Introduction

1. 1-methylcylcopropene (1-MCP) is a new pesticide active ingredient (growth regulator) being assessed by the Pesticides Safety Directorate (PSD) under EU Directive 91/414/EEC. 1-MCP blocks the effects of ethylene release in apples thus preventing over ripening and softening. The Committee was asked for advice on the risks posed by the potential for exposure to two impurities present in the active ingredient namely impurities 1 and 2 which were presumed by the Advisory Committee on Pesticides to be genotoxic carcinogens on the basis of published mutagenicty studies and life-time bioassays in rats and mice using oral administration.1,2 The COC was asked to advice on specific questions given in a referral note from DEFRA which are reproduced below. The COC was not asked to evaluate the active ingredient and data on this compound have not been reviewed. The COC has not been asked to evaluate the other two impurities present in 1-MCP.

2. The COC was provided with published information on the mutagenicity, carcinogenicity and metabolism of impurity 1 and impurity 2 and with details of the manufacture of 1-MCP, information on the formulation and product to be used in the U.K and estimates of potential exposures to impurities present in 1-MCP during use. The data holder is Rohm and Haas company. The data holder provided an estimation of the 5% Bench Mark Dose for the most sensitive carcinogenic response for these two impurities which was for forestomach tumours.3

3. The Committee considered the questions posed by DEFRA at its 26 June 2003 meeting.

Referral to COC by DEFRA

4. The view of the Committee on Carcinogenicity is sought on whether:

a. minimum risk levels for the impurities 1 and 2 can be derived

b. exposures to the impurities 1 and 2 present any significant risks to consumers or operators

c. maximum levels of the impurities 1 and 2 should be proscribed.

COC discussion

5. The Committee concurred that on the basis of the available evidence submitted it would be prudent to consider impurity 1 and impurity 2 as genotoxic carcinogens.1-7

6. The Committee considered the available carcinogenicity data and the conditions of use anticipated for 1-MCP as a fumigant for apples, together with potential exposures to impurity 1 and impurity 2 that might arise, and agreed that a pragmatic minimum risk level could be established for these two impurities. The Committee agreed that it should always be recognised that for impurity 1 and impurity 2 under likely conditions of use that a very small but unquantifiable risk existed and hence the policy of controlling exposures to "as low as reasonably possible" (ALARP) should apply. The 5%BMD for impurity 1 was reported to be 0.6 mg/kg bw/day and for impurity 2 was reported to be 12.8 mg/kg bw/day.

7. The Committee agreed an application of an Uncertainty Factor (UF) of 10,000 to the estimated 5% BMD resulted in estimated minimum risk levels of 0.06 mg/kg bw/day for impurity 1 and 1.28 mg/kg bw/day for impurity 2. The Committee noted that the US EPA and Health Canada had previously stated that a factor of 10,000 represents the highest that could be used in the setting of TDIs. In an analysis of the use of LTD10 (extra life-time cancer risk of 10%) derived from calculations based on TD50s from the Gold database, it was concluded that the reference dose derived from the Gold database and use of a 10,000 UF applied to the LTD10 gave equivalent results to cancer risk at 10-5 derived from LMS modelling and hence represented a fairly conservative approach to setting a minimum risk level.8 The Committee agreed that this was a conservative approach to estimating minimum risk levels. They had a reasonable degree of confidence that any carcinogenic risk posed at this level would be negligible.

8. The maximum predicted exposures for operators and consumers was reported to be below the proposed minimum risk level by factors varying from 3 to 5311 (as shown below). The risk of carcinogenicity posed by exposure to impurity 1 and impurity 2 following use to fumigate apples is considered to be negligible.

COC response to questions posed by DEFRA

whether a minimum risk levels for the impurities 1 and 2 can be derived

9. The COC concluded that pragmatic minimum risk levels could be established for impurity 1 and impurity 2. For impurity 1 this was equivalent to a daily oral does of 0.06 mg/kg bw/day. For impurity 2 this was equivalent to 1.28 mg/kg bw/day.

whether exposures to the impurities 1 and 2 present any significant risks to consumers or operators

10. The maximum predicted exposures for operators and consumers will be below the proposed minimum by factors varying from approximately 3 to 5311. The risk of carcinogenicity posed by exposure to impurity 1 and impurity 2 is considered to be negligible.

whether maximum levels of the impurities 1 and 2 should be proscribed

11. The COC agreed that maximum levels for these impurities should not result in doses exceeding the minimum risk level and restated that there was always a need to apply "as low as reasonably practical" (ALARP) to genotoxic carcinogens.

September 2003

References

1. IARC (1995). Monograph on carcinogenicity of impurity 1, vol 63, 315-324, Lyons, France.

2. IARC (1995). Monograph on carcinogenicity of impurity 2, vol 63, 325-333.

3. Rohm and Hass (2002). Inconfidence additional data on impurity 1-methylcyclopropene.

4. NTP (1986). National Toxicology Programme. Toxicology and Carcinogenesis studies of impurity 1 in F344/N rats and B6C3F1 mice (gavage studies), NTR 316, US DHHS, NIH.

5. NTP (1986). National Toxicology Programme. Toxicology and Carcinogenesis studies of impurity 2 (Technical grade) in F344/N rats and B6C3F1 mice (gavage studies), NTR 300, US DHHS, NIH.

6. Ghanayen BI and Burka LT (1987). Comparative metabolism and disposition of impurities 1 and 2 in rats and mice. Drug Metabolism and Disposition, vol 15, (1), 91-96.

7. Srinivas P and Burka LT (1988). Metabolism of impurity 1. Evidence for reactive chloroaldehyde metabolites. Drug Metabolism and Disposition, vol 16, (3), 449-454.

8. Gold LS et al (2003). Comparison of cancer risk estimates based on a variety of risk assessment methodologies. Regulatory Toxicology and Pharmacology, vol 37, 45-53.

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