OXFENDAZOLE First Draft prepared by Dr. Radovan Fuchs Institute for Medical Research and Occupational Health, University of Zagreb, Yugoslavia 1. EXPLANATION Oxfendazole is an anthelmintic used for the treatment of gastrointestinal parasitism in cattle, sheep and horses. Oxfendazole has not been previously evaluated by the Joint FAOP/WHO Expert Committee on Food Additives. 2. BIOLOGICAL DATA 2.1 Biochemical aspects 2.1.1 Absorption, distribution and excretion Oxfendazole, fenbendazole and febantel are three metabolically related anthelmintics. Fenbendazole and oxfendazole are metabolically interconvertible, and febendazole is a prodrug of them both. Oxfendazole and fenbendazole both undergo further metabolic oxidation and carbamate hydrolysis. Using 14C-oxfendazole it was shown that systemic exposure to total drug equivalents is the same in rats and calves for equivalent doses. Systemic exposure in the rat occurs within 24 hours while in the feeder calf it occurs slowly over 168 hours (Tomlinson et al., 1986). Plasma concentration in rats as a function of time after oral administration of 3H-oxfendazole is the same as after intravenous administration, indicating complete absorption of the oral dose. Between 0-12 hours after intravenous injection of 6 mg/kg b.w. of 3H-oxfendazole to rats, the t´ of free extractable material in the plasma was 360 minutes. In the same experiment, t´ decreased to 160 minutes during the 12-24 hour interval. The apparent volume of distribution for the drug, based on chloroform extractable tritium, was estimated to be 85 ml/rat or 607 ml/kg b.w. (Tomlinson, 1974a). In rats, the plasma metabolite pool is composed of 29% oxfendazole, 71% sulfone analogue and 1% thioether analogue. In calves, although the metabolites are the same as those found in rats, the plasma metabolite pool consists of 20% oxfendazole, 46% sulfone analogue and 20% thioether analogue (Tomlinson et al., 1986). Oxfendazole is excreted in urine and faeces (Tomlinson, 1974a; Tomlinson et al., 1986). In rats, recovery of the dose after oral administration averaged 40-50% within 48 hours (Tomlinson, 1974a). In calves, 14-20% of the dose was recovered in urine, a considerably lesser amount, and much more was eliminated via faeces (Tomlinson et al., 1986). In rats, oxfendazole or its metabolites may be cycled through the enterohepatic path as many as four times before being eliminated from the body (Tomlinson, 1974a). Both in rats and in calves the major residue burden was located in the liver and major identifiable metabolites were the same (Matin et al., 1977). Of the residue present in liver, a significant portion cannot be extracted into organic solvents. At 0.5 hours and 24 hours post-14C-oxfendazole administration, 41% and 93% respectively of the residue was protein bound (Tomlinson et al., 1986). Studies in cattle have shown that besides liver, milk from treated animals (Tomlinson, 1977) contained oxfendazole, its thioether, its sulfone and protein bound materials (liver only). The same metabolites were found in the livers of treated sheep (Tomlinson, 1974b). A metabolic scheme may be found on page 23. 2.2 Toxicological studies 2.2.1 Acute studies Table 1. Acute studies on oxfendazole Species Sex Vehicle LD50 Reference (mg/kg b.w.) Mouse M&F distilled water > 6400 Hallesy, 1973 Rat M&F distilled water > 6400 Hallesy, 1973b Chester & Bidlack, 1987a Chester & Bidlack, 1987b Dog F gelatine capsule > 1600 Hallesy, 1973c Sheep F water > 250 Braemer & Bidlack, suspension 1976 Cattle M&F water purified > 112.5 Bidlack, 1977 The gastrointestinal tract and bone marrow were the primary organ systems affected by the drug. Clinical signs, pathologic changes, and in some cases mortality were seen in rats, dogs, sheep, and cattle treated with a single high dose of oxfendazole. 2.2.2 Short-term studies 2.2.2.1 Mice Groups composed of 10 male and 10 female Swiss Webster mice were fed diets containing 0, 25, 50, 100, or 200 ppm oxfendazole (equivalent to 0, 3.75, 7.5, 15, or 30 mg/kg b.w./day) for 3 months. No signs of toxicity were observed in any of the treated groups (Hallesey & Shott, 1984). Groups of Swiss Webster mice (5 animals/sex/dose) were fed diet containing oxfendazole at concentrations of 0, 5000, 10 000, or 50 000 ppm (equivalent to 0, 750, 3000, or 7 500 mg/kg b.w./day) for 1 month. Data concerning clinical observations, body weight gain, food intake, clinical pathology, gross pathology and histopathology were recorded. No clinical signs of drug-related toxicity were observed. Increase of SGOT and SGPT were observed in intermediate and high-dose females. A dose-related significant increase of the ratio of liver weight to body weight was found in all treated animals. Significant increase in liver weight compared to controls was observed in intermediate and high-dose animals only. The ratio of testes weight to body weight in males receiving 20 000 and 50 000 ppm of oxfendazole was significantly lower than that in controls. Histopathological observations included changes in testes of intermediate and high-dose groups. Those changes were described as mild to moderately severe hypospermatogenesis with desquamation of sperm precursors. Hepatocytic vacuolation was a common finding in all groups of animals, control group included (Hallesy & Bidlack, 1987a). An additional study on oxfendazole subchronic toxicity was conducted on Swiss Webster mice. Five groups of animals composed of 5 male and female mice were fed diets containing oxfendazole at concentrations of 0, 250, 500, 1000, or 2000 ppm (equivalent to 0, 37.5, 75, 150, or 300 mg/kg b.w./day) for 3 months. During the study there were no clinical signs of toxicity. Body weight and food intake were not affected by the treatment. Changes attributed to treatment consisted of increased liver weight in males and females receiving 1000 or 2000 ppm and in female mice receiving 500 ppm oxfendazole in diet. Histopathologically, hepatocytic vacuolation was seen in all mice including controls, although the vacuolation was more severe in male mice fed diets containing 500, 1000, or 2000 ppm of the drug. Male animals from the highest group dose had testicular changes described as hypospermatogenesis with sloughing of sperm precursors (Hallesy & Bidlack, 1987b). 2.2.2.2 Rats Groups of 5 male and female Sprague-Dawley (COX-SD) rats were given doses of 0, 5, 20, 80, or 160 mg/kg b.w./day oxfendazole by gavage for 14 consecutive days. The test material was homogenized in 2% aqueous starch. Reduction in body weight was observed in animals dosed at 160 mg/kg b.w./day during the first week of treatment, but at the end of the observation period (28 days) the animals showed normal weights compared to the controls and other groups. Four out of 5 females of the 160 mg/kg b.w./day group were found dead at times up to and including the 14th day of the study. At the 80 and 160 mg/kg b.w./day doses, neutrophil counts were depressed during dosing, but at the end of the 2-week recovery period the neutrophil levels of the surviving rats had returned to normal values. Pathology was not performed on all of the animals in this study and the cause of death was not ascertained in every rat necropsied (Hallesy et al., 1976a). Groups of Sprague-Dawley (COX-SD) rats (6 animals/sex/group) were given doses of 0, 11, 33, or 100 mg/kg b.w./day oxfendazole by gavage for 14 consecutive days. During the dosing period 4 out of 12 from the high-dose group died. Decreased weight gain was seen in females of the intermediate-dose group and in males and females from the high-dose group. Haematology and clinical chemistry were studied after 2 weeks of treatment. Decreased haemoglobin and haematocrit levels in females given 100 mg/kg b.w./day, and decreased numbers of neutrophils in females given 33 or 100 mg/kg b.w./day and in males given 100 mg/kg b.w./day were seen. No changes in clinical chemistry values in treated rats were observed when compared to controls. Decreased terminal body weight for high-dose rats, decrease in splenic and testicular weight and increased liver weight for intermediate-dose and high-dose rats were noted. Numerous gross alterations were noted, which included thymic atrophy, pronounced hepatic pallor, increased alimentary tract fluids and red-brown foci in the glandular stomach. Histopathologically, lymphoid atrophy and inhibition of maturation of bone marrow myeloid and erythroid elements in intermediate and high-dose rats were observed. Inhibition of spermatogenesis and inflammatory lesions in lungs of high-dose animals were also seen. Hepatocytic vacuolation was observed in some animals of all dose groups (Hallesy et al., 1977b). In a 3-month study oxfendazole incorporated into the diet at 0, 200, 600, and 2000 ppm was given to Long-Evans rats (15 rats/sex/dose level). Thirteen rats out of 30 died by the end of the first week of dosing due to toxic effects. This group was terminated and an additional two groups receiving 50 and 100 ppm of oxfendazole in the diet (10 rats/sex/dose level) were placed on test. The approximate daily intakes of oxfendazole over the period of the study were 0, 3.8, 7.3, 16.5, and 53.8 mg/kg b.w./day for males and 0, 3.8, 7.7, 17.2, and 49.9 mg/kg b.w./day for females. By the end of the study, 24 out of 30 rats receiving 600 ppm of oxfendazole in feed died. In this group perioral and mandibular alopecia with encrustation, priapism, and enlarged clitoris were observed. Elevation of SGPT and SAP levels was observed in the 600 ppm group. SAP was slightly elevated in both sexes of the 200 ppm group and in females of the 100 ppm group. Hepatocytic hypertrophy, vacuolation and hepatocytic necrosis were seen in the 600 ppm group. Other pathological changes consisted of testicular atrophy, splenic necrosis or atrophy, abscesses and bone marrow hyperplasia or diffuse atrophy. In the 200 ppm group only slight hepatocytic hypertrophy was observed. In the 100 and 50 ppm groups no microscopic changes related to treatment were observed (Killeen & Rapp, 1974a). 2.2.2.3 Dogs Groups of 2 male and female beagle dogs were given 0, 11, 33, or 100 mg/kg b.w./day oxfendazole by gavage for 2 weeks. A slight decrease in body weight was observed in male dogs given 33 mg/kg b.w./day and in male and female dogs from the 100 mg/kg b.w./day group. None of the haematological or plasma chemistry parameters was affected by the treatment. No meaningful changes were seen in urinalysis values after 2 weeks of dosing. Histological changes attributed to oxfendazole treatment were seen in dogs from all treated groups; reduced myeloid maturation was seen in bone marrow. Reduction of splenic lymphoid tissue and thymic atrophy were seen in males but not in females (Hallesy et al., 1976b). In a second 2-week study on beagle dogs groups of 4 males and females were given oxfendazole at doses of 0, 3, 6, and 11 mg/kg b.w./day by gavage. No drug-related effects were seen in the animals killed after the dosing period (half) or in remaining dogs observed for 3 weeks after dosing. In this study a different suspension formulation of oxfendazole was used than that used in the previous study (Hallesy et al., 1977a). Groups of 3 male and female beagle dogs were given 0, 1.5, 3.0, and 6.0 mg/kg b.w./day of oxfendazole orally in hard shell gelatin capsules for 3 months. No changes related to oxfendazole treatment were observed in body weight, gross pathology, or histopathology in any of the groups at the end of the study when the dogs were killed (Killeen & Rapp, 1974b). 2.2.2.4 Cattle Hereford heifers and bulls from 6 to 8 months old were used in the study. Groups consisting of 3 male and female animals were used. Oxfendazole was injected intraruminally at doses of 0, 4.5, 13.5, 22.5, and 112 mg/kg b.w. Oxfendazole was prepared as a 22.5% drug suspension. The highest dose (112 mg/kg b.w., corresponding to 25 times intended field use level) was given as a single dose, whereas the other dose groups were treated 3 times over an 8-day period. Body weights, haematological and clinical chemistry values were not altered by the treatment. No treatment-related gross or microscopic pathological changes were observed. In only one male and one female animal digestive disturbances described clinically as non-productive eructation were seen in the highest dose group. The inflammatory reactions noted at the injection site in all groups, including control, were attributed to contaminants introduced during intraruminal injections (Glock et al., 1987). 2.2.3 Long-term/carcinogenicity studies 2.2.3.1 Mice Fifty CD-1 mice of each sex were randomly assigned to each of three treatment groups. Oxfendazole was administered in the diet at concentrations of 100, 300, or 1000 ppm, which was equivalent to dose levels of 15, 45, or 150 mg/kg b.w./day respectively. A control group of 100 animals of each sex received the same diet without oxfendazole. An additional 10 mice of each sex per group were included for haematological evaluation. The animals were treated for 78 weeks. Clinical observations and presence of palpable masses were recorded weekly, while body weight and food intake were recorded weekly for the first 4 months and monthly thereafter. Blood samples for haematological evaluation were obtained during the 6th and 12th months of treatment from the designated animals. A complete necropsy and histopathological examination was performed at study termination. No treatment-related effects were noted on clinical condition or survival. Mean body weights for treated males were often lower than those for controls during the first year of the study. High-dose females had significantly higher body weights than controls during the first year. Food intake was higher for all treated groups during the first year. No biologically significant haematological effects were noted. A slightly higher proportion of high-dose males had malignant neoplasms compared to controls. This included a higher incidence of broncho-alveolar and hepatocellular carcinomas. However, the difference was not statistically significant. In females the proportion of high-dose animals with either benign or malignant neoplasms was slightly higher than in the control group, but the difference was not statistically significant. Increased incidences of hepatocytic hypertrophy and hepatocytic vacuolation were observed in high-dose animals. Results were highly significant for hepatocytic hypertrophy in males and hepatocytic lipid vacuolation in females. The incidence of focal hepatocytic necrosis was also slightly greater in high-dose mice compared to controls. No other histopathological changes attributed to oxfendazole were observed. The NOEL was 300 ppm, equivalent to 45 mg/kg b.w./day (DePass & Bidlack, 1987c). 2.2.3.2 Rats Four groups consisting of 25 male and female Sprague-Dawley weanling rats were fed diets containing 0, 10, 30, or 100 ppm oxfendazole for one year. The daily intake of the drug over the studied period was equal to 0.65, 2.0, and 6.6 mg/kg b.w./day for males and 0.76, 2.4, and 7.8 mg/kg b.w./day for females, respectively. Body weight and food intake were measured weekly for the first 13 weeks, and monthly thereafter. Clinical observations and tissue masses were recorded at least weekly. Blood samples for haematology and serum chemistry evaluations were collected from an untreated group of 10 males and 10 females prior to the start of the study and from 10 designated males and females from each of the 4 groups at 4 intervals during the study. Eye examinations were performed on each animal prior to the first dose and during study in the 3rd, 6th, 9th and 12th months. Animals that were found dead, in moribund condition, or killed at study termination received complete necropsy examinations. No drug effect was noted on clinical or ophthalmological condition or on food intake. Increased body weight gain was observed in the high-dose female group during the first 6 months. In both sexes a drug-related increase in BUN was seen. Treatment-related increase in SAP was also observed in treated animals of both sexes. Changes in creatinine, GOT, cholesterol, triglyceride measurements, and several haematological parameters were observed several times during the study. Those changes were not considered to be of biological importance since their occurrence was inconsistent in respect to dose levels, time interval and the sex of the animals. The liver weight of high-dose animals was significantly higher compared to other groups and in males a slight reduction of accessory sex organs in high-dose animals was observed. Histopathological changes were seen in the livers of intermediate- and high-dose animals and are described as discoloration and centrilobular hepatocytic lipid vacuolation. Those changes, although present in all treated animals when compared to control animals, were not outside the range of physiological values and historical data of the laboratory. The NOEL in this study was 10 ppm, equal to 0.65 and 0.76 mg/kg b.w./day in males and females, respectively (DePass & Bidlack, 1987a). Groups of 50 Sprague-Dawley rats of each sex were fed oxfendazole-containing diet for at least 105 weeks (2 years). Drug concentration in food was 10, 30, or 100 ppm. A control group of 100 animals of each sex received the same diet without oxfendazole. Drug intake was calculated to be, on average, 0.7, 2, or 7 mg/kg b.w./day for males and 0.9, 2.5, or 8.8 mg/kg b.w./day for females. A statistically significant decrease in body weight in response to increasing dose was noted at several intervals, mostly during the early part of the study. At some intervals, the treated males appeared to have higher intake of food than the controls. However, these observations seemed to be biologically insignificant. Tissue masses were noted across all treatment groups. Approximately 40% of the control and low-dose females had masses. Intermediate and high-dose females had approximate tissue mass incidences of 35% and 25%, respectively. In males, there was a 10% incidence in the control and intermediate-dose and 6% incidence in the high-dose. There was no treatment-related mortality and the survival times were not significantly different among the groups, including controls. There were no treatment-related effects on clinical conditions or haematology. Oxfendazole at concentrations of up to 100 ppm daily for 105 weeks did not offer biological or statistical evidence of an increased incidence of neoplasms. Hepatocellular lipid vacuolation was present in the livers of intermediate and high-dose animals and was found to be dose-related. The NOEL in this study was 0.7 mg/kg b.w./day in males and 0.9 mg/kg b.w./day in females (DePass & Bidlack, 1987e). 2.2.3.3 Dogs Four groups composed of 5 male and female beagle dogs were given 0, 1.5, 4.5, and 13.5 mg/kg b.w./day oxfendazole daily for one year. A suspension of the drug was administered orally at a dose volume of 0.1 ml/kg b.w.. Eye examinations, haematology and serum chemistry assessments were conducted prior to the first dose and during the study during the 3rd, 6th, 9th, and 12th months of dosing. There were no toxic signs or effects on food intake, body weight, clinical condition, ophthalmological parameters or serum chemistry. Decreasing trends were observed for erythrocyte count, haemoglobin, and haematocrit measurements for male dogs at all time intervals, but the values were within the physiological range. After 12 months of dosing, the animals were killed for pathological examination. Liver weight to body weight ratios showed a statistically significant increase in response to increasing dose in the four groups, but absolute liver weights only slightly exceeded those of the control animals. No other gross or microscopic changes which might be related to treatment were observed. The NOEL in this study was 13.5 mg/kg b.w./day (DePass & Bidlack, 1987b). 2.2.4 Reproduction studies 2.2.4.1 Rats In a 2-generation study, 30 Sprague-Dawley rats/sex/dose were given oxfendazole incorporated into feed. The concentration of the test substance in the diet was 0, 10, 30, or 100 ppm. The females received the drug 2 weeks prior to cohabitation with treated males and until the end of the breeding period. Drug intake was calculated to be in a range of 0.9-1.0, 2.8-3.1, and 2.8-10.4 mg/kg b.w./day respectively. No drug effect was noted on the clinical condition, mean body weight or average daily food intake of treated rats. No drug effect was noted for incidence of pregnancy, length of gestation, live litter size or gestation index. The changes attributed to oxfendazole treatment consisted of increased mean liver weight and liver weight to body weight ratios, liver pallor and increased incidence of hepatocytic vacuolation in high-dose females. High pup mortality from postpartum days 7 to 14 was noticed in all dose groups of the F1 generation including controls. Male F1 pups born to high-dose dams weighed less at first observation and had a decreased rate of growth compared to male pups from control dams. No treatment-related anomalies were seen. Pups from intermediate- and high-dose litters had liver changes similar to those found in their parents. No drug-related effects were noted on live litter size or survival index for second generation litters. However, the proportion of pregnancies in high-dose dams was significantly lower than in controls. Liver changes as previously described were noted in intermediate- and high-dose parents of the second generation. Initial second generation pup weights were lower for intermediate and high-dose litters. No gross or microscopic changes were noted in second generation offspring. The NOEL for this study was 10 ppm, equal to 0.9 mg/kg b.w./day (DePass & Bidlack, 1987d). 2.2.4.2 Cattle Three groups consisting of 33 mixed-breed first calf heifers were estrus-synchronised using fenprostalene and were intraruminally treated with oxfendazole. The drug was administered prior to artificial insemination, at weekly intervals from day 14 through day 42 of gestation and at approximately 60-day intervals to the end of gestation. The dose levels applied were 0, 4.5, and 13.5 mg/kg b.w./day. Heifers which did not become pregnant were naturally bred at subsequent estrus periods. Conception rates, length of gestation, time to become pregnant, service period and weight gains of heifers during gestation and lactation were unaffected by oxfendazole treatment. During the study 1 low-dose and 1 high-dose dam, and 2 high-dose calves died. Pathological changes in those cases suggested that the deaths were not associated with oxfendazole treatment. Oxfendazole did not cause anatomic abnormalities, decreased birth weight or changes in average daily weight gain in calves. The NOEL in this study was 13.5 mg/kg b.w./day (Miller et al., 1987). 2.2.5 Special studies on genotoxicity (see also Section 2.2.7 in fenbendazole monograph and 2.2.5.1 in the febantel monograph) Table 2. Genotoxicity studies on oxfendazole Test system Test object Concentration Result Reference Ames test1 S.typhimurium 0.5-5000 µg/ml Negative Mourot, 1990 TA97a, TA98, TA100, TA102 1. With and without S9 2.2.6 Special studies on eye and skin irritation 2.2.6.1 Rabbits Groups of 6 male New Zealand white rabbits had 100 mg oxfendazole powder instilled into the conjunctival sac of the left eye. There were no signs of irritation at any time during observation (Hallesy & Hill, 1977). In a separate study, oxfendazole as a 2.265% w/v aqueous suspension was applied into the conjunctival sac of 5 New Zealand white and 1 Californian rabbit (6 animals) at a dose of 0.1 ml. No irritation or corneal damage was seen in any of the animals (Reynolds & James, 1977). The oxfendazole formulation was applied to intact and abraded skin of 6 New Zealand white rabbits. The test sites were occluded for 4 hours. After removal of dressings test sites were scored for erythema and oedema. Twenty-four and 48 hours after washing the scoring was repeated. No evidence of erythema or oedema was seen in any of the rabbits (Hallesy & Hill, 1976). 2.2.6.2 Guinea-pigs Female Hartley albino guinea-pigs were used in a dermal sensitization study. The test was performed on 3 groups of animals: a positive control group (2,4-dinitrofluorobenzene), a vehicle control group and an oxfendazole-treated group, consisting of 20 animals each. It was found that neither vehicle nor oxfendazole produced contact sensitization in guinea-pigs (Hallesy & Hill, 1978). In a separate study, oxfendazole produced no sensitizing effects and no primary irritation when tested on Dunkin-Hartley guinea-pigs. In this study dinitrochlorobenzene was used as a positive control (Harper & James, 1977). 2.2.7 Special studies on teratogenicity (see also Section 2.2.5 of the monograph on Fenbendazole) 2.2.7.1 Mice Groups of 25 mated female Swiss Webster (COX.SW) mice were fed powdered diet containing concentrations of 0, 200, 600, or 2000 ppm oxfendazole corresponding to 0, 34, 108, or 360 mg/kg b.w./day. The animals were exposed to the drug from gestation day 6 through day 15 and the females were killed on gestation day 18. Food intake was not affected among the groups during the treatment, although the body weight gains for high-dose mice were less than those for other groups. The diet containing 2000 ppm was found to be fetotoxic for mice. In this group decreased litter size, average fetal weight, and mean gestation survival index were observed. Viable fetuses from this group were found only in 2 out of 22 pregnancies, and most of the fetuses had been resorbed, resulting in an increase of the mean resorption index (p 0.01). Because of the small number of fetuses available (3 alive and 1 dead) the interpretation of probable teratogenic effects was not possible. The maternal parameters were comparable between the control and low-dose or intermediate-dose groups. Various external, skeletal, and visceral changes were observed in fetuses from the control, low- and intermediate-dose groups. Among the abnormalities, only the incidence of pelvic cavitation was increased in low- and intermediate-dose groups compared to controls. The incidence was found to be 8% in treated animals and 0% among the controls. Since similar changes with an incidence of 6 to 7% occur in untreated mice as well (Palmer, 1972), those changes are not of reliable importance. The NOEL in this study was 600 ppm, corresponding to 108 mg/kg b.w./day (Hallesy et al., 1974a). 2.2.7.2 Rats Groups of 25 mated female Sprague-Dawley rats were given oxfendazole by gavage daily at doses of 0, 10, 20, or 60 mg/kg b.w./day. The treatment lasted from the 6th to 15th days of pregnancy. On the 20th day of gestation, the females were killed. Evidence of fetotoxicity characterized by decreased litter size and fetal weight, a high incidence of total litter resorption, as well as an increased resorption index and a higher percentage of male fetuses were seen in the group receiving 60 mg/kg b.w./day. Maternal parameters for the 10 and 20 mg/kg b.w./day groups were comparable to the control animals. Fetal changes were observed in the 20 and 60 mg/kg b.w./day groups and were typical of those produced by delayed development and included delayed maturation of ossification centres. The NOEL in this study was 10 mg/kg b.w./day (Hallesy et al., 1974b). The potential embryotoxicity of oxfendazole, the principal metabolite of fenbendazole, was evaluated in Wistar rats. Sexually mature virgin female Wistar rats were mated with fertile males, to provide 4 groups of 20 pregnant animals. Dams were evaluated for presence of sperm and the day on which sperm was detected was designated gestation day one. Dams in these groups received doses of 0, 5, 6, 7.5, 10, 15, or 20 mg/kg b.w./day oxfendazole via stomach tube in a 2% starch mucilage vehicle at the rate of 10 ml/kg b.w./day on gestation days 7-16. Rats were observed daily, and weighed weekly. Doses were based on the most recent body weight. Food intake was monitored continuously. All dams were sacrificed on gestation day 21 and fetuses were delivered by caesarean section. Each dam received a gross necropsy and organs were weighed. The uterus was opened and number and placement of live and dead fetuses and resorptions were determined. Implantation sites and corpora lutea were counted. The fetuses from the control, 7.5, and 10 mg/kg b.w./day groups were examined externally for abnormalities and then about 50% were processed for Alizarin red staining to evaluate skeletal abnormalities and the remainder were processed with Bouin's solution for evaluation of soft tissue abnormalities. No treatment-related effects were observed in the dams. A significant increase in resorptions, and decrease in live fetuses as well as a reduction in fetal weight was reported for the 20 mg/kg treatment group. Examination of the control, 7.5, and 10 mg/kg fetuses revealed no treatment-related malformations (Kramer & Baeder, 1973). The teratogenicity of a series of oxfendazole metabolites and the parent were evaluated using the rat. Only the parent was found to have teratogenic activity at a dose of 21 mg/kg (Delatour et al., 1982b). In the literature, oxfendazole was reported to produce teratogenic activity when administered orally to rats from day 8 through day 15 of gestation at 15.75 mg/kg b.w./day or on days 12 and 13 at 31.5 mg/kg b.w./day. Increased incidences of external and skeletal abnormalities were reported accompanied by substantial embryolethality (12-39%) (Delatour et al., 1977, 1981, 1984). 2.2.7.3 Rabbits Groups of 15 inseminated New Zealand white rabbits were dosed orally with 0, 0.025, 0.125, or 0.625 mg/kg b.w./day of oxfendazole from days 6 to 18 of pregnancy. The animals were killed on day 29 of gestation. There was no overt maternal toxicity nor any effect on litter size, fetal weight, resorption, corpora lutea, gestation survival index, resorption index or implantation index. Minor changes including abnormal carpal and tarsal flexion and low incidence of gall bladder hypoplasia or aplasia were seen in fetuses from treated animals. Although greater numbers of high-dose fetuses had minor skeletal variations, the incidence of those changes was not significantly different from that of the controls. Based upon the historical control data and current controls those changes were considered to be spontaneous and not relevant to oxfendazole treatment. The NOEL was 0.625 mg/kg b.w./day (Thunen et al., 1981). 2.2.7.4 Sheep Groups of 27-29 estrus-synchronized ewes were treated orally with oxfendazole on the 12th, 17th or 23rd day of gestation. Two dose levels were used: 7.5 and 22.5 mg/kg b.w. Double control groups (water and vehicle) consisting of 12-14 animals were included in the study. Altogether 248 ewes were used in the experiment. About 24 hours after the first spontaneous deliveries each ewe was given an intramuscular injection of dexamethasone. All the lambs that died were submitted to autopsies, while the animals which reached a commercial weight were examined at the slaughterhouse. It was found that oxfendazole administered to pregnant ewes on the 12th or 23rd day was not related to embryotoxic properties regardless of the dose applied. On the other hand the birth rate was significantly lower in the group which received 22.5 mg/kg b.w. of the drug at gestation day 17. Weight of lambs was comparable among all the groups. Clear evidence of teratogenic activity of oxfendazole was seen in the group which was treated with 22.5 mg/kg b.w. on day 17 of gestation. Malformations were seen on backbone, ribs, face and organs. No effects were observed in animals which received 7.5 mg/kg b.w. at any time. The NOEL in this study was 7.5 mg/kg b.w. (Delatour, 1976). In a field study using 5 merino ewes, oxfendazole was given to the animals on day 17 of gestation in a single oral dose of 10 mg/kg b.w. No adverse effects were observed in lambs in this study. The NOEL was 10 mg/kg b.w. (Lloyd, 1978). Groups of pregnant Clun-Forest ewes were given a single oral dose of oxfendazole formulated as 2.265% w/v aqueous suspension. Eight animals per group received the drug on day 14, 17, or 20 of gestation at a dose of 10 or 15 mg/kg b.w. The control group did not receive treatment. There were no differences associated with oxfendazole treatment between the dosed groups and the controls. Clinical and autopsy examination revealed no oxfendazole-associated abnormalities among the lambs. The NOEL in this study was 15 mg/kg b.w. (Piercy et al., 1977). 2.2.7.5 Pigs In a field study, oxfendazole was given orally to sows during pregnancy 4 times at 7-day intervals. A control group consisting of 12 animals did not receive any treatment, while 18 animals were treated with oxfendazole at a dose of 4.5 mg/kg b.w./day and 18 animals received 13.5 mg/kg b.w./day between the 12th and the 37th days of pregnancy. No clinical signs of toxicity in the pregnant sows were observed and there were no drug-related anatomical or behavioural abnormalities in the newborn pigs. The NOEL was 13.5 mg/kg b.w./day (Morgan, 1982). 2.2.7.6 Cattle Groups of 15 Hereford-Angus heifers were dosed orally with 13.6 mg/kg b.w. of oxfendazole prepared as 2.265% w/v aqueous suspension. The drug was administered on days 11, 15, 19, 23, 27, 31, 35, and 39 of gestation. Control animals received a placebo preparation at the same time intervals. No signs of clinical toxicity were seen after dosing in either group of animals. All heifers were killed between day 79 and day 104 of gestation and fetuses were examined. No gross abnormalities were found in any of the fetuses and there were no significant differences in fetal weight or length among the groups. No anatomical abnormalities were found in any fetus. The NOEL was 13.6 mg/kg b.w. (Piercy et al., 1978b). In a separate study 12 pregnant Hereford-Angus heifers were treated with oxfendazole as described in the previous study. No sign of anatomical abnormality related to oxfendazole treatment was found. The NOEL was 13.6 mg/kg b.w. (Piercy et al., 1978a). 2.2.7.7 Horses A group of 15 mares was bred with stallions which received single oral doses of 20 mg/kg b.w. of oxfendazole. On day 26 following breeding the mares received a suspension of oxfendazole orally at a dose of 20 mg/kg b.w. Pregnant mares were re-treated with the same dose on days 180 and 280 of gestation. Two out of 15 mares required rebreeding at a second heat period. All mares maintained pregnancy and delivered healthy foals free of any teratologic effects (Herschler et al., 1979). 2.2.8 Special studies on mode of action of benzimidazoles In vitro turbidimetric techniques and competitive colchicine-binding studies demonstrated the inhibitory power of benzimidazoles on the polymerization of tubulin into microtubules. The difference in the sensitivity of host and parasites to the effects of benzimidazoles may be due to difference in the structure of microtubules in their cells (Davis & Gull, 1983). However, the selective toxicity of those compounds for parasites is not absolute, since the toxic effects are observed in mammals as well and are for the most part antimitotic (reviewed in McKellar & Scott, 1990). The differences in efficiency between members of this class of drugs against groups of parasites probably reflects differences in bioavailability of the drugs within the host animal. 2.3 Observations in man No information available. 3. COMMENTS The results of toxicological studies, including pharmacokinetic studies on rats, cattle, and sheep; carcinogenicity studies on mice and rats; mutagenicity, embryotoxicity, and teratogenicity studies on mice, rats, rabbits, sheep, cattle, pigs, and horses; studies on eye and skin irritation in rabbits and guinea pigs; reproduction studies on rats; and short-term and long-term studies on mice, rats, and dogs, were considered by the Committee. Pharmacokinetic data have demonstrated very good absorption of orally administered oxfendazole (100% in rats, 77% in cattle, and 85% in sheep). The results showed that, after administration of the drug, the plasma metabolite pool was composed of oxfendazole, oxfendazole sulfone, and fenbendazole. There was very little difference between the various animal species, apart from quantitative differences in the plasma metabolite pool. Oxfendazole is excreted in urine and faeces. The compound and its metabolites can undergo enterohepatic circulation. The genotoxic potential of the compound was tested in an Ames test using only four strains of Salmonella typhimurium; this gave negative results both with and without metabolic activation. Carcinogenicity studies were performed in mice and rats. Mice received a diet containing oxfendazole in doses up to 1000 mg/kg over a period of 78 weeks. Except for hepatocytic lipid vacuolation, no effects related to oxfendazole treatment were observed. The NOEL for this study was 300 mg/kg in the diet, equivalent to 45 mg/kg b.w./day. In the rat carcinogenicity study, animals received oxfendazole in the diet at concentrations of up to 100 mg/kg for 2 years. The only dose-related effect was seen in animals receiving 30 and 100 mg/kg, which showed hepatocellular lipid vacuolation; this was the earliest sign of compound-related effects seen in the liver in this study. The NOEL was 10 mg/kg in the diet, equal to 0.7 mg/kg b.w./day in males and 0.9 mg/kg b.w./day in females. The Committee noted that two different strains of mice were used in the range-finding and carcinogenicity studies. It was concluded, however, that this difference was not of great significance since Swiss mice were used in both studies. There was no evidence of any carcinogenic effect in rats. However, the Committee was of the opinion, based on the range-finding 90-day study in rats, that higher doses could have been used. In a two-generation reproduction study in rats in which oxfendazole was administered in the diet, no effect was observed on mating behaviour or fertility, maternal behaviour, length of gestation, live litter size, gestation index (number of fetuses/female), or survival of offspring. However, the proportion of pregnancies in the second-generation females receiving 100 mg/kg was significantly lower than in controls. The NOEL in this study was 10 mg/kg in the diet, equal to 0.9 mg/kg b.w./day. Oxfendazole did not produce irritation when tested in the rabbit eye or skin, or sensitization effects in guinea pig skin. The Committee considered data from embryotoxicity and teratogenicity studies of oxfendazole conducted on mice, rats, rabbits, sheep, cattle, pigs, and horses. A dose of 360 mg/kg b.w./day was fetotoxic in mice. The NOEL in mice was 108 mg/kg b.w./day. Results were reported from three teratogenicity studies in sheep given doses of oxfendazole ranging from 7.5 to 22.5 mg/kg b.w. on days 12, 14, 17, 20, or 23 of gestation. The sheep fetus was most susceptible to the induction of teratogenic effects on day 17, when the NOELs ranged from 7.5 to 15 mg/kg b.w. A teratogenicity study was performed in New Zealand rabbits at doses up to 0.625 mg/kg b.w./day administered on days 6-18 of gestation. No signs of maternal toxicity or effects on reproduction indices were reported. A number of minor soft tissue and skeletal changes were seen in fetuses from treated animals, but these were thought not to be treatment related, and the study gave a NOEL of 0.625 mg/kg b.w./day. While the Committee recognized that rabbits may be relatively sensitive to benzimidazole-related toxic effects, it believed that the doses used in this study were not high enough to enable the teratogenic potential of oxfendazole in the rabbit to be adequately explored. 4. EVALUATION A temporary ADI of 0-4 µg/kg b.w. was established for oxfendazole, based on a NOEL of 0.7 mg/kg b.w./day from the carcinogenicity study in rats and the use of a safety factor of 200. The Committee noted that if the NOEL for teratogenicity in sheep had been used as the basis for establishing the temporary ADI together with a safety factor of 2000, the value obtained would have been of the same order as that derived from the carcinogenicity study in rats. A temporary ADI was established because of concern that sufficiently high doses had not been used in the carcinogenicity study in rats and the teratogenicity study in rabbits and the lack of genotoxicity data. 5. REFERENCES BIDLACK, D.E. (1977) Clinical safety of oxfendazole (RS-8858) suspension in cattle when administered at 50X recommended field dose. Unpublished report from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. BRAEMER, A.C. & BIDLACK, D.E. (1976) Clinical safety of oxfendazole (RS 8858) suspension in sheep when administered at 50 times recommended field dose. Unpublished report from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. CHESTER, A.E. & BIDLACK, D.E. (1987a) Acute oral toxicity of oxfendazole (RS-8858-827) in the rat. Unpublished report from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. CHESTER, A.E. & BIDLACK, D.E. (1987b) Acute oral toxicity of oxfendazole (RS-8858-827) in the rat. Unpublished report from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. DAVIS, C. & GULL, K. (1983) Protofilament number in microtubules in cells of two parasitic nematodes. J. Parasitol., 69: 1094-1099. DELATOUR, P. (1976) Study of the effects of oxfendazole (RS-8858) on the embryonic development in sheep. Unpublished report No. VC0051 from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. DELATOUR, P., DEBROYE, J., LORGUE, G. & COURTOT, D. (1977) Experimental embryotoxicity of oxfendazole in the rat and the sheep. Rec. Med. Vet., 153: 639-645. DELATOUR, P., GARNIER, F., BENOIT, E. & LONGIN, Ch. (1984) A correlation of toxicity of albendazole and oxfendazole with their free metabolites and bound residues. J. Vet. Pharmacol. Therap., 7: 139-145. DELATOUR, P., YOSHIMURA, H., GARNIER, F. & BENOIT, E. (1982) Comparative embryotoxicity of metabolites of oxfendazole. Rec. Med. Vet., 158: 369-373. DePASS, L.R. & BIDLACK, D.E. (1987a) Chronic (1 year) feeding study in rats with oxfendazole (RS-8858). Unpublished report No. 101-R-84-8858-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. DePASS, L.R. & BIDLACK, D.E. (1987b) Chronic (1 year) feeding study in dogs with oxfendazole (RS-8858). Unpublished report No. 18-D-84-8856-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. DePASS, L.R. & BIDLACK, D.E. (1987c) Carcinogenicity study in mice with RS-8858 (oxfendazole) mixed in feed. Unpublished report No. 66-M-84-8858-PO-CA from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. DePASS, L.R. & BIDLACK, D.E. (1987d) Multigeneration reproductive study of oxfendazole (RS-8858) in rats. Unpublished report No. 83-R-84-8858-RO-RMF from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. DePASS, L.R. & BIDLACK, D.E. (1987e) Carcinogenicity study in rats with RS-8858 (oxfendazole) mixed in the feed. Unpublished report No. 53-R-83-8858-PO-CA from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. GLOCK, R.D., BIDLACK, D.E. & DePASS, L.R. (1987) Intraruminal safety study in cattle with oxfendazole (RS-8858). Unpublished report No. 42-CW-85-8858-IR-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. (1973a) Acute oral LD50 study in mice of RS 8858. Unpublished report No. 185-M-73-8858-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. (1973b) Acute oral LD50 study in mice of RS 8858. Unpublished report No. 186-D-73-8858-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. (1973b) Acute oral investigation of RS 8858 in beagle dogs. Unpublished report No. 189-D-73-8858-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. & BIDLACK, D.E. (1987a) One-month oral dosing study of oxfendazole (RS 8858) in mice (range-finding). Unpublished report No. 31-M-84-8858-PO-TXR from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. & BIDLACK, D.E. (1987b) Three-month oral dosing study of oxfendazole (RS 8858) in mice (range-finding). Unpublished report No. 162-M-83-8858-PO-TXR from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. & HILL, R. (1976) Primary dermal irritation test of RS 8858. (oxfendazole formulation) using rabbits. Unpublished report No. 70-B-76-8858-SK-LL from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. & HILL, R. (1977) Eye irritation study in rabbits with RS 8858. Unpublished report No. 19-B-77-8858-EY-LL from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. & HILL, R. (1978) Dermal sensitization study in guinea pigs with an oxfendazole (RS 8858) formulation. Unpublished report No. 46-6-77-8858-SK-SZ from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W. & SHOTT, L.D. (1984) Three-month oral dosing study of oxfendazole (RS 8858) in mice (range-finding). Unpublished report No. 59-M-83-8858-PO-TXR from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W., SHOTT, L.D. & HILL, R. (1974a) Teratology study with RS 8858 using mice. Unpublished report No. 247-M-73-8858-PO-TT from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W., SHOTT, L.D. & HILL, R. (1974b) Teratology study with RS 8858 using rats. Unpublished report No. 248-R-73-8858-PO-TT from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W., SHOTT, L.D. & HILL, R. (1976a) Comparison of the effect of repeated oral doses of RS 8858 or mebendazole on the hematology of the rat. Unpublished report No. 30-R-76-8858/Mebendazole-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W., SHOTT, L.D. & HILL, R. (1976b) Two-week oral toxicity study with RS 8858 (oxfendazole) formulation using dog. Unpublished report No. 39-D-75-8858-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W., SHOTT, L.D., BASSLER, S.A. & HILL, R. (1977a) Sub-acute (14 day) oral dosing study in dogs with RS 8858 (oxfendazole) with a 21-day recovery phase. Unpublished report No. 97-D-76-8858-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HALLESY, D.W., SHOTT, L.D. & HILL, R. (1977b) Two-week oral toxicity study with RS 8858 (oxfendazole) formulation using rats. Unpublished report No. 38-R-75-8858-PO-TX from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HARPER, D.W. & JAMES, J.A. (1977) Guinea pig sensitization study with oxfendazole using the "Maximisation" test method. Unpublished report No. HHPG 77-2 from Wellcome Research Laboratories, Berkhamsted Hill. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. HERSCHLER, R.C., HAMM, D., SCHULTZ, R.A. & BURSICK, K.N. (1979) The effects of oxfendazole on fertility and fetal safety in equine. Unpublished report. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. KILLEEN, J.C. & RAPP, W.R. (1974a) A three-month oral toxicity study of RS 8858 in rats. Unpublished report No. 73-R-905 from Bio/dynamics, New Jersey, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. KILLEEN, J.C. & RAPP, W.R. (1974b) A three-month oral toxicity study of RS 8858 in beagle dogs. Unpublished report No. 73-R-906 from Bio/dynamics, New Jersey, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. KRAMER & BAEDER (1973) A teratogenicity test of HOE 881 with oral administration in Wistar rats. Hoechst-Roussel unpublished report. Submitted to WHO by Hoechst AG, Frankfurt am Main, Germany. LLOYD, B.W.J (1978) The effect of oxfendazole on pregnant ewes when dosed at double the recommended field concentration i.c. 10 mg per kilogram, on day 17 of gestation period. Unpublished report from Wellcome Foundation, Group Research and Development, Berkhamsted, UK. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. McKELLAR, Q.A. & SCOTT, E.W. (1990) The benzimidazole anthelmintic agents a review. J. Vet. Pharmacol. Therap., 13, 233-247. MATIN, S.B., BELL, J., AMOS, B. & TSINA, J. (1977) Identification of organic solvent extractable metabolites of oxfendazole in calf liver. Unpublished report No. 77-Ca-12 from Institute of Pharmacology and Metabolism from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. MILLER, T.A., BIDLACK, D.E. & DePASS, L.R. (1987) Reproduction study with oxfendazole (RS 8858) in cattle. Unpublished report No. 44-CW-85-8858-IR-RP from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. MORGAN, D.W.T. (1982) Toxicity study of oxfendazole in pregnant sows. Vet. Record, 111, 161-163. MOUROT, D. (1990) Oxfendazole Ames test. Unpublished report from Laboratoire des médicaments vétérinaires, La Haute-Manche-Javene, Fougères. Submitted to WHO by Centre National d'Etudes Vétérinaires et Alimentaires, Javene, Fougères, France. PALMER, A.K. (1972) Sporadic malformations in laboratory animals and their influence on drug testing. In: Klingberg, MA, Abramovici, A. & Chemke, J. (eds), Drugs and Fetal Development Plenum Publishing Corp., New York, USA. PIERCY, D.W.T., REYNOLDS, J., PITFIELD, N.J. & JAMES, J.A. (1977) Foetal toxicity of oxfendazole in sheep. Unpublished report No. HHG 77-3 from Wellcome Research Laboratories, Berkhamsted. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. PIERCY, D.W.T., REYNOLDS, J.A. & JAMES, J.A. (1978a) Report on skeletal development in foetuses obtained from cows dosed repeatedly with oxfendazole during early pregnancy. Unpublished report No. HHKG 78-5 from Wellcome Research Laboratories, Berkhamsted, UK. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. PIERCY, D.W.T., REYNOLDS, J., PITFIELD, N.J. & JAMES, J.A. (1978b) Foetal toxicity of oxfendazole in cattle. Unpublished report from Wellcome Research Laboratories, Berkhamsted, UK. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. REYNOLDS, J. & JAMES, J.A. (1977) Oxfendazole, ocular irritancy in rabbits. Unpublished report No. HHPG 77-1 from Wellcome, Group Research and Development, Berkhamsted, UK. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. THUNEN, L., DUMAS, K., EDWARDS, J., BAX, P., OWEN, R. & SCHILTZ, R. (1981) Teratology study with oxfendazole (RS 8858) in rabbits. Unpublished report No. 48-B-77-8858-PO-TT from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. TOMLINSON, R.V. (1974a) Absorption, distribution, metabolism and elimination of 3H-oxfendazole after oral and intravenous administration to rats. Unpublished report No. ATV2050 from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. TOMLINSON, R.V. (1974b) Absorption, distribution, metabolism and elimination of 14C-oxfendazole after oral and intravenous administration to sheep. Unpublished report No. 76-Sh-94 from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. TOMLINSON, R.V. (1977) Oxfendazole in the milk of lactating cows. Unpublished report No. 76-C-2918 from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA. TOMLINSON, R.V., BERRY, P. & BOWEN, L. (1986) Comparison of oxfendazole disposition in the rat and feeder calf after oral administration of a 6 mg/kg dose. Unpublished report No. DM 633 from Syntex Inc., Palo Alto, CA, USA. Submitted to WHO by Syntex Inc., Palo Alto, CA, USA.
See Also: Toxicological Abbreviations OXFENDAZOLE (JECFA Evaluation)