MOXIDECTIN First draft prepared by Dr K. Woodward, Veterinary Medicines Directorate, Ministry of Agriculture, Fisheries and Food, Addlestone, Surrey, England Explanation Biological data Biochemical aspects Absorption, distribution, and excretion Biotransformation Toxicological studies Acute toxicity studies Short-term toxicity studies Long-term toxicity/carcinogenicity studies Reproductive toxicity studies Special studies on embryotoxicity and/or teratogenicity Special studies on genotoxicity Special studies on skin irritation Special studies on eye irritation Special studies on dermal sensitization Special studies on pharmacodynamic effects Comments Evaluation References 1. EXPLANATION Moxidectin had not been previously reviewed by the Committee. Moxidectin is an antiparasitic drug that is used to control a range of internal and external parasites in sheep, cattle and deer. Its chemical structure is shown in Figure 1, page 1. Moxidectin is synthesized from an intermediate nemadectin, F-alpha. The constitution of the final product is at least 90% moxidectin with not more than 4% as F-alpha and related minor components. The remainder is made up of reaction products from the production process, with the total content of moxidectin-related compounds being not greater than 9% (American Cyanamid, 1994a,b). 2. BIOLOGICAL DATA 2.1 Biochemical aspects 2.1.1 Absorption, distribution, and excretion Pharmacokinetic studies have been conducted with 14C-labelled moxidectin. 2.1.1.1 Rats Groups of Sprague-Dawley rats (2/sex/group) were given single oral doses of 1.5 mg/kg bw 14C-moxidectin in corn oil, and urine, faeces and expired air were examined at 24, 48 and 72 h post-dosing. Approximately 92% and 95% of the radioactivity was eliminated in faeces in males and females, respectively. Less than 0.7% was found in urine and no radioactivity was detected in expired air (Wu, 1991a). In a separate study, groups of 5 male and 5 female rats were given single doses of 1.5 mg/kg bw or 12 mg/kg bw 14C-moxidectin in corn oil by gavage. A third group of 15 male and 15 female rats was given oral doses of 1.5 mg/kg bw/day 14C-moxidectin for 7 days. In animals given single oral doses of moxidectin, 75-80% of the radioactivity was found in faeces and less than 1% in urine. Residues of moxidectin were 20 fold higher in fat than in other tissues and in the 7-day repeat-dose study there was no evidence of bioaccumulation. The depletion half-lives in fat, muscle and kidney/liver were 11.5, 3.9 and 2.4 days, respectively (Wu, 1991b). 2.1.1.2 Sheep Eight sheep were given single oral doses of 14C- or 2H-moxidectin at a dose of 0.2 mg/kg bw. The total recovery of the administered dose was 52% in faeces and less than 1% in urine (Afzal, 1991a). After oral, i.v. or s.c. administration of 0.2 mg/kg bw 14C-moxidectin to sheep, the tmax for total 14C in blood after oral dosing was 9 h with a Cmax of 9 µg/kg moxidectin equivalents. The elimination half-life was 19.5 h. The latter was similar to the t1/2 after i.v. administration (26 h). Based on the relative AUCs for oral and i.v. dose groups, about 23% of the oral dose was absorbed. With s.c. dosing, the tmax was 8 h with a Cmax of 12 µg/kg equivalents. Average absorption of the s.c. dose was 76% (Afzal, 1991b). After oral doses of 0.2 mg/kg bw moxidectin, highest levels of residues were found in fat at 7, 14 and 21 days post-dosing (Berger, 1991; DeLay, 1991a). High levels of moxidectin were found in fat in a 14C study after oral and s.c. administration to sheep (Wu, 1990a; Wu, 1990b). Similar results were obtained in a preliminary study where sheep were given 2 s.c. injections, each of 0.2 mg/kg bw, 10 days apart (DeLay 1991a,b; DeLay, 1994; Mortimer, 1994). 2.1.1.3 Deer Twenty red deer were treated with 0.5 mg/kg bw moxidectin as a 5% pour-on solution. Animals were sacrificed 7, 14, 21 or 28 days after treatment. Highest levels of residues were found in fat at 7 (126 µg/kg) and 28 days (31 µg/kg), whereas levels in other tissues were low at day 7 (< 24 µg/kg) (DeLay, 1993). 2.1.1.4 Cattle A group of 3 cattle received a single s.c. injection of a mixture of 14C- and 2H-moxidectin at a dose of 0.2 mg/kg bw. Up to 58% of the dose was recovered in the faeces and 3% or less in urine. The highest levels of residues were found in fat (900, 635 and 275 µg/kg at days 7, 14 and 28, respectively), with 109, 77 and 31 µg/kg in liver, 42, 38 and 13 µg/kg in kidney, and 21, 10 and 4 µg/kg in muscle at days 7, 14 and 28, respectively. The half-lives for clearance from tissues were 12-14 days for fat, and 9-12 days for liver, kidney and muscle (Zulalian, 1991a). After s.c. administration of 0.2 mg/kg bw 14C-moxidectin to cattle, the Cmax in serum occurred 8 h after dosing with peak serum levels of 60 µg/kg moxidectin equivalents. The elimination half-life was 56 h based on parent moxidectin, and 76 h based on radiolabel. There were no significant differences when i.v. doses of 0.2 mg/kg bw were given (Zulalian, 1991b). Several other studies have also demonstrated that fat is the target tissue for residues of moxidectin after topical or s.c. administration (DeLay, 1992a-d; Garces, 1992; Miller 1989; Rooney 1991a). Similar findings were made in calves (Rooney, 1991b), and relatively high levels have been found at s.c. injection sites (Rooney, 1991c). Moxidectin was excreted in the milk of cattle given a s.c. injection of 0.2 mg/kg bw. Concentrations were 103 µg/kg and 132 µg/kg at the morning and afternoon milking the day after treatment, 23 µg/kg on day 7, < 10-12 µg/kg on day 21, and < 10 µg/kg on day 22 after administration (Garces, 1994; Rooney, 1992). 2.1.2 Biotransformation 2.1.2.1 Rats After single oral doses of 1.5 or 12 mg/kg bw, or 1.5 mg/kg bw/day for 7 days, 85-99% was recovered in faeces, the major component being the parent drug (85%). Six minor metabolites were found in the liver and faeces. These were the 23-keto derivative, some monohydroxylated compounds, the C-14 hydroxymethyl and the C-4 hydroxymethyl compounds. These metabo-lites were also noted after moxidectin was incubated in vitro with rat liver microsomes (Wu, 1991b). 2.1.2.2 Sheep In sheep given oral doses of moxidectin, the faecal metabolites and those found in the liver were qualitatively similar. The major faecal metabolite was the 9-monohydroxylated derivative of moxidectin, largely C-29/C-30 (Afzal 1991a). 2.1.2.3 Cattle Five metabolites were identified in liver, kidney and muscle of cattle given moxidectin by topical application. Of these, two were identified as the C-29/C-30 metabolites and the C-14 hydroxymethyl derivative (Wu, 1992). In another study, faecal and tissue residues were found to be qualitatively similar. Six metabolites were identified as monohydroxylated and dihydroxylated derivatives of moxidectin. The main component was the C-29/C-30 hydroxymethyl derivative (Zulalian, 1991). 2.2 Toxicological studies 2.2.1 Acute toxicity studies The results of acute toxicity studies with moxidectin are summarized in Table 1. Moxidectin was moderately toxic after oral and i.p. administration to rats and mice. It was somewhat less toxic after s.c. administration to these species, and of low toxicity to rabbits after dermal application to intact skin using a 24-h occlusive dressing. In the oral studies in mice, the main clinical signs were decreased activity; surviving animals had fully recovered by day 4. No gross abnormalities were seen in animals that died or in those killed at day 14. Similar findings occurred in mice given i.p. doses of moxidectin. In rats given oral doses of moxidectin, decreased activity, prostration, tremors, chromodacryorrhea, decreased respiration, diarrhoea, hypersensitivity to touch and sound, and epistaxis occurred. Congestion of the liver, kidneys and lungs were observed in animals that died, but animals which were sacrificed at the end of the 14-day observation period showed no abnormalities. Similar signs and effects were noted in rats given i.p. doses of moxidectin. No overt signs of toxicity were noted in rabbits treated dermally with moxidectin. Table 1. Acute toxicity of moxidectin Species Sex Route LD50 Reference (mg/kg bw) Mouse M & F oral 84 Fischer, 1990a F oral 42 Fischer, 1990a F oral 50 Fischer, 1990b M & F i.p. 86 Fischer, 1990b M & F s.c. 263 Fischer, 1990c Rat M & F oral 106 Fischer, 1990d M & F i.p. 394 Fischer, 1990e M & F s.c. >640 Fischer, 1990f M & F inhal. 3.28 mg/l Hershman, 1991 (5 h LC50) Cattle treated with up to 10-fold (2 mg/kg bw) the recommended therapeutic dose (0.2 mg/kg bw) by s.c. injection showed only mild depression and ataxia, which soon resolved. No adverse effects were seen at 3-fold (0.6 mg/kg bw) or 5-fold (1.0 mg/kg bw) the therapeutic dose (Goodale, 1989; Rooney, 1989a; Rooney 1989b). Dermal doses of 12.5 mg/kg bw (25 times the therapeutic dose) were not toxic to cattle (Epperson, 1993). Similar findings were observed in calves (Kieran & Cobb, 1992). No adverse effects were seen in lambs given 0.4 mg/kg bw or 1.0 mg/kg bw (2- and 5-fold the therapeutic dose) by oral drench (Kieran & Cobb, 1991). The NOEL in sheep was 2.0 mg/kg bw (10-fold the therapeutic dose) after s.c. injection; doses above this produced salivation, diuresis, tremors, prostration and ataxia (Guerino, 1991). 2.2.2 Short-term toxicity studies 2.2.2.1 Mice Groups of CD-1 mice (5/sex/group) were given for 28 days 0, 34, 75, 100, 125 or 150 mg/kg dietary moxidectin, equal to 0, 6.9, 18, 23, 24 or 32 mg/kg bw/day. Signs of toxicity included tremors, hypersensitivity to touch, and urine-stained fur in mice given 18, 23 and 24 mg/kg bw/day. Mortality was high in the three highest dose groups (80-100%; all mice given the highest dietary level died). In the group given 18 mg/kg bw/day, 1 animal died but there were no deaths in the lowest dose group. No effects on haematology were noted in any of the dosed groups and there were no effects on absolute or relative organ weights. No gross or microscopic changes were observed in any of the treated animals. The NOEL in this study was 6.9 mg/kg bw/day (Fischer, 1989a). 2.2.2.2 Rats Groups of Sprague-Dawley rats (5/sex/group) were given 0, 100, 200, 400 or 600 mg moxidectin/kg of diet, equal to 0, 12, 23, 26 or 31 mg/kg bw/day, for 28 days. Signs of toxicity were observed from day 1 of the study in animals given the three highest doses. These included ataxia, tremors, salivation, piloerection and diuresis. At the lowest level, hypersensitivity to touch was noted in males on day 2 (5/5) and 3 (1/5) of the study. All the animals in the two highest dose groups died by day 8, and 2 female rats given 23 mg/kg bw/day died during the course of the study. There were no mortalities in the lowest dose group. Food intakes and body-weight gains were unaffected in the lowest dose group but were significantly depressed in the three highest dose groups. There were no effects on relative or absolute organ weights in any group attributable to moxidectin intake. At the two highest dose levels and in animals which died at the 23 mg/kg bw/day level, diffuse atrophy of the liver, kidneys, heart, spleen, adrenals, thyroid, testes, ovaries and epididymis occurred, which is typical of changes often seen in anorexic animals. There were no abnormalities in animals given the lowest dose level, nor in surviving rats given 23 mg/kg bw/day moxidectin. A NOEL was not identified in this study because hypersensitivity to touch was noted in several rats in the lowest dose group at days 2 and 3 (Fischer, 1988). Groups of Sprague-Dawley rats (10/sex/group) were given diets containing 0, 25, 50, 100 or 150 mg moxidectin/kg of feed, equal to 0, 1.9, 3.9, 7.9 or 12 mg/kg bw/day, for 13 weeks. Signs of toxicity in animals given the highest dose included hypersensitivity to touch, lethargy, aggressive behaviour, tremors and urine-stained fur. At the 7.9 mg/kg bw/day level, hypersensitivity to touch began on day 5 but cleared by day 14. No overt signs of toxicity were seen in rats given the two lowest doses. At the highest dietary level, 3 females died or were sacrificed in moribund condition. Food intake was reduced in animals given the highest dietary level of moxidectin for the first 2 weeks of the study. There was no effect on food intakes in any of the other groups when compared with control values. Body weights were depressed for the first 6 weeks in rats given the highest dose level, and were decreased for the remainder of the study. Body weights were also depressed in females given 7.9 mg/kg bw/day. Haematological values, clinical chemistry and urinalyses were unaffected by moxidectin treatment. Females given the highest dietary level had significantly increased absolute kidney and adrenal weights, and increases in relative kidney, liver, heart and adrenal weights. Significant increases in absolute and relative adrenal weights in females, and testes weights in males occurred at 7.9 mg/kg bw/day. These changes are probably related to decreases in body weight. No changes in organ weights occurred at the two lowest dietary intake levels. No gross or microscopic abnormalities were observed in any of the treatment groups. The NOEL in this study was 3.9 mg/kg bw/day (Fischer, 1989b). 2.2.2.3 Dogs Groups of pure-bred beagle dogs (2/sex/group) were given diets containing 0, 20, 80 or 160 mg moxidectin/kg of feed, equivalent to 0, 0.5, 2 or 4 mg/kg bw/day, for 28 days. At the highest dose, dogs developed anorexia, ataxia, prostration and diarrhoea. After day 5 they were returned to a control diet for 2 days and then resumed for the remainder of the study on a diet containing 50 mg/kg of feed, equivalent to 1.25 mg/kg bw/day. Body weight and food consumption were depressed in dogs given the two highest doses, but these increased or remained stable after week 1. In the two highest doses, tremors, a languid appearance, mydriasis, ataxia, emesis, prostration, dehydration, sensitivity to touch, slight salivation, no or few faeces and an inability to hold the head in the normal position were observed, but these effects resolved in the high-dose dogs after moxidectin intake was reduced. There were no signs of toxicity seen in those given the lowest dose. No haematological changes occurred and ophthalmoscopic examinations gave normal results. There were no gross abnormalities at necropsy but relative and absolute testes weights were reduced in dogs given the two highest doses. Histopathological examination revealed reductions in spermatogenetic activity in males given the two highest doses. In animals given 2 mg/kg bw/day, there was a slight decrease in colloid in the thyroid. The NOEL in this study was 0.5 mg/kg bw/day (Schulze, 1989a). In a 90-day study, groups of pure-bred beagle dogs (4/sex/group) were fed diets containing 0, 10, 30 or 60 mg moxidectin/kg of feed, equal to 0, 0.3, 0.9 or 1.6 mg/kg bw/day, for 90 days At the highest dose, lacrimation, tremors, salivation, slight ataxia and a languid appearance were noted. Dose-dependent reductions in absolute body weights and food consumption were noted in dogs given the two highest doses. No other signs were noted and there were no deaths during the test period. No abnormalities in haematological parameters, ophthalmoscopic examinations or urinalyses were seen. Organ weights were comparable with controls except in the high-dose females (decrease in absolute heart weights) and high-dose males (slight decreases in absolute pituitary and pituitary to brain weight ratios). No microscopic abnormalities were seen. The NOEL in this study was 0.3 mg/kg bw/day (Schulze, 1989b). Groups of pure-bred beagle dogs (6/sex/dose) were given diets containing 0, 10, 20 or 45 mg moxidectin/kg of feed, equivalent to 0, 0.26, 0.52 or 1.15 mg/kg bw/day, for 52 weeks. No signs of toxicity occurred and body weights remained comparable to controls throughout the study. There were no abnormalities in haematological parameters, clinical chemistry or urinalyses, and ophthalmoscopic examinations were normal. No gross or microscopic abnormalities were seen at necropsy. The NOEL in this study was 1.15 mg/kg bw/day (Schulze, 1991). 2.2.3 Long-term toxicity/carcinogenicity studies 2.2.3.1 Mice Groups of CD-1 mice (65/sex/group) were given diets containing 0, 15, 30 or 60 mg moxidectin/kg of feed, equal to 0, 2.5, 5.1 or 12 mg/kg bw/day, for 2 years. After 9 weeks on the study, the highest dose was reduced to 50 mg/kg of feed (7.9 mg/kg bw/day) because of increased mortality in this group. In the high-dose group, hunched-posture, decreased activity, tremors, laboured breathing and coldness to the touch were observed. During the last 13 weeks of the study, females in this group died or were sacrificed in extremis and 10 surviving females in this group were killed 2 days before scheduled sacrifice. No increase in mortality was seen in males in this group. No other clinical signs were evident in any of the other animals in all treated groups. Body weights were slightly reduced in high-dose males during weeks 0-8, probably because of reduced food intake. There were no haematological abnormalities in treated animals at 12, 18 or 24 months and no gross or microscopic changes were observed at termination. There was no increased incidence of any tumour type. The NOEL in this study was 5.1 mg/kg bw/day (Goldenthal, 1992). 2.2.3.2 Rats Groups of Sprague-Dawley Crl:CD BR rats (65/sex/group) were given diets containing 0, 15, 60 or 120 mg moxidectin/kg of feed, equal to 0, 0.8, 3.2 or 9.8 mg/kg bw/day, for 2 years. After 8 weeks on the study, the highest dose was reduced to 100 mg/kg (5.1 mg/kg bw/day) because of increased mortality in this group. During weeks 1-8, 4 of the high-dose females were found dead or were sacrificed in extremis. Signs of toxicity in this group included hunched posture, tremors, hyperactivity, rough haircoat, urine-stained fur, and hypersensitivity to external stimuli. These signs ceased when the dose was reduced to 5.1 mg/kg bw/day. No signs of overt toxicity were noted in the other treatment groups. Before the dose was reduced, high-dose females had body weights significantly lower than controls but these became similar to control values when the dose was reduced. After the 2-year treatment period, there were no abnormalities in haematological parameters, clinical chemistry or urinalyses. There were no adverse findings on ophthalmoscopic examination of treated rats. At termination, there were no gross or microscopic changes observed and there was no increased incidence of any tumour type. The NOEL in this study was 5.1 mg/kg bw/day (Zoetis, 1992). 2.2.4 Reproductive toxicity studies 2.2.4.1 Rats In a pilot single-generation (two litters) study, groups of COBS CD Sprague-Dawley derived rats (25/sex/group) were given diets containing 0, 25, 50 or 125 mg moxidectin/kg of feed, equal to 1.8, 3.9 or 9.8 mg/kg bw/day for a 9-week period prior to mating and through gestation and lactation to produce the F1a litters. The dietary levels were reduced to 0, 5, 10 or 15 mg/kg, equal to 0, 0.4, 0.8 or 1.1 mg/kg bw/day, for the F1b litter. At the highest dietary level, parental animals showed reductions in weight gains, a decrease in the number of live pups at birth and an increase in the number of dead pups at birth. All the live F1a pups died on days 0-4 of lactation. No adverse effects were seen in animals given the two lower dose levels of moxidectin. Mating, fertility, gestation length and numbers of pups born alive were comparable with controls. However, all the F1a pups died during lactation. No adverse effects were noted in parental animals following the reductions in doses for the F1b litter. Gestation length and litter size were also unaffected. At the mid-dose level, there was a reduction in pup survival rate at days 4-21, while in the high-dose group, mean pup weights were reduced at days 4, 7, 14 and 21 of lactation and pup survival at days 0-14 and 4-21 of lactation was lower than in controls. There were no effects on pups in the lowest dose group. Gross examination of the parental animals and of the F1b pups from treated rats showed no adverse effects. The NOEL in this study was 0.4 mg/kg bw/day for the F1b animals (Schroeder, 1991). In a 3-generation (2 litters) study in COBS CD Sprague-Dawley- derived rats, groups of 25 males and 25 females were given diets containing 0, 1, 2, 5 or 10 mg moxidectin/kg of feed, equal to 0, 0.07, 0.15, 0.41 or 0.83 mg/kg bw/day for a 70-day period prior to mating. Randomly selected offspring (F1b and F2b) were selected to produce the ensuing generations, while randomly selected offspring of the F1b, F2b and F3b generations were sacrificed and examined for gross abnormalities. Selected tissues from these animals (reproductive organs, pituitary and gross lesions from parental animals) were subject to microscopic examination. No excess mortality was seen in any of the parental generations (P1, F1 or F2). No adverse effects were seen in the 0.07, 0.15 or 0.41 mg/kg bw/day treatment groups with respect to growth, food consumption, maternal weight changes during gestation and lactation, reproductive performance or fertility indices. Pup weights, sex distribution and pup survival were comparable with controls. At the highest dietary level, slight reductions in weight were seen in males during the pre-mating (F2), mating and post-mating periods (F1 and F2). Significant reductions in pup survival indices were noted for days 0-21 for the F1a litters, and for days 0-4 for the F2a litters. Other parental and neonatal parameters were unaffected by compound administration. Gross examination of the P1, F1 and F2 parental animals and of selected F1b, F2b and F3b animals showed no compound-related effects while microscopic examination of primary and secondary sex organs revealed no abnormalities. The NOEL in this study was 0.4 mg/kg bw/day (Schroeder, 1992). 2.2.4.2 Dogs As part of a target species safety study, adult male beagle dogs were given oral doses of 9 µg moxidectin/kg bw, once every 30 days for 4 consecutive months. Semen quality, breeding ability and performance were unaffected and there were no gross or microscopic adverse effects seen at necropsy (Rooney, 1993a). 2.2.4.3 Cattle There were no effects on ovulation, folliculogenesis, post- ovulation or pregnancy in estrous cycling cows when animals were given 0.6 mg moxidectin/kg bw by s.c. injection (Wang, 1991c). No effects were noted in bulls given 3-fold the therapeutic dose (0.6 mg/kg bw) of moxidectin by s.c. injection; semen quality was normal as was palpation of the seminal vesicles and testes. The circumference of the scrotum was normal (Wang, 1992). 2.2.5 Special studies on embryotoxicity and/or teratogenicity 2.2.5.1 Rats Groups of 25 pregnant Crl:CD Sprague-Dawley BR rats were given gavage doses of 0, 2.5, 5, 10 or 12 mg/kg bw/day moxidectin in corn oil from days 6-16 of gestation, when the animals were killed by carbon dioxide asphyxiation. No deaths occurred in this study, but the 12 mg/kg bw/day dose resulted in urine-stained fur, and chromo- dacryorrhea. The 10 and 12 mg/kg bw/day doses resulted in significant decreases in maternal body weights and decreases in food consumption. In the post-dosing period (16 to 20 days of gestation), significant increases in food consumption and body weights occurred in these animals. However, the body weights were still reduced compared with controls, even after a correction for gravid uterine weights was made. Administration of 10 and 12 mg/kg bw/day resulted in significant increases in the total number of fetuses with abnormalities, typified by increased incidences of cleft palate and wavy or incompletely ossified ribs. No other effects were seen and it is likely that these abnormalities were due to embryotoxic effects or maternal toxicity. There was no evidence of teratogenic effects and the NOEL in this study was 5 mg/kg bw/day (Lochry, 1989). 2.2.5.2 Rabbits Groups of 18 pregnant Hra:(NZ)SPF rabbits were given gavage doses of 0, 1, 5 or 10 mg/kg bw/day moxidectin in corn oil from days 7-19 of gestation, when the animals were sacrificed. No deaths occurred in this study, but 1 control and 1 high-dose rabbit died as a result of gavage accidents. Two low-dose animals and 1 high-dose animal aborted during the course of the study, which was not considered to be compound-related and the incidence was within the range for historical controls. Dose-related decreases in body weights occurred at 5 and 10 mg/kg bw/day, accompanied by decreases in feed intake, but pregnancy rates in all treated groups were similar to control values. There were no effects on numbers of corpora lutea, implantations or resorptions when compared to control values, and fetal body weights and sex ratios were similar in all groups. There was no increased incidence of external, soft tissue or skeletal abnormalities in any dosed group when compared with controls. On the basis of maternal effects demonstrated by depression in body-weight gains, the NOEL in this study was 1 mg/kg bw/day. There was no evidence of teratogenicity up to the highest dose employed in this study (Hoberman, 1989). 2.2.5.3 Dogs As part of a target animal safety study, a group of 24 pregnant beagle dogs was given orally 9 µg/kg bw moxidectin (3-fold the therapeutic dose) from day 12 of gestation until day 42 of lactation. There were no effects on the outcome of pregnancy and no abnormalities were seen in pups from treated dogs (Rooney, 1993b). 2.2.5.4 Cattle No adverse effects were seen in cattle when moxidectin, as a single s.c. injection, was given in the first, second or third trimester of pregnancy to a total of 135 animals, using a dose of 0.6 mg/kg bw (3-fold the recommended therapeutic dose) (Wang, 1991a). No adverse effects were noted in another study where 15 pregnant cows were given a single s.c. injection of 0.2 mg/kg bw during the first, second or third trimester of pregnancy (Wang 1991b). 2.2.5.5 Sheep The outcome of pregnancy was unaffected when a group of 20 animals was given a single s.c. injection of 0.4 mg/kg bw moxidectin (2-fold the therapeutic dose) at unspecified periods of pregnancy (Parker, 1994). Similar findings were made in other studies (Cobb, 1994). 2.2.5.6 Horses Breeding and pregnant mares received oral doses of 1.2 mg/kg bw moxidectin (3-fold the therapeutic dose) every 2 weeks during gestation, or for various periods post-foaling. Moxidectin treatment did not affect the outcome of pregnancy (American cyanamid, 1993). 2.2.6 Special studies on genotoxicity The results of genotoxicity studies with moxidectin are summarized in Table 2. Moxidectin was not mutagenic in the Ames test, in a forward mutation assay with E. coli, or in a test using mammalian cells in vitro. A negative result was obtained in an in vivo study for chromosome aberrations in rat bone marrow cells. It did not induce UDS in primary rat hepatocytes. 2.2.7 Special studies on skin irritation Only mild signs of skin irritation were seen in New Zealand white rabbits exposed to moxidectin for periods of up to 72 h (Fischer, 1990 g,h). 2.2.8 Special studies on eye irritation Moderate signs of eye irritation were noted when moxidectin (0.1 g) was instilled into the conjunctival sac of New Zealand white rabbits. The irritation resolved 48-72 h after treatment (Fischer, 1990i). 2.2.9 Special studies on dermal sensitization No evidence of skin sensitization was seen when male Hartley guinea-pigs were exposed to moxidectin using the Buehler method. The positive control, 1-chloro-2,4-dinitrobenzene gave the expected positive response (Ventura, 1990). 2.2.10 Special studies on pharmacodynamic effects In a radioligand binding study, moxidectin stimulated the t-butyl-bicyclophosphorothionate binding to rat cortical membranes in a similar manner to ivermectin. In another study, the drug stimulated the binding of flunitrazepam to rat brain membranes. Such studies suggest that moxidectin has activity at the GABA-A receptor in a manner similar to ivermectin, and this may contribute to its mode of action against parasites. However, it is known that ivermectin has more than one mechanism of action and this is also likely to be true of moxidectin (Ingle & Wood, 1990). Moxidectin was investigated in a variety of screening tests for pharmacodynamic action. It had no CNS effects, nor any effects on motor activity, blood pressure, heart rate or respiration rate, and did not cause haemolysis of sheep red blood cells. It did induce weak contractions or relaxation of tracheal smooth muscle but these were not antihistamine or anticholine smooth muscle induced effects. It also increased GI motility in guinea-pig isolated ileum (Ingle, 1990). Table 2. Results of genotoxicity studies on moxidectin Test system Test object Concentration Results Reference Ames test1 S. typhimurium TA98, TA100, 50-300 µg/ neg. Traul 1990a TA1535, TA1537, plate TA1538 Reverse mutation E. coli 50-2000 µg/ neg. Traul 1990a assay1 WP2 uvrA- plate Forward mutation CHO (HGPRT locus) 0.01-15 µg/ml neg. Traul 1990b assay1 In vivo cytogenetics Rat bone marrow 0-150 mg/kg neg. Sharma 1990 assay bw UDS Primary rat 0.1-30 µg/ml neg. Curren 1990 hepatocytes 1 Both with and without rat liver S9 fraction. 3. COMMENTS The Committee considered data from pharmacodynamic, pharmacokinetic, metabolism, acute and short-term toxicity, carcinogenicity, genotoxicity, reproductive toxicity and teratogenicity studies. The pharmacokinetics and metabolism of moxidectin were studied in rats, sheep and cattle. After oral administration to sheep, about 20% of the dose was absorbed. The drug, which is very lipophilic, was found at high levels in fat, but at much lower levels in other tissues. It was excreted in the milk. After oral administration to rats, the major compound recovered in faeces was the parent drug, while small amounts of hydroxylated metabolites were found in liver and faeces. Hydroxylated metabolites were observed in sheep and cattle given oral doses of the drug. Orally administered moxidectin was found to be moderately toxic with LD50 values of the order of 50-100 mg/kg bw. In a 28-day oral toxicity study in mice in which moxidectin was administered in the feed, signs of toxicity included tremors and hypersensitivity to touch. All mice given the highest dose of 32 mg/kg bw/day died. The NOEL in this study was 6.9 mg/kg bw/day. Rats given up to 31 mg moxidectin/kg bw/day in a 28-day feeding study developed ataxia, tremors, salivation, piloerection and diuresis. At 23 mg/kg bw/day and above, dose-related diffuse atrophy of the liver, kidneys, heart, spleen, adrenals, testes, epididymis and ovaries was seen. A NOEL was not identified in this study because hypersensitivity to touch was noted in the lowest-dose group (12 mg/kg bw/day) at days 2 and 3. Similar findings were noted in a 13-week feeding study in rats, in which the NOEL was 3.9 mg/kg bw/day. In a 28-day toxicity study in dogs given up to 4 mg of moxidectin/kg bw/day in the feed, animals given the highest dose developed anorexia, ataxia, prostration and diarrhoea until the dose was reduced to 1.25 mg/kg bw/day. The NOEL was 0.5 mg/kg bw/day. In a 90-day feeding study in dogs, lacrimation, tremors, salivation and slight ataxia were noted in animals given the highest dose of 1.6 mg/kg bw/day. No major histopathological changes were observed in this study. The NOEL was 0.3 mg/kg bw/day. No signs of toxicity were noted in a 52-week feeding study in dogs. The NOEL was 1.15 mg/kg bw/day, the highest dose used. A pilot single-generation reproductive toxicity study was performed in rats, in which moxidectin was administered at doses of up to approximately 10 mg/kg bw/day for a 9-week period before mating and during gestation and lactation. None of the offspring of animals in the highest-dose group survived. Survival rates were decreased in the progeny of animals given lower doses, but there were no findings which could be attributed to effects on fertility. The NOEL in this study was 0.4 mg/kg bw/day. In a three-generation reproductive toxicity study in rats given doses of up to 0.83 mg/kg bw/day for a 70-day period before mating, there were no effects on mortality or on fertility except at the highest dose, where slight reductions in male body weights and significant reductions in pup survival were seen. The NOEL was 0.4 mg/kg bw/day. In a teratogenicity study in rats dosed at 10 or 12 mg moxidectin/kg bw/day, there was evidence of both materno- and fetotoxicity, as shown by increased incidences of cleft palate and wavy or incompletely ossified ribs. There was no evidence of teratogenic effects, and the NOEL in this study was 5 mg/kg bw/day. In a teratogenicity study in rabbits, there was evidence of materno- toxicity at 5 and 10 mg/kg bw/day, but no evidence of fetotoxicity or teratogenicity. The NOEL in this study, based on maternal effects, was 1 mg/kg bw/day. In a long-term toxicity/carcinogenicity study in CD-1 mice, moxidectin was administered in the diet at concentrations equal to 0, 2.5, 5.1 or 12 mg/kg bw/day for 2 years. After 9 weeks, the highest dose was reduced to 7.9 mg/kg bw/day because of toxic effects that included deaths, hunched posture, decreased activity, tremors and laboured breathing. There were no effects on haematological parameters and no increases in the incidence of any types of tumour were observed. The NOEL was 5.1 mg/kg bw/day. A 2-year toxicity/carcinogenicity study was conducted in Sprague-Dawley rats which were given moxidectin in the diet at concentrations equal to 0, 0.8, 3.2 or 9.8 mg/kg bw/day. After 8 weeks, the highest dose was reduced to 5.1 mg/kg bw/day because of signs of toxicity that included hunched posture, tremors, hyperactivity, urine-stained fur and hypersensitivity to external stimuli. At the end of the 2-year period there was no evidence of toxicity and no increased incidence of any type of tumour. The NOEL was 5.1 mg/kg bw/day. The Committee concluded that moxidectin has no carcinogenic potential. Moxidectin has been tested in bacterial mutation assays, in a forward mutation assay in Chinese hamster ovary cells, in a test for UDS in primary rat hepatocytes, and in an in vivo cytogenetic assay in rat bone marrow. All gave negative results, and the Committee concluded that moxidectin had no genotoxic potential. 4. EVALUATION The Committee concluded that the most relevant effects for the toxicological evaluation of moxidectin were those observed in the 90-day study in dogs, where the NOEL was 0.3 mg/kg bw/day. Based on this NOEL and using a safety factor of 200 to account for the uncertain sensitivity of the test system used to assess the neurotoxicity of moxidectin (Annex 1, reference 119, section 2.2), the Committee established an ADI of 0-2 µg/kg bw for moxidectin. The ADI was rounded to one significant figure, consistent with accepted rounding procedures (Annex 1, reference 91, section 2.7). This ADI provides an adequate margin of safety for the effects noted in the reproductive toxicity studies in rats. 5. REFERENCES Afzal J. (1991a). Moxidectin (CL 301, 423): Oral drench: Absorption, distribution, excretion and biotransformation of carbon-14 labelled CL 301, 423 in sheep. 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See Also: Toxicological Abbreviations MOXIDECTIN (JECFA Evaluation)