Introduction

The chloropropanols are a group of chemicals which include 3-chloro-1,2-propanediol (3-MCPD), 1,3-Dichloropropan-2-ol (1,3-DCP) and 2,3 dichloropropan-1-ol (2,3 DCP). Chloropropanols are contaminants of some foodstuffs and of polyamine flocculants used in the treatment of drinking water. Both the COC and COM have published statements on 3-MCPD (1,2)

The COM have reviewed mutagenicity data for 1,3 DCP and 2,3 DCP and concluded "that it would be prudent to regard 1,3-DCP and 2,3-DCP as potentially genotoxic in vivo and agreed that both compounds should be tested for genotoxicity in-vivo using the approach set out in the COM guidelines" (3)<./p>

1,3 DCP

Available toxicology, mutagenicity and carcinogenicity data for 1,3 DCP has been summarised by the Joint FAO/WHO Committee on Food Additives (JECFA)(4) although much of the key data remain unpublished. From a 13-week oral toxicity study, a NOAEL of 1mg/kg/day had been identified. Limited information on the metabolism of 1,3 DCP indicates that it may be metabolised to form epichlorohydrin, which may, via glycidol, be conjugated to form mercapturic acid derivatives (5). In vitro investigations with hepatocyte cultures indicate also a pathway involving CYP2E1 to dichloroacetone (a directly acting cytotoxic compound) leading to glutathione depletion (6-10) .

The results of mutagenicity studies with bacteria and mammalian cells show that 1,3-DCP is mutagenic in vitro. It has been suggested that the in-vitro genotoxicity of 1,3-DCP is due to the chemical formation of epichlorohydrin (11). 1,3 DCP was negative in a SMART assay in Drosophila (3).

A 104-week toxicology and carcinogenicity study with 1,3 DCP in Wistar rats (12) was previously considered by COC in 1991. At the time COC concluded that 1,3 DCP was genotoxic and carcinogenic, although a formal committee statement was not issued. Additional information on the study is now available to the Committee, together with additional mutagenicity and metabolism data which have been reported since 1991.


Carcinogenicity study (12)

1,3 DCP was administered in the drinking water to Wistar rats for 104 weeks. The study comprised four groups each containing 80 males and 80 females who received 1,3 DCP at concentrations of 0 mg/l (control), 27 mg/l (low dose), 80 mg/l (medium dose) or 240 mg/l (high dose). These concentrations were equivalent to 0, 3, 10 or 30 mg/kg bw/d for male rats and 0, 2, 6 or 19 mg/kg bw/d for female rats. Interim sacrifices of 10 animals per sex per group were carried out at weeks 26, 52 and 78 of the study, leaving 50 animals per group who were exposed to 1,3 DCP for the full 104 weeks. Parameters evaluated in the study included mortality, body weight, feed consumption, haematology, urinalysis, clinical chemistry, organ weights and gross pathological and histopathological changes.

Mortality of high dose males and females was increased when compared with controls and other dose groups. No treatment related changes in appearance and behaviour were noted in any group, and mean food and water consumption values were similar for all groups throughout the study. Mean body weight gain of all groups showed no treatment-related changes until week 75 for males and week 79 for females when statistically significant and dose-related decreases in mean body weight were seen in the high dose group. The assessment of clinical biochemistry and urinalysis data suggested an hepatotoxic effect with space-occupying lesions in mid dose and high dose groups.

At 104 weeks all tissues were examined microscopically for neoplastic lesions in all rats of the control and high dose groups and in those animals in the low and mid dose groups who had died spontaneously or who were killed in extremis. In addition the following tissues were examined microscopically in all animals in low and mid-dose groups ; adrenal glands, oesophagus, kidneys, lungs, thyroid gland and tongue.

Non neoplastic lesions considered to be treatment related were observed as follows:

In the liver,

• An increased incidence of slight to moderate fatty change along with increased incidence of haemosiderin-containing Kupffer cells in the mid and high dose groups; this was considered to reflect metabolic disturbance of the liver caused by 1,3 DCP.

• A dose-dependent increase in sinusoidal peliosis in treated animals ; peliosis may represent a pre-neoplastic stage of vascular hepatic neoplasia such as haemangiosarcoma

• Eosinophilic foci in mid and high dose groups and glycogen -free foci in the high dose group

In the kidney, there was a high level of chronic progressive nephrosis (CPN) in all groups of male rats in the study, ranging from 40/50 in controls to 48/50 in high dose males.

In the thyroid, 1,3 DCP induced thyroid follicular cell hyperplasia in dose-related manner in both male and female rats.

Increased incidences of neoplastic lesions were observed in the liver, tongue and thyroid in both sexes and additionally in the kidney of male rats.

• In the liver, combined incidences of hepatocellular adenoma and carcinoma, showed a statistically significant dose-related increase (p<0.001) in both males and females. (eg males -controls 1/50, high dose 8/50 ; females - controls 1/50, high dose 41/50).

• In the tongue, combined incidences of squamous cell papilloma and carcinoma showed a statistically significant dose-related increase (p<0.001) in both males and females. (eg males - controls 0/50, high dose 12/50; females - controls 0/49, high dose 11/49).

• In the thyroid combined incidences of follicular cell adenoma and carcinoma showed a statistically significant dose-related increase (p<0.001) in both males and females (eg males - controls 0/50, high dose 4/50 ; females - controls 1/49, high dose 5/49).

• In the kidney, combined incidences of renal tubular adenoma and carcinoma, showed a statistically significant dose-related increase (p<0.001) in males only (eg controls 0/50, high dose 9/50).

Regarding the onset of oncogenic lesions, the following findings were reported at the interim sacrifices

• at 26 weeks, hepatocellular adenoma (1/10 mid dose males) ;
• at 52 weeks, liver carcinoma (1/10 high dose females) and,
• at 78 weeks, hepatocellular carcinomas (7/10 high dose females ; 3/10 high dose males), lingual papilloma (1/10 mid dose males and 1/10 high dose males), and renal tubular adenomas (1/10 high dose males).

It was concluded that the spectrum of tumours observed in the 104-weeks rat study, particularly in the liver and tongue was evidence of a clear carcinogenic effect of 1,3 DCP. It was possible that the tumours in the male kidney could be associated with the high rate of chronic progressive nephropathy observed in the study and additionally, the thyroid follicular cell tumours could be associated with hyperplasia, a toxic finding commonly seen in male rats, although no specific mechanism data were available.

2,3 DCP

There are very few toxicological data for 2,3 DCP and carcinogenicity studies have not been carried out. Theoretically, 2,3 DCP could be metabolised to produce epichlorohydrin (and subsequently glycidol) and therefore has structural alerts for genotoxicity and carcinogenicity.

COM have recently considered 2,3 DCP (3) and while there is evidence of genotoxicity in-vitro, no studies have been performed in-vivo. COM concluded that it would be prudent to regard 2,3-DCP as potentially genotoxic in-vivo.

Although there are no carcinogenicity studies available for 2,3DCP IARC have recently evaluated the brominated analogue, 2,3 dibromo-propanol (2,3 DBP)(12) and considered that "there is sufficient evidence in experimental animals for the carcinogenicity of 2,3 dibromo propan-1-ol" Skin appplication of 2,3 DBP produced multisite tumours in both rats and mice. However, the Committee considered that no conclusions could be drawn from these studies in respect of the carcinogenicity of 2,3 DCP.

Conclusions

The Committee came to the following conclusions ;

It is prudent to assume that 1,3 DCP is a genotoxic carcinogen and that exposures to 1,3 DCP should be reduced to as low a level as technologically feasible

It is prudent to assume that 2,3 DCP may posses genotoxic activity in-vivo. Although no carcinogenicity data are available, it would however be prudent to reduce exposures to 2,3 DCP to as low a level as technologically feasible

Additionally, in view of the possible human exposure through drinking water and certain foods, the Committee recommended that relevant regulatory authorities should review the likely exposures of these compounds with the intention of achieving the above recommendations.


May 2001

References


1 Carcinogenicity of 3-Monochloro Propane 1,2-Diol (3-MPCD) COC Statement - December 2000 - COC/00/S5 (Update of COC/99/S5). http://www.doh.gov.uk/mcpd1.htm

2. Mutagenicity of 3-Monochloro Propane 1,2-Diol (3-MCPD) COM Statement - October 2000 - (COM/00/S4). http://www.doh.gov.uk/mcpd2.htm

3. Mutagenicity of 1,3 dichloropropan-2-ol (1,3 DCP) and 2,3 dichloropropan-1-ol (2,3 DCP) COM statement -May 2001- (COM/01/S2) http://www.doh.gov.uk/com.htm

4. Olsen P. (1993) Chloropropanols In: Toxicological Evaluation of Certain Food Additives and Contaminants, Joint Expert Committee on Food Additives, World Health Organization, Geneva, Switzerland, (41st Meeting) (WHO FOOD ADDITIVES SERIES) No. 32:267- 285.


5. Jones AR, Fakhouri G. (1979) Epoxides as obligatory intermediates in the metabolism of - halohydrins. Xenobiotica 9:595-599.

6. Garle MJ, Sinclair C, Thudey P, Fry JR. (1999) Haloalcohols deplete glutathione when incubated with fortified liver fractions. Xeniobiotica 29:33-545.

7. Hammond AH, Fry JR. (1997). Involvement of cytochrome P4502El in the toxicity of dichloropropanol to rat hepatocyte cultures. Toxicology, 118 ; 171-179.

8. Hammond AH, GarleMJ, FryJR. (1996) Toxicity of dichloropropanols in rat hepatocyte cultures. Environmental Toxicology and Pharmacology l; 39-43.

9. Hammond A H and Fry F. (1999). Effect of cyanamide on toxicity and glutathione depletion in rat hepatocyte cultures: differences between two dichloropropanol isomers. Chemico-Biological Interactions, 122 ; 107-115.

10. Fry JR, Sinclair D, Holly Piper C, Townsend S-L, Thomas NW. (1999) Depression of glutathione content, elevation of CYP2El -dependent activation, and the principal determinant of the fasting-mediated enhancement of 1,3-dichloro-2-propanol hepatotoxicity in the rat. Food Chem Toxicol 37;351-355.

11. Hahn H. Eder E and Deininger C. (1991). Genotoxicity of 1,3-dichloro-2-propanol in the SOS chromotests and in the Ames tests. Elucidation of the genotoxic mechanism. Chem. Biol. Interactions, 80 ; 73-88.

12. Hercules Inc. (1986). 104-Week Chronic Toxicity and Oncogenicity Study with 1,3-Dichloropropan-2-ol in the Rat. Unpublished Report No. 017820 from Research and Consulting Company AG, ltingen, Switzerland.

13. IARC (2000) IARC Monographs on the evaluation of carcinogenic risks to humans .2,3 Dibromopropan-1-ol Vol 77 p439-454

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