4.9 Fenhexamid (215)

TOXICOLOGY

Fenhexamid is the ISO approved name for 2',3'-dichloro-4'-hydroxy-1-methylcyclohexanecarboxanilide, which is a hydroxyanilide fungicide that inhibits the growth of fungal spore germ tubes and mycelia.

The Meeting has not previously evaluated fenhexamid.

All pivotal studies with fenhexamid were certified as complying with GLP.

Biochemical aspects

In toxicokinetic studies in rats given single doses (1.0 or 100 mg/kg bw) or repeated doses (1.0 mg/kg bw per day for 14 days) by gavage, radiolabelled fenhexamid was rapidly and completely absorbed from the gastrointestinal tract (> 97%). A peak in plasma concentrations of radioactivity was observed 5-10 min after dosing at 1.0 mg/kg bw. Approximately 96% of the administered dose was eliminated in excreta within 48 h; the major route of excretion was in the faeces (62-81% of the administered dose) with 15-36% of the administered dose being recovered in the urine. Approximately 60% of the administered dose was excreted in bile in the first hour and > 97% within 48 h, primarily as the glucuronide conjugate of the parent compound. A pronounced first-pass effect and extensive enterohepatic circulation was observed with hydrolysis of the glucuronide in the gastrointestinal tract and reabsorption of the parent compound. Only 0.3% of the administered dose was detected in the body at 72 h, with the gastrointestinal tract, kidney and liver having the highest concentrations of radioactivity. The main pathway of biotransformation in rats was conjugation of the aromatic hydroxyl group with glucuronic acid. Limited hydroxylation of the 2, 3 and 4 positions of the cyclohexyl ring also occurred with excretion of these compounds as glucuronide or sulfate conjugates. The main compound detected in excreta was the unchanged parent compound (62-75% of the administered dose). The glucuronic acid conjugate of the parent ranged from about 4% to 23% of the administered dose. Excretion, distribution and metabolite profiles were essentially independent of dose, pre-treatment and sex.

Toxicological data

Fenhexamid has low toxicity when administered by the oral, dermal or inhalation routes. LD₅₀ values after oral administration were > 5000 mg/kg bw in rats and mice. The LD₅₀ in rats treated dermally was > 5000 mg/kg bw. LC5₅₀s in rats treated by inhalation (nose only) was > 0.32 mg/L (aerosol) and > 5.1 mg/L (dust). Fenhexamid was not a skin or eye irritant. Fenhexamid was not a skin sensitizer in guinea-pigs (Buehler test) or in the local lymph node assay, and showed equivocal skin sensitizing potential in a Magnusson & Kligmann (maximization) test in guinea-pigs.

In short-term studies in mice, rats and dogs, very high doses of fenhexamid produced minimal systemic toxicity. In longer-term studies, the major target organ was the kidney in rats and mice and the haematopoietic system in dogs. Slight evidence of liver toxicity was also observed in rats, mice and dogs.

No systemic toxicity was seen in a 28-day study in rats given fenhexamid at doses of up to 1000 mg/kg bw per day by gavage. A 28-day dietary study in dogs given fenhexamid at doses of up to 20 000 ppm (equivalent to 500 mg/kg bw per day) did not produce systemic toxicity.

In a 90-day dietary study of toxicity in mice, increased cholesterol, bilirubin, creatinine, water and food consumption, decreased kidney weights, increased renal protein casts and cellular detritus, and renal tubular basophilia were observed at 10 000 ppm (equal to 3283 mg/kg bw per day). In a second study, similar toxicity in the kidney was observed at the highest dose of 20 000 ppm (equal to 3417 mg/kg bw per day). The lowest NOAEL in these two studies was 1000 ppm (equal to 266.5 mg/kg bw per day).

In a 90-day dietary study of toxicity in rats, decreased body weight and body-weight gains, increased food consumption, reduced food conversion efficiency and decreased liver weights in males (reversible within 4 weeks) were observed at 10 000 ppm (equal to 904 mg/kg bw per day). In females, these findings, plus an increased incidence of mild to moderate focal Kupffer cell proliferation in females, were observed at 20 000 ppm (equal to 2824 mg/kg bw per day). The NOAEL was 5000 ppm (equal to 415 mg/kg bw per day). In a second 90-day dietary study in rats, nephropathy was seen at 50 000 ppm (equal to 5585 mg/kg bw per day). The NOAEL in this study was 5000 ppm (equal to 404 mg/kg bw per day).

In a 90-day study of toxicity in dogs, increases in the number of Heinz bodies were seen at 7000 ppm (equal to 239 mg/kg bw per day) and increases in alkaline phosphatase activity were measured at the highest dose of 50 000 ppm (equal to 1748 mg/kg bw per day). The NOAEL was 1000 ppm (equal to 33.9 mg/kg bw per day). In a 52-week study of toxicity in dogs, increases in the number of Heinz bodies and decreases in erythrocyte count, concentration of haemoglobin, and erythrocyte volume fraction were seen at 3500 ppm (equal to 124 mg/kg bw per day) with increases in alkaline phosphatase activity, adrenal weights and intracytoplasmic vacuoles in females at the highest dose of 25 000 ppm (equal to 918 mg/kg bw per day). The NOAEL was 500 ppm (equal to 17.4 mg/kg bw per day).

No systemic toxicity was seen in a 28-day study of dermal toxicity in rats at 1000 mg/kg bw per day, the highest dose tested. Five-day and 28-day studies of toxicity suggest that high doses administered by inhalation were well tolerated by rats. The NOAEC in the 28-day study was 0.069 mg/L on the basis of an increase in lung weights, grey discolouration of lungs, pigment-laden alveolar microphages and an increase in liver enzymes seen at the lowest-observed-adverse-effect concentration (LOAEC) of 0.487 mg/L.

Fenhexamid gave negative results with or without metabolic activation in an adequate range of studies of genotoxicity in bacteria and cultured mammalian cells in vitro, and in a test for micronucleus formation in mice in vivo.

The Meeting concluded that fenhexamid is unlikely to be genotoxic.

In long-term studies of toxicity and carcinogenicity in mice and rats, there were no treatment-related neoplastic findings. In male mice, decreased kidney weights were observed at 2400 ppm (equal to 807 mg/kg bw per day). Additional effects observed at the highest dose of 7000 ppm (2355 mg/kg bw per day) in males included increased water consumption, increased serum concentrations of creatinine, bilirubin and albumin, decreased body weight, decreased body-weight gain. In females at 7000 ppm (equal to 3178 mg/kg bw per day, the highest dose tested), increased water consumption, decreased kidney weights and increased basophilic cortical tubules in the kidney were observed. The NOAEL for systemic toxicity in mice was 800 ppm (equal to 247 mg/kg bw per day). In rats, only mild treatment-related effects such as increased splenic extramedullary haematopoiesis, increased caecal mucosal hyperplasia, decreased body weights, decreased body-weight gains, decreased food conversion efficiency, and bone marrow hyperplasia were observed. The NOAEL for systemic toxicity was 500 ppm (equal to 28 mg/kg bw per day). Fenhexamid was not carcinogenic in mice or rats.

In view of the lack of genotoxicity and the absence of carcinogenicity in rats and mice, the Meeting concluded that fenhexamid is unlikely to pose a carcinogenic risk to humans.

In a two-generation study of reproduction in rats, reproductive parameters were not affected at the highest dose tested (20 000 ppm, equal to 1814 mg/kg bw per day). The NOAEL for parental systemic toxicity was 500 ppm (equal to 38 mg/kg bw per day) on the basis of lower pre-mating weights, increases in alkaline phosphatase activity and decreases in liver weights and kidney weights in males only. The NOAEL for offspring toxicity was 500 ppm (equal to 38 mg/kg bw per day) on the basis of decreases in body weights during lactation. Fenhexamid was not teratogenic at doses of up to 2000 and 1000 mg/kg bw per day in rats and rabbits, respectively. No systemic toxicity, embryotoxicity or fetotoxicity was observed in the study of developmental toxicity in rats at doses of up to 2000 mg/kg bw per day. At the highest dose tested in rabbits (1000 mg/kg bw per day), a slight decrease in fetal weight of males and delayed ossification (fifth sternal segments, fifteenth caudal vertebrae) was observed in the presence of maternal toxicity. The NOAEL for developmental toxicity in rabbits was 300 mg/kg bw per day.

The Meeting concluded that fenhexamid is not teratogenic nor a reproductive toxicant.

In a study of acute neurotoxicity in rats, doses of up to 2000 mg/kg bw did not produce any systemic toxicity, neurotoxicity or neuropathology findings. There were no treatment-related effects on measures of motor activity, locomotor activity or habituation.

In a study evaluating clinical parameters and physiological functions in rats, mice, and rabbits given fenhexamid as single doses at up to 5000 mg/kg bw by gavage, fenhexamid did not produce marked effects on general condition, behaviour, the nervous system, the respiratory system, the circulatory system, haematopoietic parameters or renal function.

The Meeting concluded that the metabolites of fenhexamid are likely to be less toxic than fenhexamid because the major metabolites are polar glucuronide or sulfate conjugates that are rapidly excreted. Hydrolysis of the glucuronic acid conjugate of the parent can occur in the gastrointestinal tract, with subsequent reabsorption of the parent.

The Meeting concluded that the existing database on fenhexamid was adequate to characterize the potential hazards to fetuses, infants and children.

Toxicological evaluation

The Meeting established an ADI of 0-0.2 mg/kg bw based on a NOAEL of 17.4 mg/kg bw per day for increased adrenal weight and the presence of intracytoplasmic vacuoles in the adrenal cortex of females and haematopoietic effects (increase in the number of Heinz Bodies, decrease erythrocyte count, haemoglobin concentration and erythrocyte volume fraction) seen at higher doses in both sexes in a 52-week study in dogs fed with fenhexamid, and a 100-fold safety factor.

The Meeting concluded that the establishment of an ARfD for fenhexamid was not necessary on the basis of its low acute toxicity, the absence of development toxicity in rats and rabbits, the lack of neurotoxicity after single exposures, and the absence of any other toxicological end-point that would be elicited by a single dose.

A toxicological monograph was prepared.

Levels relevant to risk assessment

^a Dietary administration
^b Gavage administration
^c Highest dose tested

Estimate of acceptable daily intake for humans

0-0.2 mg/kg bw

Estimate of acute reference dose

Unnecessary

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

Results from epidemiological, occupational health and other such observational studies of human exposures

Critical end-points for setting guidance values for exposure to fenhexamid

RESIDUE AND ANALYTICAL ASPECTS

Residue and analytical aspects of fenhexamid, or 2',3'-dichloro-4?-hydroxy-1-methylcyclohexane-carboxanilide, were considered for the first time by the present Meeting.

Fenhexamid is a protectant fungicide and has registered uses in many countries on horticultural crops and vegetables. It inhibits spore germ tube development and hyphal growth.

The Meeting received information on fenhexamid metabolism and environmental fate, methods of residue analysis, freezer storage stability, national registered use patterns, supervised residue trials, fate of residues in processing, and national MRLs. Australia and the Netherlands submitted GAP information and labels to support MRLs for fenhexamid.

Animal metabolism

The metabolism of fenhexamid was investigated in rats and goats.

One lactating goat was dosed with [phenyl-UL-¹⁴C]fenhexamid at a rate of 10 mg/kg body weight (equivalent to 133 ppm in the feed) for three consecutive days. Approximately 63.5% of the total radioactivity administered (about 99% of the recovered radioactivity) was excreted within 54 h after the first administration. The major excretory pathway was via the faeces (39% of the applied radioactivity), followed by excretion via the urine (25%). A low amount (0.03%) was secreted with the milk. At sacrifice 6 h after the last dosage, the total radioactive residues (TRR) in the edible tissues and organs accounted for 0.58% of the administrated radioactivity. The major portion and the highest equivalent concentration were observed in the liver (0.47% of the administrated radioactivity).

The metabolism of fenhexamid in the goat is comparable to the metabolism in the rat. Sulfate conjugates of hydroxy-fenhexamid were not observed in the goat but in the rat.

The unchanged parent compound was found in all goat tissue samples and ranged from 19% of the TRR (equiv. to 0.007 mg/kg) in muscle, 21% (equiv. to 0.69 mg/kg) in kidney, 36% (equiv. to 0.031 mg/kg) in fat to 54% (equiv. to 2.5 mg/kg) in liver. No fenhexamid was detected in milk.

4-Hydroxy-fenhexamid was identified as a main metabolite in the goat tissues ranging from 18 to 31.5% of the respective TRR (equiv. to 0.007 mg/kg in muscle and 0.027 mg/kg in fat). The glucuronide of fenhexamid was the predominant metabolite in milk (71% of the TRR, equiv. to 0.13 mg/kg) and a main component in tissues, except liver (9.0 of the TRR in fat, equiv. to 0.008 mg/kg; 24% in muscle, equiv. to 0.009 mg/kg and 31% in kidney, equiv. to 1.01 mg/kg). In addition, the glucuronide of 4-hydroxy-fenhexamid was detected in kidney (9.4% of the TRR, equiv. to 0.31 mg/kg).

The Meeting concluded that the elimination of fenhexamid in the goat was rapid via conjugation of the phenyl hydroxyl group and hydroxylation of the cyclohexyl ring.

Plant metabolism

The behaviour and metabolism of [phenyl-UL-¹⁴C]fenhexamid was investigated under simulated field conditions in grapes, apples, tomatoes, lettuce and field peas using spray application. In addition, separate translocation experiments were carried out for grapes, apples and tomatoes to investigate the possible occurrence of the metabolite 2,3-dichloro-4-hydroxyaniline (DCHA).

The studies demonstrated that the metabolic pathway of fenhexamid is similar in all crops investigated. The rate of degradation in/on plants is quite low and the parent compound was always the major component.

The metabolism of fenhexamid proceeded along two pathways:

conjugation (glucoside) of the parent compound at the phenolic hydroxyl group,

hydroxylation at the 2- and 4-position in the cyclohexyl ring followed by conjugation of the hydroxyl group.

These two metabolic routes occurred only to a limited extent. In the different crop studies it was shown that the majority of radioactivity remained on the surface of the fruits as unchanged parent compound, approaching 90% of the TRR. The sum of all metabolites did not exceed 20% of the TRR, and no single metabolite was present at above 3.2%. Most of the metabolites identified were hydroxy-derivatives of fenhexamid. No DCHA was detected.

Translocation experiments found that fenhexamid was not systemic.

The Meeting concluded that fenhexamid is stable when used as a foliar spray on various food crop plants. There was no appreciable metabolism or degradation under typical GAP conditions.

Nature of residues after hydrolysis under processing conditions

The Meeting received information on the fate and nature of [phenyl-UL-¹⁴C]fenhexamid residues during different conditions of hydrolysis (pH 4-6, temperature 90-120°C, time 20-60 min). The results showed that the parent compound is not significantly affected by these processes. At the end of the study the content of fenhexamid was in the range of 96% to 100% of applied radioactivity.

The Meeting concluded that it is unlikely that processing will affect the nature of fenhexamid residue.

Environmental fate

Because fenhexamid is used for foliar spray treatment, only studies of hydrolysis, photolysis and rotational crops were considered.

Fenhexamid is hydrolytically stable at pH 5-9. No formation of hydrolysis products was observed. Considering the degree of hydrolytic stability determined under environmental pH and temperature conditions, it is not expected that hydrolytic processes would contribute to the degradation of fenhexamid in the environment. However, when irridated with a xenon lamp, fenhexamid underwent photolysis with a half life equivalent to 1.8 h at the equivalent of 40° latitude midday midsummer solar light. Therefore, it can be concluded that while fenhexamid is stable at a range of environmental pHs, rapid photochemical degradation may occur.

The metabolism of [phenyl-UL-¹⁴C]fenhexamid was investigated in the rotational crops wheat, Swiss chard and turnips from three consecutive rotations. The TRRs decreased significantly from the first to the third rotation in all raw agricultural commodities. The maximum TRR (0.73 mg/kg) was observed in the first rotation for Swiss chard sown 30 days after soil application. The TRRs of the second rotation were all £ 0.1 mg/kg. The TRRs of the third rotation ranged from £ 0.01 mg/kg (turnip roots) to 0.08 mg/kg (wheat straw).

The Meeting concluded that residues, from the use of fenhexamid, in succeeding crops are not to be expected.

Methods of analysis

The Meeting received descriptions and validation data for analytical methods for fenhexamid in plant and animal matrices. Plant matrices are extracted with acetone from samples with high water content and with a mixture of water/acetone from dry samples and cleaned up by solid phase extraction. The residues are detected with HPLC/electrochemical detection or HPLC/MS/MS and generally achieved LOQs of 0.02-0.05 mg/kg. The recoveries were in the range of 63-120%.

Animal matrices were extracted with acetonitrile or n-hexane and cleaned-up by liquid-liquid partitioning and finally by column chromatography on a silica gel column. The residues were detected with HPLC-UV and achieve LOQs between 0.01 mg/kg (milk) and 0.05 mg/kg (egg, meat and fat). The recoveries were in the range of 67% to 101%.

Stability of pesticide residues in stored analytical samples

The Meeting received information on the stability of fenhexamid in various plant matrices at freezer temperatures for 5.5-17 months. Fenhexamid residues were generally stable (less than 30% disappearance) for the duration of the testing.

Definition of the residue

The behaviour and metabolism of fenhexamid was investigated in a number of fruiting crops (grape, tomato and apple), leafy crops (lettuce) and oil seed/pulses (peas). The studies demonstrated that the metabolic pathway of fenhexamid is similar in all crops investigated. The rate of degradation on plants is quite low and the parent compound was always the major component. The sum of all metabolites does not exceed 20% of the radioactive residue, and no single metabolite was present at above 3.2%. The residue definition for plants is therefore parent compound only.

Parent fenhexamid is in concentrations from 19 to 54% of TRR detectable in goat tissues where it is hydroxylated to derivatives that form glucuronic acid conjugates. The log P_OW of fenhexamid is 3.6 suggesting that it is fat-soluble. This is confirmed by the goat metabolism study which shows a higher residue concentration in fat than in muscle.

The Meeting agreed that the residue definition for compliance with MRLs and for estimation of dietary intake should be fenhexamid per se. The definition applies to plant and animal commodities.

The residue is fat-soluble.

Results of supervised trials on crops

The Meeting received supervised trials data on citrus fruit (oranges, mandarins and lemons), stone fruit (cherries, peaches and nectarines), berries (grapes, strawberries, black currants, blueberries, raspberries and blackberries), kiwi, cucumbers, tomatoes, sweet peppers, lettuce and almonds.

Citrus fruits

The use of fenhexamid as a foliar spray is registered in Japan (GAP of 1-2 applications at rates of 0.03-0.05 kg ai/hL, PHI 14 days).

Seven field trials (reversed decline studies) were conducted in Japan between 1995 and 1997 with fenhexamid on citrus (orange 2 trials, mandarin 2 trials, lemon 3 trials). Fenhexamid was applied twice (orange, lemon) or three times (mandarin) at rates of 0.05 kg ai/hL. The spray interval was 7-8 days. The residues in whole fruits were

The residues in pulp were

The Meeting concluded that the data, in particular on oranges and mandarins, were not sufficient to estimate a maximum residue level and STMR for residues in citrus fruits as a major crop.

Stone fruits

Supervised residue trials were presented on cherries, peaches, nectarines and plums. In some trials the residue concentrations were calculated on whole fruit basis and in other cases for the edible portion. The Meeting agreed to use both kinds of data to estimate maximum residue levels and STMRs because the ratio of residue/weight of flesh and whole fruit differed by not more than 20%.

Cherries

Fenhexamid is registered for use on cherries in some European countries as pre-harvest foliar spray treatment. Residue trials were carried out in Germany, France and Italy. The German GAP is 1-3 applications at a rate of 0.25 kg ai/ha per m crown height (equiv. to 0.75 kg ai/ha for a tree with a crown of 3 m) with a 3-days PHI. The residues in whole fruits were 0.68, 0.82, 0.87, 1.0, 1.2, 1.6, 2.1 and 2.8 mg/kg in six German and two French (North) trials on sour and sweet cherries matching the German GAP.

The Italian GAP (1-4 applications at 0.75 kg ai/ha, 1 day PHI) is matched by two trials with residues in whole fruits of 0.63 and 0.91 mg/kg.

In the USA fenhexamid may be used as foliar spray treatment on cherries at 0.84 kg ai/ha with a 0-day PHI after up to 4 applications. In trials matching GAP the fenhexamid residues in the edible portion in ranked order were 1.1, 1.1, 1.1, 1.5, 1.9 and 4.7 mg/kg.

Fenhexamid is also approved in the USA as a post-harvest dip or spray to cherries at a rate of 0.34 kg ai in 378.5 L water to 11,300 kg of fruit (equiv. to 0.09 kg ai/hL or 3 g ai/100 kg fruit). In two trials matching GAP conditions residues found were 1.9 and 2.4 mg/kg. Two further trials were carried out with two pre-harvest spray applications of 0.85 kg ai/ha followed by one post-harvest treatment of 0.09 kg ai/hL. The residues found in the edible portion were 2.3 and 3.7 mg/kg.

The Meeting considered that the data from foliar spray and post-harvest use are from the same pool and decided to combine all cherry residue data. The combined results (n = 20) were 0.63, 0.68, 0.82, 0.87, 0.91, 1.0, 1.1, 1.1, 1.1, 1.2, 1.5, 1.6, 1.9, 1.9, 2.1, 2.3, 2.4, 2.8, 3.7 and 4.7 mg/kg.

The Meeting estimated a maximum residue level of 7 mg/kg and an STMR of 1.35 mg/kg for residues of fenhexamid in cherries.

Peaches and nectarines

Fenhexamid is registered for use on peaches and nectarines in a number of European countries as a pre-harvest foliar treatment. Residue trials were carried out in Spain and Italy. The Italian GAP (maximum of 4 applications at 0.75 kg ai/ha, with a 1 day PHI) was matched by two Spanish trials each on nectarines and peaches with residues found of 0.18, 0.36, 0.36 and 0.44 mg/kg in the whole fruit. The edible portion was analysed in two trials only with residues of 0.22 and 0.39 mg/kg found.

In the USA fenhexamid is approved for use at 0.84 kg ai/ha with a 0-day PHI after four foliar spray applications. In trials on peaches matching GAP, fenhexamid residues in the edible portion were found to be 0.62, 0.66, 0.69, 1.2, 1.3, 1.3, 1.4, 1.9 and 2.1 mg/kg.

Fenhexamid is also approved in the USA as a post-harvest dip or spray at 0.34 kg ai in 378.5 L water to 90,700 kg of fruit (equiv. to 0.09 kg ai/hL or 0.37 g ai/100 kg fruit). In six peach trials matching GAP conditions the residues in the edible portion were 0.65, 1.6, 2.9, 4.1, 4.6 and 5.9 mg/kg. Six further trials were carried out with two pre-harvest spray applications of 0.84 kg/ha followed by one post-harvest treatment at 0.09 kg ai/hL. Residues found in the edible portion were 0.63, 2.8, 3.8, 3.9, 4.8 and 5.7 mg/kg. The combined results were 0.63, 0.65, 1.6, 2.8, 2.9, 3.8, 3.9, 4.1, 4.6, 4.8, 5.7 and 5.9 mg/kg. These residues were considered to belong to a different population from those resulting from foliar spray use.

The Meeting estimated a maximum residue level of 10 mg/kg and an STMR of 3.85 mg/kg on the basis of post-harvest treatment use for fenhexamid residues in peaches and nectarines.

Plums

Fenhexamid is registered for the use on plums in some European countries as pre-harvest foliar treatment. Residue trials were carried out in Germany, UK, the Netherlands, France and Italy. The German GAP consists of a maximum of 3 applications at a rate of 0.25 kg ai/ha per metre of crown height (equiv. to 0.75 kg ai/ha for a 3 m tree) with a three day PHI. In four German, one French (North), two UK and one Dutch trial on plums, matching the German GAP, residues found in the whole fruit were 0.08, 0.14, 0.31, 0.31, 0.37, 0.39, 0.66 and 0.79 mg/kg.

The Italian GAP (maximum of four applications at 0.75 kg ai/ha, with a one day PHI) is matched by two French (South) trials and one Italian trial, residues found in the whole fruit were < 0.05, 0.14 and 0.37 mg/kg.

In the USA, fenhexamid may be used on plums at 0.84 kg ai/ha with a 0-day PHI after 4 foliar applications. In trials matching GAP conditions the fenhexamid residues in the edible portion were < 0.05, 0.06, 0.06, 0.06, 0.06, 0.15, 0.27, 0.33 mg/kg.

All results from pre-harvest foliar treatments, in ranked order were: < 0.05, < 0.05, 0.06, 0.06, 0.06, 0.06, 0.08, 0.14, 0.14, 0.15, 0.27, 0.31, 0.31, 0.33, 0.37, 0.37, 0.39, 0.66 and 0.79 mg/kg.

In the USA fenhexamid is also registered for post-harvest use as dip or spray in plums at a rate of 0.34 kg ai in 378.5 L of water to 90,700 kg of fruit (equiv. to 0.09 kg ai/hL or 0.37 g ai/100 kg fruit). In four trials matching GAP the residues in the edible portion were 0.23, 0.34, 0.38 and 0.65 mg/kg. Four further trials were carried out with two pre-harvest spray applications of 0.84 kg ai/ha followed by one post-harvest treatment with 0.09 kg ai/hL. The residues in the edible portion were 0.33, 0.35, 0.37 and 0.60 mg/kg. The combined residues were 0.23, 0.33, 0.34, 0.35, 0.37, 0.38, 0.60 and 0.65 mg/kg.

The Meeting decided to combine all plum residue data. The combined results (n = 27) were < 0.05, < 0.05, 0.06, 0.06, 0.06, 0.06, 0.08, 0.14, 0.14, 0.15, 0.23, 0.27, 0.31, 0.31, 0.33, 0.33, 0.34, 0.35, 0.37, 0.37, 0.37, 0.38, 0.39, 0.60, 0.65, 0.66 and 0.79 mg/kg.

The Meeting estimated a maximum residue level of 1 mg/kg and an STMR of 0.31 mg/kg for residues of fenhexamid in plums (including prunes).

Apricots

In Italy, Switzerland and the USA the approved use patterns for apricots is identical to that for cherries, peaches and plums. The Meeting agreed to extrapolate from cherries, peaches and plums to apricot. The data on cherries (STMR 1.35 mg/kg), peaches (STMR 3.85 mg/kg) and plums (STMR 0.31 mg/kg) belonged to different populations and could not be combined. Therefore, the extrapolation is based on the peaches data set with the highest STMR.

The Meeting estimated a maximum residue level of 10 mg/kg and an STMR of 3.85 mg/kg for residues of fenhexamid in apricots.

Grapes

The use of fenhexamid in grapes is registered in a number of countries in Europe, North America (Canada, USA), Africa (South Africa), Asia (Japan, South Korea), Australia and New Zealand. Trials on grapes were conducted in Australia, Canada, France, Germany, Japan, Italy, Spain, Portugal, South Africa and the USA.

In the trials grape bunches were the main commodity analysed. However, the portion of the Codex commodity to which the MRL applies and which should be analysed is the "whole commodity after removal of caps and stems." The Meeting therefore decided to use available residue data only from berries/fruits, to estimate the MRL and STMR for grapes.

The highest GAP for northern Europe corresponds to a rate of up to 0.8 kg ai/ha applied up to two times with a PHI of 21 days (Austria, Germany) or a rate of up to 0.75 kg ai/ha applied once with a PHI of 14 days (France). Six trials were conducted using different grape varieties during 1995 and 1998 in Germany (4 trials) and northern France (2 trials). The residues found in berries, 21 days after two applications, were 0.25, 0.27, 0.35, 0.35, 0.44 and 0.47 mg/kg.

The highest GAP for southern Europe corresponds to a rate of up to 0.75 kg ai/ha applied up to two times with a PHI of 7 days (Italy), or up to 0.5 kg ai/ha applied up to 3 times with a PHI of 7 days (Romania). In nine trials from Spain, Italy, Portugal and France (South) matching Italian GAP residues found in berries were 0.37, 0.39, 0.45, 0.47, 0.78, 0.96, 1.1, 1.4 and 1.6 mg/kg.

In two trials from Portugal and Italy fenhexamid was applied 3 times at a rate of 0.5 kg ai/ha and a PHI of 7 days, matching Romanian GAP. The residues in berries were 0.51 and 0.75 mg/kg.

The Meeting considered that the data from northern and southern Europe are from the same population and combined them, resulting in the following ranked order of concentrations in berries of 0.25, 0.27, 0.35, 0.35, 0.37, 0.39, 0.44, 0.45, 0.47, 0.47, 0.51, 0.75, 0.78, 0.96, 1.1, 1.4 and 1.6 mg/kg.

In South Africa fenhexamid is approved for use in table grapes with a maximum of three applications at a rate of 0.038 kg ai/hL with a 3 days PHI. In the trials four to five applications were made rather than three. The residues in the grape bunches were 0.52, 0.54, 1.1, 1.3 and 2.4 mg/kg. Because no berries were analysed, the trials were not included into the evaluation.

In the USA, fenhexamid is approved for use up to 3 times at a rate of 0.56 kg ai/ha with a 0 day PHI. In seven Canadian and 15 USA trials matching USA GAP fenhexamid residues in grape bunches were 0.55, 0.62, 0.71, 0.78, 0.87, 0.91, 0.97, 1.0, 1.1, 1.1, 1.1, 1.2, 1.2, 1.3, 1.4, 1.6, 1.6, 1.8, 1.9, 2.1, 2.2 and 2.8 mg/kg. Because no berries were analysed, the trials were not included into the evaluation.

In Australia, fenhexamid is used on grapes with a maximum of 2 applications at rate of 0.05 kg ai/hL (high volume spray) or 0.25 kg ai/hL (low volume spray) with a 21 days PHI. In five trials matching GAP conditions fenhexamid residues were 1.5, 2.5, 3.5, 4.7 and 6.1 mg/kg in berries.

In Japan, fenhexamid is registered for up to 2 applications at a rate of 0.05 kg ai/hL and a 14 day PHI. Four outdoor and two indoor trials were conducted that matched GAP. The residues in the fruit were 4.3, 6.3, 6.7 and 11 mg/kg in the outdoor trials and 0.14 and 3.2 mg/kg in the indoor trials.

The Meeting compared the data sets from Australia and Japan using the Mann-Whitney U-test (see FAO Manual, p. 73) and decided that they belonged to the same population and could be combined. The combined Australian and Japanese residues were 0.14, 1.5, 2.5, 3.2, 3.5, 4.3, 4.7, 6.1, 6.3, 6.7 and 11 mg/kg.

The Meeting considered that the data sets from Australia/Japan and from Europe were from different populations. The Meeting therefore estimated a maximum residue level of 15 mg/kg and an STMR of 4.3 mg/kg for residues in grapes, on the basis of Japanese and Australian data.

Strawberries

A total of 49 trials were conducted with fenhexamid in strawberries in North America, Asia, Australia, northern and southern Europe.

The highest GAP for northern Europe (outdoor) corresponded to a maximum of 3 applications at a rate of 1 kg ai/ha with a PHI of 3 days (Austria). Eight field trials were conducted in northern Europe. The fenhexamid residues found were 0.57, 0.70, 0.78, 0.81, 1.1, 1.2, 1.2 and 1.9 mg/kg.

The highest GAP for southern Europe (outdoor) corresponded to a maximum of 4 applications at a rate of 0.75 kg ai/ha with a PHI of one day (Spain). Eight field trials were conducted in southern Europe. The fenhexamid residues found were 0.48, 0.66, 0.74, 1.0, 1.1, 1.1, 1.3 and 1.5 mg/kg.

Fenhexamid is registered in Italy for indoor (greenhouse) use on strawberries at a rate of 0.75 kg ai/ha with a 1 day PHI but with no apparent restriction on the number of applications indicated. A spray interval of 7-10 days is recommended. Four indoor trials from Italy, with 4 applications at 0.75 kg ai/ha, were considered to match GAP and showed residues of 0.71, 0.81, 1.1 and 1.7 mg/kg.

The USA use pattern on strawberries allows fenhexamid to be sprayed a maximum of 4 times at a rate of 0.84 kg ai/ha with a PHI of 0 days. In 14 trials matching GAP conditions residues found of fenhexamid were 0.35, 0.38, 0.42, 0.49, 0.57, 0.67, 0.97, 1.1, 1.2, 1.2, 1.3, 2.0, 2.1 and 2.3 mg/kg.

Data from two indoor trials were submitted from Japan, in which fenhexamid was applied three times at a rate of 0.05 kg ai/hL. It was decided that the data could not be used for evaluation as the Japanese and Korean GAP specified only outdoor use.

Six further outdoor trials studies were submitted from Australia where five applications were made at rates of 0.4-0.56 kg ai/ha with a PHI of 0 days. The residues found were 0.53, 0.54, 2.7, 3.9, 5.6 and 5.9 mg/kg.

Based on the Australian data, the Meeting estimated a maximum residue level of 10 mg/kg and an STMR of 3.3 mg/kg for residues in strawberries.

Blueberries and black currants

Residue data was received for blueberries and black currants and were evaluated together.

The use of fenhexamid in bilberry and similar berries (incl. blueberry) is registered in the USA with 1-4 spray applications of 0.84 kg ai/ha and a 0-day PHI. Eight residue trials from six US states on blue berry complied with GAP. At the day of treatment, the concentrations of residues were: 1.0, 1.2, 1.4, 1.6, 1.7, 2.6, 2.8 and 2.9 mg/kg.

In Germany and Austria, the GAP for berries (except grapes and strawberries) includes 1- 4 treatments of 1 kg ai/ha and a 7-day PHI. A total of 8 residue trials were performed in Germany and the UK with 4 × 1 kg ai/ha, 0.2 kg ai/hL on black currants. With a 7-day PHI, the fenhexamid residues were: 0.93, 1.0, 1.2, 1.6, 1.7, 1.7, 1.8 and 2.1 mg/kg.

The Meeting noted that the data on blueberries and black currants were similar and could be combined for mutual support. The combined residues were, in rank order: 0.93, 1.0, 1.0, 1.2, 1.2, 1.4, 1.6, 1.6, 1.7, 1.7, 1.7, 1.8, 2.1, 2.6, 2.8 and 2.9 mg/kg.

The Meeting agreed to extrapolate from blueberries and black currants to other bush type berries and estimated a maximum residue level of 5 mg/kg and an STMR of 1.65 mg/kg for residues in bilberries, blueberries, currants (black, red, white), elderberries, gooseberries and juneberries.

Raspberries and blackberries

In Germany and Austria, the GAP for berries (except grapes and strawberries) includes 1- 4 treatments of 1 kg ai/ha and a 7-day PHI. Five residue trials were performed in the UK and 2 in Germany with 4 × 1 kg ai/ha on raspberries. With a 7-day PHI, the fenhexamid residues were: 0.9, 1.1, 1.4, 1.5, 1.6, 2.0 and 4.0 mg/kg.

In the USA, fenhexamid is registered in blackberry and raspberry with 1-4 spray applications of 0.84 kg ai/ha and a 0-day PHI. A total of 6 GAP residue trials were performed with foliar spray application in North America, one on blackberries and two on raspberries in Canada and three on raspberries in the USA. The application rate was 4 × 0.79-0.88 kg ai/ha. The residue concentrations were 0.55, 3.0, 4.0, 5.2, 11 and 11 mg/kg after a 0-day PHI.

The Meeting compared data sets from Europe and the USA by the Mann-Whitney U-test (see FAO Manual, p.73) and decided that they belonged to one population and could be combined. The combined residues were, in rank order: 0.55, 0.9, 1.1, 1.4, 1.5, 1.6, 2.0, 3.0, 4.0, 4.0, 5.2, 11 and 11 mg/kg.

The Meeting agreed to extrapolate from raspberries and blackberries to other cane type berries and estimated a maximum residue level and an STMR value for fenhexamid in dewberries (boysenberries, loganberries), raspberries and blackberries of 15 mg/kg and 2.0 mg/kg.

Kiwifruit

Fenhexamid may be used in Europe (Greece and Italy) as post-harvest dip or spray with a 0.05-0.06% solution on kiwifruit with a 60 day PHI. Four trials were performed in Italy with dipping in a 0.075% solution. The residues were 60 days after treatment in whole fruits 3.5, 4.0, 4.8 and 6.3 mg/kg.

In the USA fenhexamid is registered for post-harvest use by 30 s dipping in a solution of 0.09% or as a packing line spray at a rate of 0.37 g ai/100 kg fruits. Three trials were performed with dipping (0.09%) and two with spraying (0.375 g ai/100 kg fruits). The residues were 3.5, 6.3, 6.5, 9.5 and 11 mg/kg.

The Meeting compared both kiwifruit data sets from Europe and the USA by the Mann-Whitney U-test (see FAO Manual, p.73) and decided that they belonged to one population and could be combined. The combined residues were, in rank order: 3.5, 3.5, 4.0, 4.8, 6.3, 6.3, 6.5, 9.5 and 11 mg/kg.

The Meeting estimated a maximum residue level and an STMR value for fenhexamid in kiwifruit of 15 mg/kg and 6.3 mg/kg.

Cucumber, gherkin and summer squash

The highest GAP for indoor uses in Europe in/on cucumber corresponds to 0.75 kg ai/ha, applied up to 3 times with a PHI of 3 days (Austria) or sprayed at 0.05 kg ai/hL with a PHI of 1 day in the Netherlands, where no maximum number of application is stated. The GAP for Israel is the same as for Austria without specifying the maximum number of applications, but because cucumbers are harvested continuously and spray intervals were 7 days or more it is unlikely that the same fruit received more than 3 applications. The fenhexamid residues in cucumbers from 16 European indoor trials (3 Belgium, 3 German, 1 Dutch, 2 French, 2 Italian, 3 Spanish, 2 Greek) meeting these conditions were 0.10, 0.12, 0.14, 0.14, 0.14, 0.15, 0.16, 0.18, 0.19, 0.19, 0.20, 0.20, 0.21, 0.29, 0.33 and 0.65 mg/kg with a 1-day PHI.

The registered use in The Netherlands on gherkin and summer squash is the same as on cucumber. The Meeting agreed to extrapolate the cucumber values to gherkin and summer squash.

The Meeting estimated a maximum residue level of 1 mg/kg and an STMR of 0.185 mg/kg for residues in cucumber, gherkin and summer squash.

Tomato

The highest GAP for outdoor and indoor uses in Europe in tomato corresponds to 0.75 kg ai/ha, 0.05-0.075 kg ai/hL with a PHI of 1 day (Italy) and spray intervals of 10-14 days, no maximum number of applications is stated.

Seven outdoor trials (4 French, 1 Italian, 2 Portuguese) on tomato matching the GAP with a rate of 3 × 0.75 kg ai/ha were submitted with residues of 0.29, 0.32, 0.34, 0.42, 0.62, 0.63 and 0.93 mg/kg.

A total of 17 tomato residue trials (1 Spain, 2 France, 4 Italy, 4 Germany, 3 Belgium, 1 Greece, 2 Netherlands) were performed indoor according to Italian GAP in Europe in 1995/96/98/99. In each trial, 3 applications (interval 7 days) were made. All applications were carried out approximately at the highest label application rate (0.75 kg ai/ha). At the 1-day PHI, the concentrations of residues were: 0.17, 0.24, 0.24, 0.25, 0.27, 0.32, 0.34, 0.34, 0.39, 0.40, 0.41, 0.42, 0.54, 0.63, 0.72, 0.80 and 0.86 mg/kg.

The Meeting considered that the data from indoor and outdoor trials on tomato are from the same pool and combined them, resulting in a ranked order as follows (n = 24): 0.17, 0.24, 0.24, 0.25, 0.27, 0.29, 0.32, 0.32, 0.34, 0.34, 0.34, 0.39, 0.40, 0.41, 0.42, 0.42, 0.54, 0.62, 0.63, 0.63, 0.72, 0.80, 0.86 and 0.93 mg/kg.

The Meeting estimated a maximum residue level of 2 mg/kg and an STMR of 0.395 mg/kg for residues of fenhexamid in tomato.

Peppers

The highest GAP for indoor uses in Europe in/on peppers corresponds to 0.75 kg ai/ha, applied up to 3 times with a PHI of 3 days (Austria) or sprayed at 0.05 kg ai/hL with a PHI of 1 day in the Netherlands, where no maximum number of application is stated. The GAP for Israel is the same as for Austria without specifying the maximum number of applications, but because peppers in greenhouse are harvested continuously and spray intervals were 7 days or more it is unlikely that the same fruit received more than 3 applications.

The fenhexamid residues in sweet peppers from 18 European indoor trials (3 Belgium, 3 German, 3 Dutch, 2 French, 4 Italian, 2 Spanish, 1 Portuguese) meeting these conditions were 0.38, 0.41, 0.43, 0.45, 0.48, 0.63, 0.66, 0.67, 0.67, 0.75, 0.76, 0.84, 0.86, 0.89, 0.90, 0.92, 1.0 and 1.5 mg/kg with a 1-day PHI.

The Meeting agreed to extrapolate from data for sweet pepper on the whole subgroup including chili and sweet peppers and estimated a maximum residue level of 2 mg/kg and an STMR of 0.71 mg/kg for residues of fenhexamid in peppers.

Egg plant

The registered use on egg plant is the same as on tomato and peppers in the Netherlands. The Meeting agreed to extrapolate from tomato and sweet pepper to egg plant. The data on tomato and peppers belonged to different populations and could not be combined. Therefore, the extrapolation based on the sweet pepper data set.

The Meeting estimated a maximum residue level of 2 mg/kg and an STMR of 0.71 mg/kg for residues of fenhexamid in egg plant.

Lettuce

The Austrian use pattern for lettuce grown indoor and outdoor allows fenhexamid to be sprayed 2 times at 0.75 kg ai/ha with a PHI of 7 days.

Eight outdoor trials on head lettuce from northern European countries (3 Germany, 3 Netherlands, 2 UK) matching maximum GAP with a rate of 2 × 0.75 kg ai/ha were submitted with fenhexamid residues at day 7 of 0.10, 0.11, 0.24, 0.30, 0.47, 1.1, 2.0 and 5.3 mg/kg.

Eight further outdoor trials on head and leaf lettuce were carried out in southern Europe (2 Spain, 3 Italy, 2 Portugal, 1 France-South) under the same application conditions. The residues were in head lettuce < 0.05, 0.07, 0.69, 0.84 and 2.0 mg/kg and in leaf lettuce 0.48, 0.94 and 2.7 mg/kg.

Six indoor trials on head lettuce from European countries (4 Germany, 2 Italy) matching maximum GAP with a rate of 2 × 0.75 kg ai/ha were submitted with fenhexamid residues at day 7 of 1.3, 2.7, 6.4, 11, 12 and 17 mg/kg. Two further indoor trials on leaf lettuce were carried out under the same application conditions in Italy with residues of 14 and 19 mg/kg at day 7.

The Meeting compared both data sets from indoor and outdoor use by the Mann-Whitney U-test (see FAO Manual, p.73) and decided that they belonged to different populations and could not be combined. The Meeting decided to use the greenhouse lettuce data to support the evaluation.

In summary, fenhexamid residues in lettuce from greenhouse trials in rank order were: 1.3, 2.7, 6.4, 11, 12, 14, 17 and 19 mg/kg.

The Meeting noted that the 24 trials covered 15 varieties of lettuce and decided to make recommendations for both head and leaf lettuce.

Based on the indoor data set, the Meeting estimated a maximum residue level and an STMR value for fenhexamid in head and leaf lettuce of 30 mg/kg and 11.5 mg/kg.

Almonds

Fenhexamid is registered in the USA for use on almonds up to 4 times at 0.84 kg ai/ha up to 4 times at 0.84 kg ai/ha up to 28 days after petal fall.

Five trials on almonds from the USA with 4 treatments at 0.85 kg ai/ha and a 142?173 days PHI matching the GAP for foliar spray up to 28 days after petal fall were reported. The fenhexamid residues in almond nuts without shells were all < 0.02 (5) mg/kg.

The Meeting estimated a maximum residue level and an STMR value for fenhexamid in almonds of 0.02*mg/kg and 0.02 mg/kg.

Almond hulls

From the five trials described above the fenhexamid residues in almond hulls were 0.15, 0.47, 0.54, 0.77 and 1.1 mg/kg (fresh weight).

The Meeting estimated a maximum residue level of 2 mg/kg, a highest residue of 1.2 and an STMR of 0.6 mg/kg on dry weight basis.

Fate of residues during processing

The effect of processing on the level of residues of fenhexamid has been studied in cherries, plums, grapes, strawberries and tomatoes. The processing factors (PF) shown below were calculated.

In Australian grape processing studies, five PF values for juice, wine, wet pomace and raisin could be calculated per trial. In these cases, only the maximum PF per trial was used for the evaluation. The mean PF was calculated from two values, otherwise the median PF was calculated.

Cherries (RAC residues 0.86, 1.0 mg/kg) were processed into juice and preserve with processing factors of 0.02 and 0.23. Based on the STMR value of 1.35 mg/kg for cherries, the STMR-Ps were 0.03 mg/kg for cherry juice and 0.31 mg/kg for preserves.

Plums (RAC residues < 0.05 mg/kg) were processed into sauce and dried prunes. No detectable residues were reported in sauce but 0.1 mg/kg in prunes. As the concentration of residues was at the LOQ in the RAC, no STMR-P values could be estimated.

Grapes were processed into juice, must, wine and dried fruit (raisins) with processing factors of 0.51, 0.415, 0.28 and 1.86 respectively. Based on the STMR value of 4.3 mg/kg for grapes, the STMR-P for juice was 2.2 mg/kg, for must 1.8 mg/kg, for wine 1.2 mg/kg and for raisins (dried grapes) 8.0 mg/kg. Based on the highest fenhexamid residue of 11 mg/kg, the Meeting estimated a maximum residue level of 25 mg/kg for residues in raisins (dried grapes).

Strawberries (RAC residues 0.66 mg/kg) were processed into jam with a processing factor of 0.29. Based on the STMR value of 3.3 mg/kg for strawberries, the STMR-P value was 0.96 mg/kg for residues in strawberry jam.

Tomatoes (RAC residues 0.34, 0.96 mg/kg) were processed into juice, paste and preserve with processing factors of 0.34, 5.2 and 0.3, respectively. Based on the STMR value of 0.395 mg/kg for tomato, the STMR-Ps were 0.13 mg/kg, 2.05 mg/kg and 0.12 mg/kg for residues in tomato juice, paste and preserves, respectively.

Lettuce head Two processing-type studies were performed with fenhexamid on head lettuce. The trials were designed to determine the extent of the residue deposits on the outer leaves as well as the effect of washing on residue levels. Processing was conducted using household practices. The residues measured in different plant parts indicate variations in the distribution of fenhexamid on the plant.

The residue levels of fenhexamid in lettuce head RACs sampled on day 3 after the last applications were 1.3-6.0 mg/kg. Values of 4.2-11.0 mg/kg were measured in the outer leaves, which demonstrate that the major portion of the residues was deposited on the surface, as is to be expected. The residue level in the inner head samples (heads without outer leaves) from these trials were 1.5-2.6 mg/kg, and those in the inner leaf samples ranged from 1.5-3.5 mg/kg. The residues in "inner leaves, washed" ranged from 0.35-0.99 mg/kg and from 0.27-0.91 mg/kg in the washing water.

The studies demonstrated that the residues of fenhexamid are concentrated on the outer leaves (factors 1.7, 3) and washing reduces the concentration of residues on leaves.

Residues in animal commodities

Fenhexamid treated raw agricultural commodities are not fed to farm animals. The only processed feedstuff might be almond hulls. The dietary burden of fenhexamid for beef and dairy cattle arising from almond hulls is very low: 0.12 mg/kg for the maximum and 0.06 mg/kg for the median animal dietary burden.

Estimated maximum dietary burden of farm animals

Estimated median dietary burden of farm animals

No feeding studies of fenhexamid on farm animals were received. The Meeting noted that in the metabolism study on a goat dosed for three days with the equivalent of 133 ppm fenhexamid in the feed the residues in all tissue samples were low and ranged from 0.007 mg/kg in muscle, 0.69 mg/kg in kidney, 0.031 mg/kg in fat to 2.5 mg/kg in liver. No fenhexamid was detected in milk.

As this dosing level is more than 1100 times higher than the maximum estimated dietary burden of 0.12 ppm, the Meeting agreed that residues would not be expected in animal commodities and estimated STMRs and HRs of 0 for meat (from mammals other than marine mammals), edible offal (mammalian) and milks.

The Meeting estimated maximum residue levels of 0.01* (F) mg/kg for milks, 0.05*(fat) mg/kg for meat (from mammals other than marine mammals) and 0.05* mg/kg for edible offal (mammalian).

DIETARY RISK ASSESSMENT

Long-term intake

The International Estimated Daily Intakes (IEDIs) of fenhexamid, based on the STMRs estimated for 30 commodities, for the five GEMS/Food regional diets were in the range of 0% to 6% of the maximum ADI (Annex 3). The Meeting concluded that the long-term intake of residues of fenhexamid resulting from its uses that have been considered by JMPR is unlikely to present a public health concern.

Short-term intake

The 2005 JMPR decided that an ARfD is unnecessary. The Meeting therefore concluded that the short-term intake of fenhexamid residues is unlikely to present a public health concern.