4.11 Imazalil (110)

TOXICOLOGY

Evaluation for an acute reference dose

Imazalil (synonym: enilconazole, a pharmaceutical), 1-[2-(2,4-dichlorophenyl)-2-(2-propenyloxy)ethyl]-1H-imidazole), was first evaluated by the JMPR in 1977 when a temporary ADI of 0-0.01 mg/kg bw was established. The ADI of 0-0.01 mg/kg bw was reaffirmed in 1986 on the basis of the NOAEL in a 2-year study in dogs. In 1991, the JMPR reconsidered imazalil and a new ADI of 0-0.03 mg/kg bw was established based on a NOAEL for clinical signs, decreased body-weight gain and food consumption, decreased serum concentration of calcium, increased alkaline phosphatase activity, and increased liver weight in a study in dogs. In 2000, the JMPR reaffirmed the ADI and concluded that an ARfD was unnecessary.

The present Meeting was asked to reconsider the need for an ARfD by the Codex Committee on Pesticide Residues in view of refinements to the criteria used to establish ARfD values since 2000.

The present Meeting considered six new studies of acute toxicity (investigating end-points such as death and irritation) that were submitted by the sponsors. The Meeting also reconsidered the existing database on imazalil as previously evaluated and described in the monograph; however, the original studies were not available to the Meeting.

All the studies submitted complied with the essential elements of the applicable test guidelines and GLP requirements.

Toxicological data

The present Meeting evaluated the following studies:

The acute oral LD₅₀ of imazalil technical and its salts in rats ranged between 200 and 664 mg/kg bw. Clinical signs that were observed at 160 mg/kg bw and above in survivors were ataxia, piloerection, hypotonia, hypothermia, and ptosis.

Imazalil was a slight irritant to the skin of rabbits and was moderately irritating to the eye. It had sensitizing potential when tested by the Magnusson & Kligman method.

The 2000 JMPR evaluated the following studies:

In a series of studies of developmental toxicity in mice, rats and rabbits, the lowest NOAEL for maternal toxicity after dosing by gavage was 5 mg/kg per day on the basis of reduced food consumption at higher doses. No teratogenicity was seen in any species. The lowest NOAEL for fetal toxicity in rabbits was 5 mg/kg bw per day on the basis of an increased number of resorptions and a reduced number of live pups.

In a two-generation study, the NOAEL for maternal toxicity was 20 mg/kg bw per day on the basis of reduced body-weight gain. The NOAEL for fetotoxicity was 20 mg/kg bw per day on the basis of a decreased number of live pups and an increased number of stillbirths at 80 mg/kg bw per day. A statistical re-examination on a litter basis showed that the rate of mortality of F₁ pups during lactation was significantly increased at the highest dose of 80 mg/kg bw per day.

In two studies of developmental toxicity in mice, the overall NOAEL for maternal toxicity (reduced body-weight gain) and fetotoxicity (reduced number of live fetuses, body weight and number of resorptions) was 10 mg/kg bw per day.

A published case study involving only one woman indicated that imazalil used to treat a fungal infection was well tolerated after oral ingestion at high doses (50 mg per day progressing to 1200 mg per day over 6 months). The only adverse effect noted was nausea.

Toxicological evaluation

The Meeting considered that an ARfD was necessary on the basis of mortality at doses of less than 1000 mg/kg bw, and acute clinical signs at and above 160 mg/kg bw.

On the basis of the data reviewed and previous evaluations, the Meeting established an ARfD of 0.05 mg/kg bw, using the NOAEL of 5 mg/kg bw per day for maternal and fetal toxicity in a study of developmental toxicity in rabbits and a safety factor of 100. It was considered that this ARfD would also be protective of the potential effects observed during gestation and lactation. The Meeting concluded that it would be inappropriate to use a human case study with only one individual for the purpose of establishing an ARfD.

The Meeting recognized that an ARfD based on maternal and fetal toxicity would be conservative for the general population, but that in the absence of a more suitable study this value was considered appropriate.

An addendum to the toxicological monograph was prepared.

Levels relevant to risk assessment

^a Dietary administration at a nominal concentration
^b Gavage administration

Estimate of acute reference dose

0.05 mg/kg bw

Information that would be useful for the continued evaluation of the compound

Additional end-points relevant for establishing an ARfD