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Introduction

1. 3-Monochloro propane 1,2-diol (3-MCPD) can be present as a contaminant in epichlorhydrin/amine copolymers used as flocculants or coagulant aids in water treatment. These polyamine flocculants have been available for many years as approved products for use in water treatment and thus 3-MCPD may be present in drinking water from their use. 3-MCPD is a member of a group of contaminants known as chloropropanols. This group includes some known genotoxic carcinogens in animals such as 1,3-dichloropropan-2-ol. The COC was asked to evaluate and advise on the available carcinogenicity data on 3-MCPD by the Committee on Chemicals and Materials of Construction for use in Public Water Supply and Swimming Pools (CCM), a statutory committee which provides advice to the Secretary of State for the Environment on the approval of chemical substances in contact with public water supplies.

2. The Committee was aware that 3-MCPD had been detected as a contaminant of several foods and food ingredients, including acid hydrolysed vegetable protein (acid-HVP) and that the EU Scientific Committee for Food had published an opinion in 1994 where it was agreed that 3-MCPD should be regarded as a genotoxic carcinogen.(1) The Committee also had access to published mutagenicity data on 3-MCPD, a safety evaluation prepared by CanTox. Inc (Ontario, Canada) for the International Hydrolysed Protein Council,(2) and a review document published by the Institute of Toxicology, National Food Agency of Denmark.(3) The COC asked for advice from the Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) in respect of the mutagenicity of 3-MCPD. In reviewing these documents in 1999, members commented that the available metabolism data on 3-MCPD were relatively old and focused on metabolic pathways following intraperitoneal administration. There was no oral mass balance investigation available. The Committee considered the proposal by CanTox Inc regarding the formation of bacterial-specific mutagens and agreed that there was no evidence to support this speculation. However, additional in-vivo mutagenicity data became available to the COM in 2000, namely a bone marrow micronucleus test and a rat liver UDS assay. Both studies were conducted to appropriate protocols and 3-MCPD was negative in both studies.


Conclusions


3. The Committee, has now reached the following conclusions on all the available mutagenicity and carcinogenicity data.

i) 3-MCPD has a chemical structure which suggests that it may be metabolised to genotoxic intermediates (particularly glycidol).

ii) The COM has advised that 3-MCPD is an in-vitro mutagen but has no significant genotoxic potential in-vivo. (The COM statement on mutagenicity of 3-monochloropropane 1,2-diol) has also being revised. The COM also noted that the predominant urinary metabolite in rats following dietary or intraperitoneal doses of 3-MCPD was beta-chlorolactic acid (4),(i.e. resulting from a pathway not producing glycidol or other genotoxic intermediates). A study has also shown that 3-MCPD may be also metabolised by a minor pathway and undergo conjugation with glutathione ultimately to form a mercapturic acid in urine of rats (N-acetyl-S-(2,3-dihydroxypropyl) cysteine (5)

iii) 3-MCPD has been tested in four long-term animal carcinogenicity experiments, two in mice and two in rats (6-8). However, three of these studies (6,7) were conducted between 1970 and 1981 to inadequate protocols. The conclusions reached by the COC therefore refer to the one study conducted to contemporary standards (8). The Committee had access to the full study report (8) and to published reviews of this study. (2,3) The tumour data have been evaluated by a number of statistical methods. The analyses reported below refer to the Fishers pair-wise comparisons with controls.

iv) In the study undertaken by Sunhara et al (1993) (8) 3-MCPD was administered via drinking water to groups of 50 male and 50 female F344 rats (aged 6 weeks at study initiation) for a period of 104 weeks. Concentrations of 0, 20, 100, and 200 ppm were used. These equated to dose levels of 0, 1.1, 5.2, or 28 mg/kg bw/day in males and 0, 1.4, 7.0, or 35 mg/kg bw/day in females. 3-MCPD was also detected in the drinking water used in this study at 2.7 ppm and thus control animals were given doses of approximately 0.1 mg/kg bw/day. The high dose group exceeded the Maximum Tolerated Dose as evidenced by a decrease in body weights relative to controls of 33% and 35% in males and females respectively. There was no evidence of any treatment-related increase in mortality in this study. Survival to termination was acceptable (i.e.>50%) in all dose groups with the exception of the male high dose group where 21/50 animals survived to termination.

v) In males, a statistically significant increase in the incidence of Leydig-cell adenoma was documented at the intermediate and high dose levels. Three animals at the high dose level had Leydig-cell carcinomas. A statistically significant increase in the incidence of mammary gland fibroadenoma was noted in the high dose male group. A statistically significant increase in mammary gland hyperplasia was recorded in the male mid and high dose groups. A small but not statistically significant increase in the incidence of preputial gland adenoma was recorded in the mid and high dose male groups. One animal in the intermediate dose group and two in the high dose group had preputial gland carcinomas. It is difficult to evaluate these findings since only a limited number of preputial glands were examined histologically (5-16/group) in this study. A small (not statistically significant) increase in renal tubular adenomas was documented in the intermediate and high dose male groups. A statistically significant increase in the incidence of nephropathy and renal tubular hyperplasia was also recorded at the intermediate and high dose levels in this study.

vi) In females, a statistically significant increase in the incidence of renal tubular adenoma was recorded at the high dose level. A statistically significant increase in nephropathy and renal tubular hyperplasia was also recorded at the intermediate and high dose levels in this study. A slight but statistically non-significant increase in mammary gland hyperplasia was reported at the high dose level.

vii) The Committee noted that tumours were reported in both sexes in the kidney and in males only at hormonally responsive sites (ie the testes, mammary gland and preputial gland) at dose levels which exceeded the maximum tolerated dose. Evidence from previously conducted investigations with 3-MCPD was considered in evaluating possible explanations for these findings.

viii) In the kidney, the Committee noted that tumours in both sexes were benign (renal tubular adenoma) and that these were accompanied by a chronic progressive nephropathy. In considering possible mechanisms, the Committee were aware of earlier findings that metabolism to beta-chlorolactic acid is a major pathway in the rat (4) and that this metabolite is further broken down to yield oxalate and CO₂. Oxalate is known to induce severe renal cytoxicity (3,9). Other evidence, including a study which reported crystals of oxalate in the urine of rats treated with 3-MCPD (single dose of 100mg/kg ip) (4), supported a role for sustained cytotoxicity as a possible mechanism for the induction of kidney tumours. The renal adenoma recorded in one female animal at the lowest dose was not considered to be biologically significant, and the Committee agreed that a dose 1.1mg/kg bw/day, was a no observed effect level for the induction of kidney tumours. The Committee, however noted some evidence of a toxic effect upon the kidney at this dose level (ie increased tubular hyperplasia and statistically significant increase in absolute kidney weight).

ix) With regard to the sex-specific tumours in male rats (in the testes, mammary gland and preputial gland), the Committee noted that the testicular tumours needed to be viewed against the high spontaneous incidence of Leydig-cell tumours common in ageing F344 rat, which may be upto 100% in control groups (10,11) . The high proportion of Leydig cell adenoma (between 86% and 100% in treated animal groups, compared to 76% in controls) was particularly noted in this study. However, Leydig-cell carcinoma developed only at the highest dose in 3/50 treated animals. As 3-MCPD has been shown to induce a prolonged increase in circulating hormone levels (a single intraperitoneal dose of 80mg/kg bw causing an increased serum levels of follicle stimulating hormone (FSH), luteinising hormone (LH) and prolactin) (12), it is possible that increases in the spontaneous rate of Leydig-cell tumours may have been promoted by hormonal imbalance caused by 3-MCPD. Subsequently, the increase in tumours at other hormonally responsive sites (ie in the male mammary gland and the preputial gland) may be secondary to further hormonal disturbances known to be induced by proliferating Leydig cells (2). Overall, the Committee noted that there was no evidence of a significant increase in tumourigenic response at any of these sites at a dose of 1.1 mg/kg bw/day.

x)The Committee considered the suggestion that all of the increases in tumours noted in this study in rats were mediated by non-genotoxic mechanisms involving either cytotoxicity (kidney) or hormonal disturbances.(2,3,8). The possible influence of the stereoisomerism of 3-MCPD was also discussed. Members agreed that the proposed non-genotoxic mechanisms advanced were plausible, now that specific evidence was available that reactive metabolites were not produced in-vivo in tissues where genotoxicity was assessed.

xi)The Committee concluded that the no observed effect level (NOEL) for tumourigenic effects of 3-MCPD in rats was approximately 1.1mg/kg bw/day.

xii) The Committee agreed that an approach utilising the NOEL with appropriate uncertainty factors would be acceptable for carcinogenic risk assessment for 3-MCPD. An overall uncertainty factor of 1000 was considered appropriate in view of the uncertainties identified in the data, particularly in respect of the quality and incompleteness of the metabolic data on 3-MCPD.

xiii) The Committee concluded that 3-MCPD was unlikely to present a carcinogenic risk to man, provided the exposure was 1000 times lower than the NOEL of 1.1mg/kg bw/d for tumourigenicity.

December 2000



References

1. SCF (1994). Opinion on 3-Monochloro-propane 1,2-diol (3-MCPD). Expressed 16 December 1994. Reports of the Scientific Committee for Food (thirty-sixth series)
   
   
2. Lynch BS, Bryant DW, Hook GJ, Nestmann ER, and Munro IC (1998). Carcinogenicity of monochloro-1,2-propanediol (alpha-chlorohydrin, 3-MCPD). International Journal of Toxicology, 17, 47-76.
   
   
3. Olsen P (1993). Chloropropanols In JECFA. Toxicological Evaluation of Certain Food Additives and Contaminants. 41st Meeting of WHO Food Additives Series, 32, 267-285. World Health Organisation, Geneva, Switzerland.
   
   
4. Jones, AR, Milton, DH, and Murcott, C (1978). The oxidative metabolism of alpha-chlorohydrin in the male rat and the formation of spermatoceles. Xenobiotica, 8, 573-582.
   
   
5. Jones AR (1975). The metabolism of 3-chloro, 3-bromo, and 3-iodopropan 1,2-diol in rats and mice. Xenobiotica, 5, 155-165.
   
   
6. Van Duuren BL, Goldschrnidt BM, Katz C, Seidman CK and Paul JS (1974). Carcinogenic activity of alkylating agents. Journal of the National Cancer Institute, 53, 695-700.
   
   
7. Weisburger EK, Ulland BM, Nam J, Gart JJ and Weisburger JH (1981). Carcinogenicity tests of certain environmental and industrial chemicals. Journal of the National Cancer Institute, 67, 75-88.
   
   
8. Sunahara G, Perrin I, and Marchessini M (1993). Carcinogenicity study on 3- monochloro propane 1,2,-diol (3-MCPD) administered in drinking water to Fischer 344 rats. Report No RE-SR93003 Nestec Ltd, Research and Development Switzerland.
   
   
9. Jones, AR, Gadiel, P and Murcott C (1979). The renal toxicity of the rodenticide alpha-chlorohydrin in the rat. Naturwissenschaften, 66, 425.
   
   
10. Boorman GA, Eustis SL, Elwell MR, Montgomery Jnr CA and McKenzie WF eds (1990) Pathology of the Fischer rat. Academic Press New York
    
    
11. Thurman JD, Bucci TJ, Hart RW and Turturro A (1994) Survival, body weight and spontaneous neoplasms in ad libitum-fed and food restricted Fischer F344 rats. Toxicol Pathol, 22, 1-9
    
    
12. Morris ID and Jackson CM (1978) Gonadotrophin changes in male rats following a sterilising dose of alpha-chlorohydrin. Intern J Androlog 1, 85-95

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