TOXICOLOGY
Abamectin (a mixture containing ³ 80% avermectin B1a and £ 20% avermectin B1b) was evaluated toxicologically by the Joint Meeting in 1992 and 1994. An ADI of 0-0.0002 mg/kg bw was allocated in 1994 on the basis of an NOAEL of 0.12 mg/kg bw per day in a multigeneration study of reproductive toxicity in rats, using a safety factor of 500. The increased safety factor was used because of concern about the teratogenicity of the 8,9-Z isomer (earlier identified as the D -8,9 isomer), which is a photolytic degradation product that forms a variable proportion of the residue on crops. In 1995, the Joint Meeting established a separate ADI of 0-0.001 mg/kg bw for abamectin itself, as the basis for risk assessment when abamectin is used as a veterinary drug and the residue does not contain the 8,9-Z isomer. The present Meeting reviewed information that was requested by the 1994 JMPR and reconsidered the decision of the 1995 JMPR.
Data submitted to the 1994 JMPR indicated that the high sensitivity of CF-1 mice to the neurotoxicity of avermectins is associated with P-glycoprotein deficiency in the small intestine and in the capillary endothelial cells of the blood/brain barrier. It was speculated that the heterogeneity of the response in CF-1 mice may explain the absence of a dose-response relationship for maternal toxicity in the studies of teratogenicity. Data submitted to the present Meeting resolved the issue of the variability seen in earlier studies in CF-1 mice.
In a study to establish the LD50 in CF-1 mice genotyped for P-glycoprotein expression, similar signs of toxicity were seen in +/+ (homozygous) and +/- (heterozygous) mice. The oral LD50 for +/+ mice was 28 mg/kg bw, and that for +/- mice was 14 mg/kg bw. Separate studies indicated an LD50 for -/- mice of 0.3-0.4 mg/kg bw. Thus, in CF-1 mice, the oral LD50 appears to be related to the genotype for P-glycoprotein.
A four- to five-day study with CF-1 and CD-1 mice given 0.8 mg/kg bw per day resulted in severe toxicity in 17% of the CF-1 mice after the first dose. P-Glycoprotein was not detectable in the brain or jejunum of these mice, except in one mouse which had minimal expression in the brain. Insensitive CF-1 mice showed slight to intense P-glycoprotein staining, and CD-1 mice showed intense P-glycoprotein staining. Oral administration of challenge doses (10 mg/kg bw) to groups of insensitive CF-1 mice after five days of treatment at 0.8 mg/kg bw per day caused slight toxicity, with complete recovery within one to two days. The results indicate severe toxicity in mice of the -/- genotype and variable toxicity in those of the +/- and +/+ genotypes. No toxicity was seen in CD-1 mice, which are probably of the +/+ genotype. These results indicate that the genotype of CF-1 mice with respect to P-glycoprotein expression governs the toxicity of abamectin. There is no evidence that mutations of this genotype occur in CD-1 mice.
8,9-Z isomer
Studies of tissue distribution in genotyped CF-1 mice after administration of radiolabelled 8,9-Z isomer indicated marked differences according to genotype. In the brain, the levels in -/-mice of each sex were about 60 times those in +/+ mice. By 24 h, the difference was even greater, since clearance occurred in +/+ mice but not in -/- mice. A similar pattern was seen in the testes, with the highest levels in -/- mice. At 24 h, the testicular levels in +/- and +/+ genotype mice were in equilibrium with those in plasma. In plasma, the level of radioalabel was highest in -/- mice, but the differences between the +/+ and -/- genotypes were much less than in the organ systems.
A single oral dose to CD-1 and CF-1 mice resulted in oral LD50 values of 220 mg/kg bw for female CD-1 mice and about 20 mg/kg bw for male CF-1 mice. Data on other avermectins indicates no sex difference for acute toxicity. Since the signs fit the pattern for neurotoxicity, it is probable that the low LD50 value (i.e. increased susceptibility) in CF-1 mice is related to the accessibility of the target organ to the test material and hence to the presence or absence of P-glycoprotein expression.
A number of studies of developmental toxicity were performed in CF-1 mice. In the first study, the NOAEL for both maternal and developmental toxicity was 0.06 mg/kg bw per day, the highest dose tested. Cleft palate and exencephaly were observed, but the incidence was within historical control limits. A second study showed an NOAEL for maternal toxicity of 0.1 mg/kg bw per day and an LOAEL, based on signs of toxicity, of 0.5 mg/kg bw per day. The NOAEL for teratogenicity was 0.03 mg/kg bw per day, the incidences of cleft palate at doses of 0.1 mg/kg bw per day and above being greater than those in historical controls; however, at 0.1 mg/kg bw per day, cleft palates were seen in only one litter; at 0.5 mg/kg bw per day, the incidence of cleft palate showed clumping within litters. A third study with the 8,9-Z isomer was performed in female CF-1 mice which had been screened for sensitivity to abamectin before the start of the study. Sensitive and insensitive female mice were paired with males of unknown sensitivity, and the doses given to sensitive female mice were varied during exposure. Marked effects on sensitive mice occurred at doses above 0.5 mg/kg bw, only 4/18 animals surviving to term. Of these, only one mouse had a live litter. No effects were seen on insensitive mice at doses up to 1.5 mg/kg bw per day; however, cleft palates were observed at all doses between 0.05 and 1.5 mg/kg bw per day. This study demonstrates that the incidence of malformations is not related to maternal toxicity.
Yet another study of developmental toxicity was performed using parental mice of known genotype for the mdr-1 gene, which encodes for P-glycoprotein expression. This study indicated a relationship between the parental genotype and the incidence of cleft palate: at 1.5 mg/kg bw per day, cleft palate was observed in none of the offspring of +/+ x +/+ crosses, in 12% of those of +/+ male x +/- female crosses, and 58% of those of-/- male x +/- female crosses; one cleft palate occurred in the control +/- x +/- cross and none in the -/- x -/- cross. Genotypic analysis of the fetuses from treated females showed no cleft palates in +/+ mice, 41% in +/- mice, and 97% in -/- mice. Analyses of the placentae for P-glycoprotein showed a correlation with the genotype of the fetus, the levels being highest in +/+ fetuses and absent in -/- fetuses; the +/- control matings yielded a Mendelian distribution of 15 +/+, 32 +/-, and 18 -/- pups. The close relationship between fetal genotype and the presence of P-glycoprotein in the placenta would be expected, since much of the placenta is formed from fetal tissue. The relationship between the incidence of cleft palate and genotype appears to be a reflection of prevention by P-glycoprotein expression of penetration of the test material through placental membranes.
The presence of placental P-glycoprotein was investigated in +/+ male and +/+ female CF-1 mice. Western blotting of the placentae indicated the presence of P-glycoprotein on day 9 of gestation, the levels increasing with the duration of gestation. Levels present at the time of palatal closure (~ day 15) would be sufficient to hinder placental transfer of the 8,9-Z isomer of abamectin. Passage of the radiolabelled isomer across the placenta was investigated after administration to +/- female mice on day 17 of gestation. The maternal plasma levels of radiolabel were variable but maximal 8 h after treatment. The levels of radiolabel in the fetus depended on the fetal genotype, being lowest in +/+ fetuses and highest in -/- fetuses, indicating that blockage of placental transfer depends on genetically controlled expression of placental P-glycoprotein.
A study of developmental toxicity in CD-1 mice treated by gavage with doses of 0, 0.75, 1.5, or 3 mg/kg bw per day of the 8,9-Z isomer showed no adverse effects on the maternal mice. The incidences of cleft palate were 0, 2, 1, and 4 (or 0, 0.73, 0.31, and 1.4%) at 0, 0.75, 1.5, and 3 mg/kg bw per day, respectively. These incidences were not dose-related and fell within control incidences seen after oral or intravenous administration of vehicles in the same laboratory. The NOAEL for maternal, embryo-, and fetal toxicity was 3 mg/kg bw per day.
Ivermectin
A multigeneration study in rats given doses of 0.4 mg ivermectin/kg bw per day and above resulted in early mortality of pups post-partum and reduced pup body-weight gain. The study was terminated early. A further study at doses of 0.05-0.4 mg/kg bw per day showed no effects, except increased pup mortality in the F3a litters at 0.4 mg/kg bw per day between days 1 and 7 post-partum. Postnatal toxicity was assessed in a series of cross-fosterings of newborn pups; toxicity was shown to be due to postnatal, not in-utero, exposure. The postnatal toxicity was further investigated with radiolabelled ivermectin either before or throughout mating and gestation. In the rats dosed post-partum, the levels of radiolabel in the plasma were initially low but were comparable to those observed after long-term exposure by day 9 post-partum. The levels of radiolabel in the milk were consistently three to four times the plasma levels in both groups, which may reflect mobilization of ivermectin from fatty tissues. In the offspring of parents treated post-partum, radiolabel was not detected in plasma on day 1 post-partum, but was half that in the long-term group of offspring on days 4 and 6, and equivalent on day 9. The tissue levels in the pups on day 9 were two to three times those in the parents. The plasma: brain ratios of radiolabel in the offspring of both groups were 1 on days 1 and 4 post-partum and 2-3 on days 6-9. These data can be interpreted to indicate that the development of the blood/brain barrier in rat offspring is delayed, occurring some time after parturition. The postnatal toxicity observed in rats may be a function of the accessibility of the target organ to the toxin, owing to the late formation of the blood/brain barrier and to possible mobilization of ivermectin from adult fatty tissues.
P-Glycoprotein distribution in adult and young animals
In the immature rat (about six weeks old), P-glycoprotein is present in the brain and in the brush border epithelial cells of the jejunum. In fetal animals (day 20 of gestation), however, minimal P-glycoprotein was detected in the brain, the levels being less than 10% of that in adult animals up to day 14 and then increasing rapidly. No P-glycoprotein was detected in the jejunum of fetal rats or in rats on days 2 or 5 post-partum; P-glycoprotein was detectable by day 8 post-partum, and the levels increased with time thereafter. These data indicate late expression of P-glycoprotein, occurring some 10-15 days post-partum. In non-pregnant adult rats, P-glycoprotein was not observed in the uterus; it was present, however, on the luminal surface of the uterine epithelium in pregnant rats.
P-Glycoprotein was present on the endothelial surface of capillaries in the cerebrum, cerebellum, cerebellar peduncle, and pons of rhesus monkey fetuses. The staining intensity was comparable in all areas of the brain. P-Glycoprotein was also present in the placenta, but none was detected in fetal jejunum. The brain levels of P-glycoprotein in monkey fetuses were comparable to those in the brains of one- to two-year-old rhesus monkeys examined in another study.
In humans, P-glycoprotein was detected in the brain capillaries of fetuses aborted at 28 weeks, but not at earlier gestational ages. The levels found were comparable to that in the adult brain. In human placenta, P-glycoprotein was found in the syncytiotrophoblast microvillus border and in some placental macrophages in the first trimester, but mainly in the placental macrophages at term.
Species sensitivity to avermectins
Increased sensitivity has been seen in CF-1 mice and in Collie dogs. In no other species or strain of animal has increased sensitivity to avermectins been observed. In humans, 50000000 doses of 0.2 mg/kg bw ivermectin have been administered for treatment of parasitic diseases, with no report of toxicity directly attributable to the drug. Higher doses (1.6 mg/kg bw) have also not resulted in toxicity. Treatment of humans is not usually required more often than yearly.
The data reviewed on the effects of the 8,9-Z isomer on developmental toxicity in the CF-1 mouse clearly indicate a strong relationship between the increased incidence of cleft palate and reduced expression of P-glycoprotein in this strain of mouse. Since the phenomenon is seen only in these animals, the Meeting considered that the use of the results of studies with this strain is not appropriate in establishing the ADI. The NOAEL for teratogenic activity in the CD-1 mouse was 3 mg/kg bw per day.
Data on the avermectins have been used in the overall review of abamectin. In the multigeneration studies of reproductive toxicity of ivermectin and abamectin in rats, the critical adverse effects were those on pups during early lactation. The data on ivermectin indicate that the pup mortality and reduced body-weight gains seen early in lactation may be associated with delayed development of P-glycoprotein expression. Reduced glycoprotein expression in early lactation correlates with the mortality of pups. Young pups are not only more susceptible to abamectin because they lack P-glycoprotein expression, but they are also exposed to levels of abamectin in milk that are two to three times those in maternal plasma. P-Glycoprotein expression in humans is fully developed by week 28 of gestation. The appropriateness of the multigeneration study of reproductive toxicity of abamectin as the basis for the ADI is, therefore, questionable.
Because of the hypersusceptibility of rats postnatally, the Meeting determined that a reduced interspecies safety factor would be appropriate for establishing an ADI. A safety factor of 50 was therefore applied to the NOAEL from the multigeneration study in rats (0.12 mg/kg bw per day) to give an ADI of 0-0.002 mg/kg bw, which is supported by the NOAEL of 0.24 mg/kg bw per day in the one-year study in dogs, applying a safety factor of 100. A single ADI for both abamectin and its 8,9-Z isomer was deemed to be appropriate, since the potential teratogenicity of the isomer has been satisfactorily explained.
An addendum to the toxicological monograph was prepared.
TOXICOLOGICAL EVALUATION
Levels that cause no toxicological effect
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Abamectin |
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Mouse: |
4 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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Rat: |
1.5 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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0.12 mg/kg bw per day (two-generation study of reproductive toxicity) |
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Dog: |
0.25 mg/kg bw per day (one-year study of toxicity) |
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8,9-Z isomer |
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Mouse: |
3 mg/kg bw per day (study of developmental toxicity in CD-1 mice) |
Estimate of acceptable daily intake for humans (sum of abamectin and 8.9-Z isomer)
0-0.002 mg/kg bw
Studies that would provide information useful for the continued evaluation of the compound
Further observations in humans, possibly involving repeated exposure
RESIDUE AND ANALYTICAL ASPECTS
Abamectin was first evaluated at the 1992 JMPR and subsequently in 1994. MRLs have been recommended for a number of crops and animal commodities.
The Meeting received information on current registered uses, methods of analysis and data on residues in supervised trials on the additional crops apples, potatoes and hops as well as new trials on pears, cucurbits, lettuce and tomatoes. Processing data were available for apples, pears, potatoes and hops.
The predominant residues from the use of abamectin on crops are avermectin B1a, avermectin B1b and the photoisomers 8,9-Z-avermectin B1 (B1a and B1b produced during exposure to sunlight. Analytical methods that measure the components of the residue rely on HPLC separation and fluorescence detection of derivatives formed by converting the cyclohexene ring to an aromatic ring. The abamectin residue appears as two peaks on the chromatogram (B1a and its photoisomer in one peak and B1b and its photoisomer in the other). The LOD for each peak is in the range 0.002-0.005 mg/kg.
Abamectin residues were shown to be stable in samples of fresh and dried hops during freezer storage for the periods tested (150-190 days).
The Meeting noted that the definition proposed by JECFA (1997) for residues in the liver, kidney and fat of animals subject to veterinary treatment with abamectin does not include the 8,9-Z- isomer (D -8,9- isomer), because it is not present in animal tissues when abamectin is used directly on the animal. However, residues in animal tissues arising from residues in animal feed would include the 8,9-Z- isomer. The Meeting agreed that the wider definition (including the 8,9-Z- isomer) was appropriate for a laboratory carrying out enforcement or monitoring analyses because the analyst would not know whether the residue in the animal originated only from veterinary treatment or also from the feed. The wider definition accommodates both situations.
Inclusion or exclusion of avermectin B1b from the definition of the residue is a matter of judgement. In many crop situations B1b is present at approximately 10% of the total residue and the analytical methods measure B1a and B1b by the same procedure so B1b results are always available and may as well be used.
Avermectin B1b forms a photoisomer 8,9-Z-avermectin B1b in sunlight in the same way as avermectin B1a does. The studies of photolysis were with avermectin B1a, so when the JMPR reviewed the studies in 1992 the possibility of 8,9-Z avermectin B1b being produced was not taken into account. In practice the contribution of 8,9-Z avermectin B1b to the residue will be small but it should be recognized that the HPLC measurement of avermectin B1b residues includes any 8,9-Z avermectin B1b. The Meeting agreed to revise the definition of the residue accordingly, and recommended the following definition for compliance with MRLs and for the estimation of dietary intake.
Sum of avermectin B1a, avermectin B1b, 8,9-Z avermectin B1a and 8,9-Z avermectin B1b.
The Meeting received data from supervised residue trials on apples, pears, cucumbers, melons, summer squash, tomatoes, lettuce, potatoes and hops.
The B1b, component, when its residues were measurable, was consistently about 10% or less of the total residue. For the purposes of evaluation, when B1a was positively detected and B1b was not detectable the total residue was calculated by taking the undetectable residue to be zero.
When both components in a trial were not detectable (ND) the total residue was taken as below the limit of detection. A residue reported as NQ (not quantifiable, detected but below the limit of determination LOD) is treated as equal to the LOD when it is to be added to a measurable residue.
The method of calculating the total residue for various situations is illustrated by the examples below.
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B1a |
B1b |
Total residue |
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0.013 |
NQ (>0.001 but 0.002) |
0.015 |
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0.006 |
ND (0.001) |
0.006 |
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NQ |
ND |
0.002 |
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ND |
ND |
0.001 |
Abamectin is registered for single applications on apples in Australia at 0.014 kg ai/ha with harvest after an interval of 14 days. In three trials corresponding to this use pattern the abamectin residues were 0.002, 0.003 and 0.005 mg/kg.
Abamectin is permitted for use on pome fruit in New Zealand with one application at 0.027 kg ai/ha and a PHI of 14 days. Abamectin residues on apples were 0.004 and 0.007 mg/kg in two New Zealand trials where GAP was followed except that two applications were made instead of one.
Abamectin is registered in the USA for two applications on apples at a rate of 0.026 kg ai/ha with harvest 28 days after the final application. In 14 US trials according to these conditions abamectin residues in rank order (median underlined) were 0.001 (2), 0.002 (3), 0.002, 0.003 (4), 0.004, 0.006, 0.007 and 0.012 mg/kg.
The residue data from Australia, New Zealand and the USA appear to be from one population and can therefore be combined. The residues of abamectin in apples in rank order in the 19 trials (median underlined) were 0.001 (2), 0.002 (4), 0.002, 0.003 (5), 0.004 (2), 0.005, 0.006, 0.007 (2) and 0.012 mg/kg.
The Meeting estimated a maximum residue level of 0.02 mg/kg and an STMR level of 0.003 mg/kg for abamectin in apples.
In the USA abamectin is registered for use on pears at 0.013-0.026 kg ai/ha with two applications permitted at the higher rate and a 28-day PHI. Data from four US trials were provided. The results of supervised trials on pears had previously been reported to the 1992 JMPR. A number of residue decline trials on pears in the USA had shown that the typical half-life was approximately 18 days. At such a rate residues at harvest 21 and 37 days after the final treatment would be ±30% of those at 28 days. The range of pre-harvest intervals for acceptance of the residues was therefore taken as 21-37 days. Abamectin residues in pears from the four trials according to US GAP were 0.004, 0.006, 0.009 and 0.011 mg/kg.
The 1992 monograph recorded one pear trial according to Argentinian GAP, (abamectin <0.005 mg/kg), one according to French GAP (<0.002 mg/kg) and four according to Italian GAP (<0.002 and <0.005 (3) mg/kg).
The residues in the trials in different countries appear to be of the same order, giving residues in rank order (median underlined) of <0.002 (2), 0.004, <0.005 (4), 0.006, 0.009 and 0.011 mg/kg.
The Meeting estimated a maximum residue level for abamectin in pears of 0.02 mg/kg, to replace the previous estimate of 0.01* mg/kg, and an STMR level of 0.005 mg/kg.
In the USA melons may be treated with abamectin at 0.011-0.021 kg ai/ha on three occasions at the higher rate and harvested 7 days after the final treatment. Abamectin residues were not detectable (<0.002 mg/kg) in 9 trials in the USA on cantaloupes according to US GAP, except that there were 4 or 5 applications instead of 3, or in two trials on watermelons under the same conditions. Because the use patterns are the same, watermelons and melons can be evaluated together.
Melons may be treated with abamectin three times at rates up to 0.022 kg ai/ha and harvested three days after the final application according to the registered use in Spain. Abamectin residues were not detected (<0.002 mg/kg) in cantaloupes treated according to Spanish GAP, except that there were four applications, in two glasshouse trials in Spain. Three trials on cantaloupe in France with the same treatment yielded residues of <0.002, <0.005 and <0.005 mg/kg.
Trials on cantaloupes in Brazil and Mexico and on honey-dew melons in Mexico could not be evaluated because there was no information on corresponding GAP. In the Brazilian trials the edible pulp was analysed for abamectin and no residues were detected in any samples in any trial, suggesting that abamectin residues are probably absent from the edible parts of melons.
In summary abamectin residues in melons from trials according to GAP were <0.002, <0.005 and <0.005 mg/kg in France, <0.002 mg/kg (2)) in Spain, <0.002 (9) mg/kg in the USA and <0.002 mg/kg (2) in watermelons in the USA. The residues in melons and watermelons in rank order were <0.002 (14) and <0.005 (2) mg/kg.
The Meeting estimated maximum residue levels of 0.01* mg/kg as being a practical limit of determination, and an STMR level of 0.002 mg/kg, for abamectin in melons and watermelons.
Abamectin is registered for use in the USA on cucumbers and squash at 0.011-0.021 kg ai/ha with three applications at the higher or six at the lower rate, and harvest 7 days after the final treatment. In four US trials on cucumbers at 0.021 or 0.022 kg ai/ha, but with four applications instead of three, residues were undetectable in three trials (<0.002 mg/kg) and below the LOD in the other (<0.005 mg/kg). In four US trials on zucchini (summer squash) under the same conditions no abamectin residues were detectable (<0.002 mg/kg).
Mexican trials on cucumbers and pickling cucumbers could not be evaluated because no information on relevant GAP was available.
The registered use of abamectin on glasshouse cucumbers in Germany permits 5 applications of 0.023 kg ai/ha with harvest three days after the final application. Treatment is not permitted between November and February. Two French trials according to this use pattern were recorded in the 1992 monograph. The resultant abamectin residues were <0.002 and <0.005 mg/kg. A third trial with applications during October and November produced a residue of 0.034 mg/kg, but the conditions were no longer according to GAP.
GAP for abamectin on cucumbers in Spain permits three applications at 0.022 kg ai/ha with harvest three days after the last. Two glasshouse trials in Spain and three trials in Italy (one glasshouse) according to this use pattern but with 4 or 5 applications were recorded in the 1992 monograph. The residues were <0.002, <0.005 (2), 0.006 and 0.008 mg/kg.
GAP for glasshouse cucumbers in The Netherlands allows 5 applications of 0.023 kg ai/ha and harvest three days after the final application. In two trials on cucumbers under these conditions the residues were 0.007 and 0.008 mg/kg, as recorded in the 1992 monograph.
In summary, the residues in cucumbers from trials according to GAP were 0.002 (3) and <0.005 mg/kg in the USA, <0.002 and <0.005 mg/kg in France, <0.002, <0.005 (2), 0.006 and 0.008 mg/kg in Spain and Italy, and 0.007 and 0.008 mg/kg in The Netherlands. The residues in rank order (median underlined) were 0.002 (5), 0.005 (4), 0.006, 0.007 and 0.008 (2) mg/kg.
The Meeting estimated a maximum residue level for abamectin in cucumbers of 0.01 mg/kg, to replace the previous estimate of 0.05 mg/kg, and an STMR of 0.005 mg/kg.
The four trials on summer squash in the USA were evaluated with the support of the four on cucumbers. Abamectin residues from the 8 trials were <0.002 (7) and <0.005 mg/kg.
The Meeting estimated a maximum residue level for abamectin on summer squash of 0.01 * mg/kg as being a practical limit of determination, and an STMR of 0.002 mg/kg.
Abamectin is registered for four applications to glasshouse tomatoes in The Netherlands at 0.023 kg ai/ha with a PHI of three days. Abamectin residues in tomatoes from trials which complied with GAP were 0.007 (2), 0.009, 0.012 (2) and 0.017 mg/kg. Two of the tomato trials in The Netherlands reported in the 1992 monograph (refs 211 and 212) were not according to current GAP because applications were made during the months of November and December. Current GAP restricts the treatment of glasshouse tomatoes to the months of March to October when photodegradation of abamectin residues is sufficient. Two other trials (refs 217 and 218) were according to current GAP because abamectin was applied in May and June. The residues from these two trials were 0.008 and 0.005 mg/kg.
GAP in Argentina permits 9 applications of abamectin at 0.022 kg ai/ha to tomatoes with a 3-day PHI. In the three trials with conditions close to GAP (0.020-0.028 kg ai/ha and 5-9 applications) recorded in the 1992 monograph the residues were <0.002 (2) and <0.005 mg/kg.
In Brazil abamectin may be applied to tomatoes at 0.022 kg ai/ha with harvest three days after the final application. Three Brazilian trials recorded in the 1992 monograph were close to these conditions, with residues of <0.005 (2) and 0.017 mg/kg.
Three French trials recorded in 1992 were evaluated according to German GAP (5 applications of 0.023 kg ai/ha applied to glasshouse tomatoes with harvest three days after the final application). Tomatoes were treated 10 times in one trial, but it was evaluated because residues apparently disappeared quickly and the number of applications would not influence the final residue. The residues were <0.002 (2), and <0.005 mg/kg.
Two Italian trials recorded in 1992 complied with the Italian application rate (<0.022 kg ai/ha) and PHI (7 days), but there were ten applications instead of two. The results were again considered acceptable because the residues were disappearing quickly. The residues in both trials were <0.002 mg/kg.
In Spain abamectin may be used on tomatoes at 0.022 kg ai/ha with a PHI of three days. The residues in tomatoes from four trials recorded in the 1992 monograph with application rates in the range 0.015-0.027 kg ai/ha were <0.005 (3) and 0.009 mg/kg.
GAP in the USA specifies three applications of 0.021 kg ai/ha and harvest 7 days after the final application. Eighteen US trials are recorded in the 1992 monograph at this application rate and a PHI of 7 days or less, but with 8-12 applications. The residues had usually disappeared within a few days so it is unlikely that early applications had any influence on the final residues. The residues were 0.002 (13), 0.005 (4) and 0.005 mg/kg.
In summary, the residues in tomatoes from trials according to GAP were 0.005, 0.007 (2), 0.008, 0.009, 0.012 (2) and 0.017 mg/kg in The Netherlands, <0.002 (2) and 0.<005 mg/kg in Argentina, <0.005 (2) and 0.017 mg/kg in Brazil, 0.002 (2) and <0.005 mg/kg in France, <0.002 (2) mg/kg in Italy, <0.005 (3) and 0.009 mg/kg in Spain and <0.002 (13), <0.005 (4) and 0.005 mg/kg in the USA. The residues in rank order (median underlined and Netherlands results in bold) were <0.002 (19), <0.005 (11), 0.005, 0.005, 0.007 (2), 0.008, 0.009, 0.009, 0.012 (2), 0.017 and 0.017 mg/kg.
The residues in The Netherlands appear to belong to a different population from the others, with a median of 0.0085 mg/kg.
The Meeting estimated a maximum residue level for abamectin in tomatoes of 0.02 mg/kg, the same as the previous estimate, and an STMR of 0.0085 mg/kg.
GAP in The Netherlands permits four applications of abamectin to lettuce at 0.014 kg ai/ha with harvest 14 days after the final application, but only from 1 March to 1 November. In four glasshouse trials in The Netherlands according to GAP the residues in head lettuce were 0.016, 0.025, 0.029 and 0.029 mg/kg.
Abamectin may be used four times on lettuce in France at 0.009 kg ai/ha with harvest 7 days after the final application. In three French trials where the application rate was approximately 25% higher than this, but within the acceptable range for evaluation, the residues were <0.001, 0.004 and 0.023 mg/kg.
In Spain abamectin may be applied three times to lettuce at 0.022 kg ai/ha with harvest 14 days after the final application. In two Spanish and three French trials at this rate and PHI, but with four applications instead of three, the abamectin residues were <0.002, 0.005, 0.013, 0.028 and 0.040 mg/kg.
Trials on lettuce in the USA recorded in the 1992 monograph could not be evaluated because the number of applications, 6-10, was excessive for a sometimes persistent residue compared with the three applications permitted.
In summary, the residues in head lettuce from trials according to GAP were 0.016, 0.025, 0.029 and 0.029 mg/kg in The Netherlands, <0.001, 0.004 and 0.023 mg/kg in France and 0.002, 0.005, 0.013, 0.028 and 0.040 mg/kg in Spain. The residues in rank order (median underlined) were <0.001, <0.002, 0.004, 0.005, 0.013, 0.016, 0.023, 0.025, 0.028, 0.029, 0.029 and 0.040 mg/kg.
The Meeting estimated a maximum residue level of 0.05 mg/kg, and an STMR of 0.020 mg/kg for abamectin in head lettuce.
Only two trials according to GAP were available on leaf lettuce (in Spain). The residues were <0.002 and 0.002 mg/kg. The Meeting agreed that two trials were insufficient and that results could not be extrapolated from head lettuce to leaf lettuce.
Abamectin is registered in Brazil for foliar application to potatoes at 0.018 kg ai/ha with a PHI of 14 days. Abamectin was not detected (<0.005 mg/kg) in three trials at the GAP rate and three at twice that rate in potatoes harvested 0,3 and 7 days after the last of four applications.
In the USA three foliar applications to potatoes are permitted at 0.021 kg ai/ha with harvest 14 days after the last. No abamectin residues were detected (<0.002 mg/kg) in 11 trials with treatment at 0.021 kg ai/ha or in 9 trials at the exaggerated rate of 0.11 kg ai/ha.
The Meeting estimated a maximum residue level for abamectin in potatoes of 0.01 * mg/kg as being a practical limit of determination. Because no residues were detected in a number of trials, some of which were at exaggerated rates, the Meeting estimated an STMR level of 0 mg/kg.
In the USA abamectin is registered for foliar use on almonds with two applications at 0.014-0.028 kg ai/ha and harvest 21 days after the second. Residues were not detected (<0.002 mg/kg) in almonds from 6 US trials according to maximum US GAP and recorded in 1992, or from four additional trials at a double rate.
The residues on the almond hulls from the six US trials reported in 1992 in rank order (median underlined) were 0.016, 0.016, 0.033, 0.047, 0.059 and 0.077 mg/kg.
The Meeting estimated a maximum residue level for abamectin in almonds of 0.01* mg/kg as being a practical limit of determination and, because no residues were detected in the trials at normal and double rates, an STMR of 0 mg/kg. The Meeting also estimated maximum residue and STMR levels for abamectin on almond hulls of 0.1 mg/kg and 0.040 mg/kg respectively.
GAP in the USA for walnuts is the same as for almonds. Abamectin residues were not detected (<0.002 mg/kg) in walnuts from six US trials recorded in 1992 according to the maximum US application rate but harvested after 14 days, or in those from four other trials at a double rate.
The Meeting estimated a maximum residue level for abamectin in walnuts of 0.01* mg/kg as being a practical limit of determination, and an STMR of 0 mg/kg.
Abamectin is registered for use on hops in Germany and the USA with two applications of 0.023 and 0.022 kg ai/ha respectively and a PHI of 28 days. The residues in dry hops from 12 German and 4 US trials according to GAP in rank order (median underlined) were <0.003 (4), <0.005, 0.011, 0.012, 0.015, 0.017, 0.022 (2), 0.023, 0.025, 0.030, 0.062 and 0.086 mg/kg.
The Meeting estimated maximum residue and STMR levels of 0.1 mg/kg and 0.016 mg/kg respectively.
A feeding study on dairy cows recorded in the 1992 monograph showed that residues in the milk, liver, muscle, fat and kidney did not exceed 0.004, 0.020, 0.002, 0.014 and 0.005 mg/kg respectively at a feeding level of 0.1 ppm. The residues in animal commodities arising from the consumption of abamectin-treated almond hulls should not exceed current draft MRLs.
Information on the fate of abamectin residues during the processing of apples, pears, potatoes and hops was provided.
Abamectin residues were not detectable in the juice or sauce produced from treated apples, but were concentrated in pomace, a result expected from the nature of abamectin as a surface residue. The calculated processing factors were 0.062 for juice, 0.12 for apple sauce and 17.3 for dry pomace. The "<" signs indicate derivation from the LOD for abamectin in the processed commodities.
The supervised trials median residues for the processed commodities (STMR-Ps) calculated from the processing factors and the STMR level for apples (0.003 mg/kg) are apple juice 0.00019 mg/kg, apple sauce 0.00036 mg/kg and dry apple pomace 0.052 mg/kg.
Abamectin residues were not detectable in pear halves or pear puree produced from treated pears. The calculated processing factors were canned pear halves <0.046 and pear purée 0.048.
The STMR-Ps for the processed commodities calculated from the processing factors and the STMR for pears (0.005 mg/kg) were canned pear halves 0.00023 mg/kg and pear purée 0.00024 mg/kg.
The processing study on potatoes could not be completed because no abamectin residues were detectable in the treated potatoes.
Abamectin-treated hops were processed by exhaustive hexane extraction of dry hops to produce a solvent extract and spent hops. The extract contains flavour components and is used in the brewing industry while the spent hops become a minor feed commodity. Most of the abamectin residues remained in the spent hops. The mean processing factor from dry hops to spent hops was 0.71.
The mean processing factor for abamectin residues during the conversion of fresh hops to dry hops was 4.09, suggesting that approximately 80% of the abamectin survived the drying process.
The 1992 JMPR recommended MRLs for cattle meat and offal of 0.01 * and 0.05 mg/kg respectively on the basis of possible abamectin residues in animal feed commodities.
On the basis of veterinary uses the 1996 JECFA recommended MRLs for residues defined as avermectin B1a of 100 m g/kg for cattle fat and liver, and 50 m g/kg for kidney.
The Meeting agreed that MRLs should accommodate both agricultural and veterinary uses where the necessary information is available, and agreed to replace the recommendation for edible offal with recommendations for MRLs in fat, liver and kidney in line with the levels recommended by JECFA.
It is not clear whether the current recommendation for cattle meat (0.01 mg/kg) would accommodate veterinary uses. The Meeting recommended that JECFA be requested to suggest an appropriate maximum residue level in cattle meat, and to consider accepting the broader definition of the residue to accommodate the residues which occur as a result of agricultural as well as veterinary uses.
