radical initiators such as dibenzoyl peroxide. Mono- and di-chlorinated intermediates are observed as benzyl chloride and benzal chloride: : C6H5CH3 + Cl2 → C6H5CH2Cl + HCl : C6H5CH2Cl + Cl2 → C6H5CHCl2 + HCl : C6H5CHCl2 + Cl2 → C6H5CCl3 + HCl In the presence of Lewis acids, chlorination occurs at the ring, giving chlorotoluenes. == Regulation ==

Benzotrichloride is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and hence its use is subject to a list of reporting requirements by companies or institutions which synthesize, store or use it in large quantities. In 2018, EU member states have approved a European Commission proposal to restrict the use of carcinogenic, mutagenic and reprotoxic (CMR) substances in clothing, textiles and footwear. In 2015, the Commission published a preliminary list of 286 CMRs it proposed to restrict. Benzotrichloride was listed in this document as a toxic and carcinogenic compound. According to the harmonised classification and labelling (CLP00) approved by the European Union (EU), this substance is toxic if inhaled, causes serious eye damage, may cause cancer, causes skin irritation, is harmful if swallowed, and may cause respiratory irritation. == Metabolism ==

In a rat experiment with radiolabeled [14C]-benzotrichloride a single 40 mg/kg body weight dose was administered. The absorption half-life of BTC from the gastrointestinal tract was determined to be 3 hours. The concentration in the blood peaked at 4 h reaching 6.5 ppm, this decreased to 2.6 ppm after 24 h. The elimination of half-life in blood was 22 h. Elimination took place for 90% through urine and 10% through faeces. After 72 hours 1.5% of the dose was still present in tissue. The highest concentration levels were present in liver, kidney and fat. 90% of the BTC was recovered from the rat urine as hippuric acid while small amounts of benzoic acid (0.7%) and phenyl acetic acid (0.8%) were also present. Four unidentified metabolites (5.5%) were also present in urine. == Toxicity ==

Signs of toxicity Several symptoms are related to the tested exposure to benzotrichloride (BTC) in rats: irritation of the eyes, the skin and the respiratory tract. Under occlusive conditions, rabbit skin which was exposed to BTC showed irritation. Next, severe eye irritation was reported in rabbits, after administering 0.1 mL of BTC. This eye irritation lasted up to 7 days. Finally, several rat studies into the acute toxic effects indicate that the respiratory system will be irritated after inhalation or oral uptake of BTC. The toxicity of BTC in mammals was assessed by Chu I. et al. (1984) by tracking several characteristics in rats for 28 days after oral intake of BTC. Growth rate and food consumption were not found to be affected by treatment. No deaths occurred during these trials. Animal toxicity Acute toxicity Inhalation Inhaling 1147 mg/m3 of benzotrichloride (BTC) for 3 hours resulted in 1 out of 6 male rats dying (after 3 days). On the other hand, inhaling 995 mg/m3 of BTC for 3 hours resulted in 4 out of 6 female rats dying within 13 days. However, reducing the duration of exposure to only one hour with a concentration just above 800 mg/m3 resulted in no male or female rats dying. The treated rats had irritated oral and ocular mucous membranes, while behaviour and breathing were altered for up to 13 days. Repeated dose toxicity Inhalation The toxic effects of repeated benzotrichloride exposure have been assessed for inhalation, dermal exposure and oral ingestion. After repeated exposure to a concentration of 12.8 mg/m3 twice weekly for 30 minutes, over 12 months in mice, severe bronchitis and bronchial pneumonia were observed. After exposure of 5.1 mg/m3 for 6 hours a day, 5 days a week for 4 weeks, no adverse effects were observed in rats. Research, after suspicion of carcinogenicity in benzoyl-chloride producing factories, on ICR mice also showed significant incidence of tumors: skin-cancer (68%) and pulmonary tumors (58%) after applying 2.3 microliter/animal twice weekly for 50 weeks. Oral In humans only a few cases of lung cancer are linked to either benzoyl chloride or benzotrichloride, although smoking also might have played a role. Both NCI thesaurus and NPT carcinogen reports classify BTC as "reasonably anticipated to be a human carcinogen", based on limited evidence of carcinogenicity from studies in humans and sufficient evidence of carcinogenicity from studies in experimental animals. Aquatic effects Daphnia magna (a planktonic crustacean) were tested and a 24 h-EC50 of 50 mg/L was found. The toxic effects were attributed to HCl formation, as benzotrichloride dissociates rapidly into the far less toxic benzoic acid and HCl on water exposure. Compensating the pH decrease in water from the HCl negated toxic effects, suggesting that water acidification is the reason for the low aquatic life toxicity. Benzoic acid has an EC50 of >100 mg/L towards aquatic life, is readily biodegradable and does not accumulate, so is not regarded as toxic towards aquatic life. Fertility No extensive studies were done on fertility effects. As the carcinogenic potential on its own already warrants extensive restrictions, no additional restrictions are needed for effect on fertility, although the genotoxic properties suggest that fertility might be affected. == Mechanism of toxicity ==

Part of the toxicity of benzotrichloride can be explained by its hydrolysis to benzoic acid, whose further metabolism can cause toxic effects. Benzoyl-CoA formation can deplete acetyl-CoA levels, hampering processes requiring acetyl-CoA, like gluconeogenesis via pyruvate carboxylase. Hepatic ATP levels are also lowered by 70-80%, at doses of 720–1440 mg/kg benzoic acid via intraperitoneal injection, by reducing acetyl-CoA availability for ATP production, which can have a wide range of consequences for affected cells. Benzoic acid therefore might have a role in benzotrichloride carcinogenicity, but benzotrichloride has more carcinogenic potential than benzoic acid, suggesting that an intermediate in hydrolysis is responsible for at least part of the carcinogenicity. ==References==