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Toxicokinetics, metabolism and distribution

Chlorine is a strong oxidising agent which forms both hypochlorous and hydrochloric acid in contact with most mucous membranes. The former compound decomposes into hydrochloric acid and oxygen free radicals (O2-). Damage results from the disruption of cellular proteins caused by its strong oxidising nature.

The primary available chlorine species in aqueous solution are not different from those coming from hypochlorous acid at similar pH. In biological systems, characterised by pH values in the range 6-8, the most abundant active chemical species is HOCl, in equilibrium with ClO-. The latter is predominant at alkaline pH values, while Cl2 is mainly present at pH below 4. Therefore, ADME studies performed with hypochlorite and its salts are used in this document. Limited data are available only for the oral route.

Hypochlorite readily reacts with organic material such as amino acids, proteins, nucleic acids, lipids and carbohydrates. The resulting organic compounds may possess their own inherent toxicity as well as causing cellular damage (BIBRA, 1990).

Due to the reactive nature of chlorine, the question can be raised whether it is chlorine or a by-product that is responsible for any effect. Studies examining the formation of chlorinated by-products in the gastro-intestinal tract involved administration of higher concentrations of chlorine versus those that would be encountered in chlorinated drinking water. Consequently, the by-products formed may not be representative of the by-products that would be seen in the consumption of modest to moderate levels of chlorinated drinking water. The high organic carbon concentration relative to chlorine that would be encountered in the gastrointestinal tract when water is consumed at low concentrations should dissipate the hypochlorite before sufficient oxidative power would be present to break down substrates to small molecules. The bulk of the by-products formed remain as higher molecular weight products, which may have little toxicological importance. (IPCS 1999, Environmental Health Criteria for disinfectants by-products, EHC 216.)

Studies in animals

Inhalation

The effects of the exposure of rats and mice to chlorine are dependant on the exposure concentration. At moderate to high concentrations chlorine can exert its effect over the whole respiratory tract. In a 6 week inhalation study at 9 ppm in rats hyperplasia and hypertrophy of epithelial cells was observed in bronchioles, alveolar tracts and alveoli (Barrow et al., 1979). On the other hand, at low concentrations (≤ 2.5 ppm, 7.5 mg/m3) effects of chlorine exposure occur only in the upper airways as was demonstrated by the results of a 2-year inhalation study in rats and mice, in which lesions were confined to the nasal passage (Wolf DC et al.).

Dermal

Due to the gaseous nature of chlorine, no specific studies are available. Also no toxicokinetic information following dermal exposure studies of chlorine solutions in water is available.

Oral

A series of pharmacokinetic studies using 36Cl-labelled hypochlorous acid were conducted (Abdel-Rahman et al., 1983) in rats. These studies are of limited value as the form of 36Cl could not be determined in various body compartments. Three groups of 4 Sprague-Dawley rats were orally administered with different quantities of HO36Cl solution. A peak of radioactivity in rat plasma occurred 2 hours after HO36Cl administration in fasted rats and 4 hr after administration in non-fasted rats. 36Cl radioactivity was distributed throughout the major tissues, 96 hr after HO36Cl administration. The highest levels were found in plasma, whole blood, bone marrow, testis, skin, kidney and lung. The lowest levels were found in the liver, carcass and fat tissue. HO36Cl-derived radioactivity was not detected in expired air throughout the 96 hr study. During the same period, 36.43% + 5.67 (mean + S.E.) of the administered dose was excreted through the urinary route, while 14.8% + 3.7 was recovered in the faeces, giving a poor total recovery of 51.23% + 1.97 (Abdel-Rahman et al., 1983).

Vogt et al. (1979) reported that chloroform could be measured in the blood, brain, liver, kidneys and fat of rats to which sodium hypochlorite was administered by gavage at doses of 20, 50 or 80 mg in 5 ml of water. Thus, the by-product chloroform can be formed by the reaction of chlorine with stomach contents.

Other by-products formed in vivo by the interaction of chlorine and stomach content that have been reported are dichloroacetonitriles (DCAN), dichloroacetic acid (DCA) and trichloroacetic acid (TCA) (Mink et al., 1983). Fasted and non-fasted rats received 7 ml of an 8 mg/ml solution of sodium hypochlorite at pH 7.9 (about 140 mg/kg bw) by gavage. TCA was found in the gut contents and in the plasma 1 hour after the treatment, suggesting the formation of trichloroacetic acid independently from foreign organic material in the gut. Chloroform and DCA were also detected, generally associated with TCA. DCAN was also detected in some of the non-fasted rats (Mink, 1983).

Scully and co-workers reported on the formation of organic chloramines in stomach contents by chlorination of free amino acids. The chlorine demand of free amino acids in stomach contents was found to be only about 4% of the total. Consequently, this process may be substrate-limited at concentrations of chlorine found as residuals in drinking-water. However, use of higher concentrations of chlorine would also lead to breakdown of proteins present in the stomach fluid. Thus, as concentrations are increased to levels that would be used in animal studies, these products would be formed at a much higher concentration, similar to the phenomena noted with trihalomethanes (THM) and haloacetic acids (HAA) by-products (Scully et al., 1990).

No chlorination reaction products were observed in urinary extracts of rats after ingestion of 8 and 16 mg/day sodium hypochlorite solution for 8 days (Kopfler, 1985).

Studies in humans

Although the possible effects of human exposure via different routes to chlorine, whether as chlorine gas, chlorite ion or hypochlorite, are well-known, few data are available on quantitative rates of by-products formed, distributed, metabolised and excreted.

Inhalation

Also in humans effects of chlorine will primarily be confined to the upper airways. Groups of 5 men and 5 women were exposed to various concentrations of a bolus peak concentration of 3 ppm (9 mg/m3) chlorine at respiratory flows of 150, 250 and 1000 ml/sec. Differences in uptake between mouth and nasal breathing were examined. Because Cl2 rapidly and reversibly hydrolyses in aqueous solution, increasing the respiratory flow does not increase the Cl2 that reaches the respiratory air spaces during either nasal or oral breathing. Less than 5% of the inspired Cl2 penetrated beyond the upper airways and none reached the respiratory air spaces. In all cases, more than 95% of the chlorine inhaled was absorbed in the upper airways (Nodelman and Ultman, 1999).

Dermal

No specific studies available. There is also no toxicokinetic information available from human exposure studies with chlorine solutions in water by dermal route.

Oral

There is no specific data available on oral exposure to chlorine gas. Also no toxicokinetic information is available from human oral exposure studies with chlorine solutions in water.

Summary of toxicokinetics, metabolism and distribution

Chlorine reacts at the site of contact where its primary activity is destruction of organic molecules present. It will therefore not be absorbed into the bloodstream. Although only moderately soluble in the epithelial lining fluid, its fast reaction to surface material and tissue of the respiratory tract causes it to be a potential toxic gas. Mice and rats are obligate nose breathers and have a more complex nasal structure then humans, and develop more severe nasal responses to inhalation toxicants than humans. However, available data indicate that in both humans and rodents at low concentrations (below 2.5 ppm, 7.5 mg/m3) almost all chlorine is absorbed in the upper airways and does not reach the lower airways.

Oral administration of a hypochlorous acid solution in rats resulted in a quick uptake and distribution of the chlorine-ion in the blood, with a peak concentration between 2 and 4 hours and a half-life between 2 and 4 days. Interaction of chlorine and stomach can result in the possible formation of chlorinated organic compounds as chloroform, DCAN, DCA, TCA and chlorinated amino acids.

There are no data on kinetic behaviour of chlorine gas upon dermal exposure. It can be assumed that no systemic exposure to chlorine will occur after dermal absorption. Therefore, dermal absorption is not taken into account.

References

- Abdel-Rahman MS, Waldron DM and Bull RJ (1983). A comparative Kinetics Study of Monochloramine and Hypochlorous Acid in Rat. J. Appl. Toxicol. 3, 175-179.

- BIBRA (1990) BIBRA Toxicity Profile 1990.

- Barrow CS, Kociba RJ, Rampy LW, Keyes DG, and Albee RR (1979). An Inhalation toxicity study of chlorine in Fischer 344 Rats following 30 days of exposure. - Toxicology and applied Pharmacology, 49, 77-78.

- IPCS 1999, Environmental Health Criteria for disinfectants by-products, EHC 216

- Kopfler FC, Ringhand HP and Coleman WE (1985), Reactions of chlorine in drinking water, with humic acids in vivo. Water Chlorination Conference proceedings, Vol.5, Lewis Publisher. 161-173.

- Mink FL, Coleman WE, Munch JW, Kaylor WH and Ringhand HP (1983). In vivo formation of halogenated reaction products following peroral sodium hypochlorite. Bull. Environ. Contam. Toxicol. 30, 394-399.

- Nodelman and Ultman (1999), Longitudinal distribution of chlorine absorption in human airways: comparison of nasal and oral quiet breathing. J. Appl. Physiol. 86(6): 1984-1993

- Scully FE, Mazina KE, Ringhand HP, Chess EK, Campbell JA and Johnson JD (1990). Identification of organic N-chloramines in vitro in stomach fluid from the rat after chlorination. Chem Res Toxicol, 3: 301-306.

- Wolf DC, Morgan KT, Gross EA, Barrow C, Moss OR, James-RA and Popp JA (1995). Two-year inhalation exposure of female and male B6C3F1 mice and F344 rats to chlorine gas induces lesions confined to the nose. Fundam Appl Toxicol 24(1), 111-131.

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