TIABENDAZOLE (THIABENDAZOLE) First draft prepared by Dr G. Roberts Environmental Health Branch Department of Health, Housing and Community Services Canberra, Australia 1. EXPLANATION Tiabendazole (also known as thiabendazole) had not been previously reviewed by the Committee, but was evaluated at the 1970 and 1977 Joint FAO/WHO Meetings on Pesticide Residues (FAO/WHO, 1971, 1978). At the 1977 Joint Meeting, an ADI of 0-0.3 mg/kg bw was established. Tiabendazole is a benzimidazole compound used both as a broad-spectrum anthelminthic in various animal species and for the control of parasitic infestations in humans. 2. BIOLOGICAL DATA 2.1 Biochemical Aspects 2.1.1 Absorption, distribution, biotransformation and excretion 2.1.1.1 Mice Pregnant Jcl:ICR mice were administered a single gavage dose of 1000 mg/kg bw of 14C-tiabendazole on gestation day 9. When an olive oil vehicle was used, peak plasma radioactivity occurred within 30 min and was 5-fold higher than the peak level with an aqueous gum arabic vehicle, achieved 6 h after dosing. After 12 h, plasma levels were similar with both vehicles and by 72 h they were negligible. The time course for levels of radioactivity in the conceptus was similar to that in plasma. Over a 3-day period, excretion was 74 and 60% in urine and 23 and 18% in faeces for the olive oil and aqueous gum arabic vehicles, respectively (Yoneyama et al., 1984). Pregnant Jcl:ICR mice received single gavage doses of 1300 mg/kg bw of 14C-tiabendazole on gestation day 11. Use of an olive oil vehicle resulted in 7-fold higher peak blood levels than with gum arabic. The initial rate of urinary excretion was higher with the olive oil vehicle, otherwise elimination kinetics were similar for both vehicles. Over 7 days, 60% was recovered in urine and 37% in faeces with each vehicle. Chromatographic analysis of urine revealed 12 to 15% as parent drug, 22 to 24% as 5-hydroxy tiabendazole, 28 to 29% as 5-hydroxy tiabendazole glucuronide and 30 to 31% as 5-hydroxy tiabendazole sulfate. Additionally, a small amount of N-methyl tiabendazole was identified (Tsuchiya et al., 1987). Pregnant Crj:CD-1(ICR) mice were given a single oral dose of 1000 mg/kg bw of 14C-tiabendazole in olive oil on gestation day 10. HPLC analysis of 24 h urine revealed the major metabolites as unchanged tiabendazole, 5-hydroxy tiabendazole and the glucuronide and sulfate conjugates of the latter. An additional 2 minor metabolites, eluting between tiabendazole and the 5-hydroxy metabolite, were detected but the amounts were too low to enable identification (Fujitani et al., 1991). 2.1.1.2 Rats Following a dose of 100 mg/kg bw, tiabendazole labelled with 14C in the benzene ring was rapidly absorbed from the gastrointestinal tract of rats, with a maximum blood concentration two to three hours after treatment. Radio-activity gradually disappeared from the blood, and approximately 92% of a dose of 25 mg/kg bw and 80% of a 100 mg/kg bw dose was excreted in the urine and faeces within three days. Most of the drug and its metabolites were excreted within the first 24 h. Of the metabolites, 50% appeared as the glucuronide of 5-hydroxy tiabendazole and 40% as the sulfate ester of the same aglycone. Traces of unchanged tiabendazole and 5-hydroxy tiabendazole were also evident (FAO/WHO, 1971). Male F344/DuCrj rats were given a single oral dose of 800 mg/kg bw tiabendazole. In addition to the major urinary metabolites described above, the same 2 minor degradation products as were found in mouse urine were also detected. Using mass spectrometry, the new metabolites were identified as 2-acetyl benzimidazole and 4-hydroxytiabendazole (Fujitani et al., 1991). 2.1.1.3 Dogs Dogs given a single oral dose of 50 mg/kg bw of 14C-labelled tiabendazole were found to have maximum plasma levels within two hours. Excretion was essentially complete in eight days, with approximately 35% of the dose appearing in the urine and 47% appearing in the faeces (FAO/WHO, 1971). 2.1.1.4 Humans Sixteen male subjects were administered tiabendazole at dosages of 1 to 2 g per person in the form of tablets, wafers, capsules or suspension. The lower dose was rapidly absorbed and peak plasma concentrations were observed about one hour after treatment. Plasma drug levels declined rapidly thereafter and reached essentially zero values between 24 and 48 h. Tiabendazole and its metabolic products were excreted rapidly in the urine (81-91%) and faeces (2-7%) within 48 h. Approximately half of the material in the urine was associated with compounds identified as the glucuronide and sulfate esters of 5-hydroxy tiabendazole. In plasma, both unchanged tiabendazole and free 5-hydroxy tiabendazole were also found. At the higher dosage level, maximum drug levels in plasma appeared three hours following dosing. These studies utilized 14C-labelled and unlabelled tiabendazole (FAO/WHO, 1971; Robinson, 1965). Based on the metabolism studies, the pathway for tiabendazole degradation in mammals may be represented as in Figure 1.2.2 Toxicological Studies 2.2.1 Acute toxicity studies The results of acute toxicity studies with tiabendazole are summarized in Table 1. Table 1. Acute toxicity Species Sex Route LD50 Reference (mg/kg bw) Mouse M&F oral 2400-3810 FAO/WHO, 1971 M&F ip 430 FAO/WHO,1971 M&F iv 150 FAO/WHO, 1971 Rat M&F oral 3330-3600 FAO/WHO, 1971 M&F ip 1850 FAO/WHO, 1971 M&F iv 130 FAO/WHO, 1971 M&F inhalation >397 mg/m3 Gurman et al., 1981 Rabbit M&F oral 3850 FAO/WHO, 1971 M&F dermal >2000 Blaszcak & Auletta, 1987 Sheep ? drench 2000 FAO/WHO, 1971 Goat ? drench >2000 FAO/WHO, 1971 Toxic signs following administration of large doses of tiabendazole by oral or intraperitoneal routes were generally similar and consisted of lethargy and stupor. The intravenous administration of a large dose of tiabendazole hydrochloride produced narcosis. Death appeared to be due to respiratory failure. Rabbits that survived large oral doses initially lost weight but recovered after several days. 2.2.2 Short-term toxicity studies 2.2.2.1 Mice In an investigation of renal function, Crj:CD-1 (ICR) mice were given gavage doses of 0, 250 or 500 mg/kg bw/day tiabendazole (purity 98.5%) in olive oil. Groups of 6 to 8 males and females were killed after dosing for 1, 3, 5 or 7 days. There was no effect on body weight. Water intake was unaffected but urine volume was increased in all treated groups, significantly so in males given 500 mg/kg bw/day. There were no meaningful effects on serum creatinine or urea nitrogen, urinary glucose or protein or the presence of occult blood in urine. Electrophoresis however, revealed relatively high molecular weight protein in treated mice, while low molecular weight protein was found in all groups. There was a progressive dose-related increase in renal lesions including tubular dilatation and degenerative desquamation, cell infiltration, fibrosis and regeneration of tubular epithelium. Electron microscopy showed evidence of glomerular damage such as flattening of the foot processes of podocytes and oedematous changes in the mesangium in treated mice (Tada et al., 1989). In a 6-week pilot study, groups of 10 male and 10 female Charles River CD-1 (HaM/ICR) mice were given 0, 50, 150, 300, 600 or 900 mg/kg bw/day tiabendazole (purity unknown) via the diet. There were no clinical signs or mortality. Food intake and weight gain were depressed in males at 600 and 900 mg/kg bw/day. Other parameters were not monitored (Bokelman & Zwickey, 1977). 2.2.2.2 Rats Rats (Sprague-Dawley Holtzman, 10 males and 10 females per group) were administered tiabendazole by gavage at dosage levels of 0, 100, 400, 800, 1200 or 1600 mg/kg bw/day. During the 30 day experimental period, rats in the 800 mg/kg bw/day group decreased their food intake and gradually lost weight. They were slightly less active, had ruffled fur and became slightly flaccid; three males and three females died during the course of the experiment. All of the rats in the 1200 and 1600 mg/kg bw/day groups died during the 30-day test period. Rats dosed at 100 and 400 mg/kg bw/day appeared normal throughout the test period, although a slight depression in body-weight gain was noted in males at 100 mg/kg bw/day and in females at 400 mg/kg bw/day. Higher doses produced greater effects on body-weight gain. Haematologic studies on rats receiving 800 mg/kg bw/day showed a mild neutrophilia with concurrent lymphopenia. There was also a suggestion of a decrease in red blood cell elements at 400 mg/kg bw/day and above. Blood biochemistry showed no meaningful changes. No gross anatomical changes were noted in rats dosed with 100 mg/kg bw/day, whereas male and female rats treated with 400 mg/kg bw/day showed thymic involution. A slight enlargement of the liver was also noted in females at 400 mg/kg bw/day. Animals surviving 800 mg/kg bw/day showed gross signs indicating starvation; normal body fat depots and subcutaneous fat appeared to be depleted. The liver and adrenals were slightly enlarged in males and females and the thymus was involuted. Microscopic pathology showed bone marrow hypoplasia, thymus haemosiderosis and colloid depletion in the thyroid at 400 mg/kg bw/day (FAO/WHO, 1971; Robinson, 1964). Groups of 12 male and 12 female Albino Crj:CD (SD) rats were administered gavage doses of 0, 50, 100, 200 or 800 mg/kg bw/day thiabendazole (purity 100%), suspended in 0.5% methylcellulose, for 28 to 31 days. Severe toxicity was observed at 800 mg/kg bw/day in the form of decreased activity, sedation, ataxia, recumbency, flaccidity, loss of righting reflex, piloerection, emaciation, rough hair coat, alopecia and a high level of mortality. Food intake and body-weight gain were depressed at 200 and 800 mg/kg bw/day. Laboratory analyses were carried out in week 4. Serum albumin, total protein and cholesterol were increased and erythrocytes, haemoglobin and haematocrit were decreased at 200 and 800 mg/kg bw/day with reticulocytosis and leucocytopenia at the higher level. Urinalysis was unchanged. Autopsy revealed changes at all dose levels. There was haemosiderosis and increased extramedullary haematopoiesis in the spleen at all doses with increased spleen weight at 200 mg/kg bw/day and above. Increased thyroid weight and follicular cell hyperplasia and decreased thymus weight were seen at 50 mg/kg bw/day and above. Lymphoid depletion was observed in the thymus at 100 mg/kg bw/day and above, in bone marrow at 200 mg/kg bw/day and above and in spleen and lymph nodes at 800 mg/kg bw/day. Liver weight and centrilobular hepatocytic hypertrophy were increased at 100 mg/kg bw/day and above (Usui & Sakaguchi, 1989). Groups of 20 male and 20 female Sprague-Dawley Crl:CD (SD) BR rats were given gavage doses of 0, 25, 100 or 400 mg/kg bw/day tiabendazole (purity not stated), suspended in 0.5% methyl cellulose, for 13 weeks. Alopecia was noted in some rats of each treatment group. There was no mortality. Body-weight gain was reduced at 100 and 400 mg/kg bw/day with lower food intake in 400 mg/kg bw/day males. Ophthalmology at the end of study was unremarkable. Clinical laboratory parameters were studied in weeks 6 and 13. Decreased erythrocytes, haemoglobin and haematocrit and increased cholesterol were induced at 100 and 400 mg/kg bw/day. Urinary levels of bilirubin, urobilinogen and nitrite were increased at 400 mg/kg bw/day. At 100 and 400 mg/kg bw/day, increased liver weight and centrilobular hypertrophy, enlarged thyroids with follicular cell hyperplasia and splenic congestion and pigmentation were observed. In the kidney, renal calculus and transitional epithelial hyperplasia were evident at 100 and 400 mg/kg bw/day with tubular degeneration at the highest level. The stomach exhibited acanthosis and/or degeneration of non-glandular mucosa at 100 and 400 mg/kg bw/day and cytoplasmic rarefaction and necrosis of glandular mucosa at 400 mg/kg bw/day. The NOEL was 25 mg/kg bw/day (Kangas et al., 1989). Groups of 10 male and 10 female Sprague-Dawley Crl:CD BR rats were fed diets containing tiabendazole (purity 99.4%) for 13 weeks. Based on food intake the calculated doses were 0, 9, 37, 150 or 302 mg/kg bw/day. There was no effect on survival or on the eyes at the end of study. Alopecia was increased at 150 and 302 mg/kg bw/day. Doses of 37 mg/kg bw/day and above were associated with decreased body-weight gain and food intake in males; females were similarly affected at 150 mg/kg bw/day and above. Clinical laboratory analyses were undertaken in weeks 6 and 13. At doses of 150 and 302 mg/kg bw/day serum cholesterol was increased, glucose, erythrocytes, haemoglobin and haematocrit were depressed and there were increased numbers of abnormal erythrocytes. Urinalysis was unaffected. Liver weight increases and centrilobular hypertrophy, increased thyroid weight and follicular cell hypertrophy and bone marrow erythroid hyperplasia were observed at 37 mg/kg bw/day and above. At 150 and 302 mg/kg bw/day there was spleen pigmentation and thymus atrophy with skeletal muscle atrophy in females given 302 mg/kg bw/day. The NOEL was 9 mg/kg bw/day (Myers & Lankas, 1990). Rats (Sprague-Dawley Holtzman, 30 males and 30 females per group) were administered tiabendazole, suspended in 1% methocel, by gavage for 180 days, at doses of 0, 12.5, 25, 50, 100, 200 or 400 mg/kg bw/day. All of the animals survived throughout the duration of the experiment. At 400 mg/kg bw/day, a depression in body weight was observed in both sexes. At 200 mg/kg bw/day, the male rats showed a slight depression in weight gain. No clinical signs of toxicity were observed. Haematological studies at 400 mg/kg bw/day indicated a slight suggestion of a fall of the red blood cell elements, neutrophilia and lymphopenia which were not evident at levels below this dose. Blood biochemistry studies and urinalysis were normal at all dosage levels with a slight polyuria in both male and female rats at 400 mg/kg bw/day, which was apparently the result of a slight increase in water consumption at this dosage level. Gross pathology showed thymic involution in both males and females at 400 mg/kg bw/day and in females at 200 mg/kg bw/day. There was an increase in liver size at doses of 100 mg/kg bw/day and above in males and at 50 mg/kg bw/day and above in females. Males dosed with 200 and 400 mg/kg bw/day and females at 400 mg/kg bw/day showed an apparent increase in kidney weight. Microscopic examination of animals at 100 mg/kg bw/day showed a small incidence of haemosiderosis of the thymus. At 200 and 400 mg/kg bw/day, these examinations showed considerably more haemosiderosis of the thymus and colloid depletion in the thyroid. The NOEL was 25 mg/kg bw/day (FAO/WHO, 1971; Robinson, 1964). 2.2.2.3 Rabbits Groups of 5 male and 5 female New Zeeland white rabbits received dermal doses of tiabendazole (purity 98.9%) moistened in 0.9% saline. The drug was applied to the shaved trunk of animals at doses of 0, 50, 200 or 1000 mg/kg bw, 6 h/day for 3 weeks. Oral ingestion was prevented by use of a collar. Clinical laboratory parameters and pathology were investigated at the end of the study. There was no evidence of local or systemic toxicity (Cavagnaro & Yamamoto, 1989). 2.2.2.4 Dogs Groups of 4 male and 4 female beagle dogs were given capsules of tiabendazole (purity 99.4%) at doses of 0, 35, 75 or 150 mg/kg bw/day for 14 weeks. Emesis was increased at 75 and 150 mg/kg bw/day with salivation at 150 mg/kg bw/day. There were no deaths. During the first 2 weeks of treatment, food consumption and body-weight gain were decreased in all treated groups. Subsequently, food was made available overnight rather than for 1 h per day which led to comparable food intake and weight gain in all groups. Ophthalmology and ECG examinations were normal throughout the study. Red blood cells, haemoglobin and haematocrit were depressed at 150 mg/kg bw/day, more so at weeks 4 and 8 than at week 12. Blood chemistry and urinalysis were unchanged at any time. Relative but not absolute liver weights were slightly increased in all treated groups but with no dose-relationship. At 75 and 150 mg/kg bw/day, gallbladder cytoplasmic vacuolation was increased in incidence and severity. The NOEL was 35 mg/kg bw/day (Batham et al., 1989). Groups comprising two male and two female beagle dogs were orally administered tiabendazole for periods of over two years at doses of 0, 20, 100 or 200 mg/kg bw/day. No clinical signs or morbidity were observed, food and water consumption were normal and blood and urine chemistry were normal. A slight retardation in body-weight gain was observed at 200 mg/kg bw/day, which was accompanied by a slight reduction in total erythrocyte count. At this level, changes in haemoglobin concentration and haematocrit were also observed. No gross pathological observations were noted at the conclusion of this test and organ weights appeared normal. A significant haemosiderosis was present in dogs at 100 and 200 mg/kg bw/day in the spleen, liver, lymph nodes and bone marrow. This was not associated with an increase in serum haemoglobin. The NOEL was 20 mg/kg bw/day (FAO/WHO, 1971; Robinson, 1964) Groups of beagle dogs (three males and three females) were orally administered tiabendazole in capsules for two years at doses of 0, 20, 50 or 125 mg/kg bw/day. At 125 mg/kg bw/day, two of six dogs died. One of these dogs had marked liver cirrhosis, seminal tubular degeneration, bone marrow atrophy and degenerative renal changes. Slight to moderate reduction in haemoglobin and packed cell volume occurred. Elevated blood urea nitrogen, serum alkaline phosphatase and serum GOT and chronic inflammatory liver changes were evident. Urinary albumin was seen more frequently than in controls. Inspissated bile entwined in the gall bladder villi was also observed in one dog. One dog of this group was sacrificed and was found to have pulmonary arteritis of parasitic origin. At 50 mg/kg bw/day, growth of male dogs was slightly depressed. All six dogs given tiabendazole at 50 mg/kg bw/day survived the study and their tissues differed from those of the control dogs in that some liver glycogen depletion was observed in three dogs and inspissated material was found adhering to the gall bladder mucosa in one. Five of six dogs given tiabendazole at 20 mg/kg bw/day survived the study. Three of the five showed slight liver glycogen depletion. A general impression in this study was of an overall appearance of mild chronic inflammatory degenerative renal changes in all treated dogs. The NOEL was 20 mg/kg bw/day (FAO/WHO, 1971; Woodard, 1964). 2.2.2.5 Chickens Groups of 0.5 week-old male white leghorn chicks (10 to 20 per group) were fed tiabendazole in the diet at dosage levels ranging from 1 to 10 000 ppm for a period of 2 1/2 weeks. This level corresponded to a mean daily intake of tiabendazole ranging from 0.1 to 1200 mg/kg bw. A gradual decrease in growth appeared to occur with concentrations of 100 ppm tiabendazole in the diet. This dose corresponded to approximately 13 mg/kg bw/day. Gross pathological examination of the chicks at a dietary level of 4000 ppm tiabendazole showed them to be normal except for a smaller size (FAO/WHO, 1971). 2.2.2.6 Sheep Thirty weanling wethers were employed in a 16-week study at doses of 0, 10, 50, 100, 200, 400 or 800 mg/kg bw/day. Tiabendazole was administered in gelatin capsules. Two of the four sheep dosed at 100 mg/kg bw/day did not survive the test period. However, because of infection, tiabendazole may not have been directly related to the cause of their death. All the animals treated at 200 mg/kg bw/day and above died before the end of the test period. No significant effects on blood biochemistry or urinalysis were observed. Doses of 50 mg/kg bw/day and above affected body-weight gain after approximately 120 days on the test. Doses of 10 mg/kg bw/day had no effect. Food consumption was unaffected at 10 mg/kg bw/day but a minor decrease was noted at 50 and 100 mg/kg bw/day and a significant decrease at 200 mg/kg bw/day and above. No gross pathological changes were observed at doses below 200 mg/kg bw/day. Starvation and loss of body weight complicated the interpretation of data concerning organ weights at 200 mg/kg bw/day and above. At 200 to 800 mg/kg bw/day, a moderate hypoplasia of the bone marrow with replacement by adipose tissue was observed. Loss of colloid in thyroid was evident at 800 mg/kg bw/day, as well as lymphoid atrophy at the higher dose levels (FAO/WHO, 1971). Five groups of two ewe lambs (10 to 12 weeks old) and eight wether lambs (10 to 19 weeks old) were fed diets containing 0, 100, 320, 1000 or 3200 ppm tiabendazole for periods up to 50 weeks. Sheep 10 weeks of age tolerated 1000 ppm tiabendazole in the diet for the duration of the experiment. This dose corresponded to 30 to 50 mg/kg bw/day. The sheep tolerated 3200 ppm in their diet for the first 14 weeks but thereafter lost weight in the final stages of the experiment (FAO/WHO, 1971). 2.2.2.7 Pigs Five groups of four barrows each were given a diet containing 0, 320, 1000, 3200 or 10 000 ppm tiabendazole for 14 weeks. A concentration of 320 ppm was tolerated without observable effects for the 14-week period. This concentration corresponded to an intake of 15 mg/kg bw/day. The concentration of 10 000 ppm tiabendazole in the diet caused reduced weight gain and reduced food consumption with no mortality. Gross pathologogical examination revealed no abnormal conditions (FAO/WHO, 1971). 2.2.2.8 Cattle Five female holstein calves (seven months old) were fed a diet containing 0, 320, 1000, 3200 or 10 000 ppm of tiabendazole for a 14-week test period. Calves tolerated 3200 ppm tiabendazole in their diet without observable effects on growth, food intake or general condition. This concentration corresponded to a mean daily intake of 90 mg/kg bw. At 10 000 ppm tiabendazole, the calves grew normally for the first two weeks, but in the following 12 weeks the weight gain was about half that observed for the controls. Gross examination at the time of autopsy revealed no pathological condition and histological examination of several tissues showed no changes resulting from the incorporation of tiabendazole in the diet (FAO/WHO,1971). 2.2.3 Long-term/carcinogenicity studies 2.2.3.1 Mice Groups of 50 male and 50 female Charles River CD-1 (HaM/ICR) mice were fed diets containing tiabendazole (purity 99.3%) for up to 2 years. The study was commenced using dietary concentrations of 0 (three groups), 220, 660 or 2000 ppm in males and 0 (three groups), 660, 2000 or 5330 ppm in females. From the seventh week the concentration of tiabendazole in the feed of the low-dose males and females was reduced to 60 ppm in an effort to establish a NOEL. The intake of tiabendazole was 5.6-8.3, 63-121 or 184-372 mg/kg bw/day in males and 5.7-9.9, 209-368 or 534-1005 mg/kg bw/day in females. Mortality was increased in groups given the intermediate and high-doses. At 2000 ppm in males and females and 5330 ppm in females, myocardial thrombosis was the primary cause of death. The reason for decreased survival in 660 ppm males was not apparent. When survival reached 20%, the remaining animals of the group were sacrificed. Thus 5330 ppm females were killed in week 81, 2000 ppm males were killed in week 85, 660 ppm males and 2000 ppm females were killed in week 93, 60 ppm males (originally 220 ppm) were killed in week 101 and 60 ppm females (originally 660 ppm) were killed in week 105. A proportion of each control group was killed at each of these sacrifice times. Body-weight gain was depressed in 2000 ppm males and females and 5330 ppm females. Males given 660 ppm had slightly lower weight gain in the early and latter parts of the study. At the lowest dose, slightly lower weight gain was noted early in the study, but following dosage reduction, no further effect was observed. Food consumption showed no meaningful alterations. Ophthalmoscopy conducted at termination was unremarkable. Laboratory parameters were not studied. At autopsy liver weight was significantly increased in 2000 ppm males and females and 5330 ppm females. Kidney weight was significantly decreased in 5330 ppm females with slight decreases in 2000 ppm males and females and 660 ppm males. There were no pathological lesions associated with the organ weight changes. A high incidence of atrial thrombosis was seen in 2000 ppm males and females and 5330 ppm females and was judged to be a major cause of intercurrent mortality. Tumour incidences were unrelated to treatment. The NOEL was 6 mg/kg bw/day (Bagdon et al., 1980). 2.2.3.2 Rats Groups of Charles River rats (35 of each sex) were fed dietary levels adjusted to provide 0, 10, 40 or 160 mg/kg bw/day of tiabendazole for up to two years. At the 160 mg/kg bw/day level, a reduction of weight gain of about 25%, with concomitant reduction in food consumption and slightly reduced haemoglobin and haematocrit values were the only changes attributable to compound administration. No effects attributable to compound administration were noted with respect to survival, time of death in non-survivors, incidence or location of neoplasms and histopathological examination of the tissues. No effect on food consumption or haemograms were seen at either 10 or 40 mg/kg bw/day. Very slight depression in growth rate was observed in male rats at 40 mg/kg bw/day but not at 10 mg/kg bw/day. At 10 mg/kg bw/day, the mean absolute thyroid weights of the male rats were heavier than the mean thyroid weight of the controls. This effect was not observed in the rats given 40 or 160 mg/kg bw/day. The NOEL was 10 mg/kg bw/day (FAO/WHO, 1971; Woodard, 1964). In a carcinogenicity study, groups of 30 male and 30 female F344/DuCrj rats were fed diets containing 0, 500, 1000, 2000 or 4000 ppm tiabendazole (purity 98.5%) for 2 years. Based on food consumption the drug intake was calculated as 21, 43, 90 or 207 mg/kg bw/day in males and 26, 53, 112 or 237 mg/kg bw/day in females. There were no signs of toxicity or effects on survival. Food intake was lower at 4000 ppm whereas body weight gain was reduced at 1000 ppm and above, leading to small and poorly developed animals at 2000 and 4000 ppm. Clinical laboratory parameters were not examined. At the end of 2 years, all animals were necropsied. Liver microgranulomas and aggregations of foamy cells in the lung were increased at 1000 ppm and above. Renal epithelial hyperplasia of papilla and pelvis were increased at 2000 and 4000 ppm. Preputial or clitoral gland adenoma incidences were higher than control values at 4000 ppm. The increase was statistically significant (p <0.05) only for adenomas in the preputial gland. There were no adverse effects at 500 ppm, equal to a NOEL of 20 mg/kg bw/day (Fujii et al., 1991). 2.2.4 Reproduction studies 2.2.4.1 Mice A five-generation reproduction study utilized 25 male and 25 female mice given diets containing tiabendazole at concentrations of 0, 200, 1000 or 5000 ppm. When the mice attained the age of eight weeks, they were mated and continued on the same diet. The young from these matings, when they were weaned, were maintained on the test diet and mated when they reached the age of eight weeks. This procedure continued for five complete reproductive cycles. No effects were noted at 200 ppm. At 1000 ppm, a slight decrease in the weights of weanlings was observed in all five generations. At 5000 ppm, the number of mice born and weaned per litter was reduced and a marked reduction in the average weanling weight of the young was observed. The NOEL was 200 ppm, equivalent to 30 mg/kg bw/day (FAO/WHO, 1971). 2.2.4.2 Rats A three-generation, two-litter reproduction study (10 male and 10 female FDRL albino rats per group) at dosages of 0, 20, 40 or 80 mg/kg bw/day showed no adverse effects on reproduction, lactation or histomorphology in the three generations of rats examined. The only treatment-related findings were decreased body-weight and decreased food consumption in the male rats at all dosage levels in the F0- and F2-generations. Slight decreases in final body weights and food consumption at the 80 mg/kg bw/day dose level in the F1- and F2-generation females were also observed (FAO/WHO, 1971; Vogin, 1968) 2.2.5 Special studies on embryotoxicity and teratogenicity 2.2.5.1 Mice A series of developmental studies were undertaken in Jcl:ICR mice. Pregnant females were given gavage doses of tiabendazole (purity 98.5%) in olive oil at various times during the gestation period. Females were killed on gestation day 18. Exp. 1: Groups of 39 mice were dosed with 0, 700, 1300 or 2400 mg/kg bw/day on gestation days 7-15. Maternal weight gain was depressed in a dose-related manner with mortality at 1300 mg/kg bw/day (5 out of 39) and 2400 mg/kg bw/day (24 out of 39). The resorption rate was increased at 1300 and 2400 mg/kg bw/day. At all treatment levels, there were reduced fetal weights and increased malformations such as cleft palate, fusion of vertebral arches and vertebral bodies. Exp. 2: Groups of 7-12 mice were given a dose of 2400 mg/kg bw on a single day of gestation between days 6 and 15. Mortality was 8 to 55% in treated groups but there were no data on body weight. In each group, resorptions were increased and fetal body weights were decreased. Fetal malformations detected were: microcephaly and exencephaly (following treatment on gestation days 6 to 8); short or absent tail and anal atresia (day 9); open eyelids (days 7, 8, 10, 13, and 14); reduction deformity of limbs and cleft palate (days 9 to 12); fusion of vertebral arches and bodies (days 7 to 10, and 13) and fusion of ribs (days 7 to 9). The fetal abnormalities were judged to be most prominent on gestation day 9. As the types of malformation were diverse and primarily related to the timing of treatment, it was suggested that tiabendazole was a non-specific teratogen. Exp. 3: Groups of 21 to 31 mice were given a single dose of 30 to 2400 mg/kg bw on gestation day 9. Mortality was induced at 1670 mg/kg bw and above and maternal weight gain was reduced at 1160 mg/kg bw and above. The resorption rate was increased at 1670 mg/kg bw and above while fetal weight was lower at 60 mg/kg bw and above. The limb reduction deformity was seen regularly at doses of 480 mg/kg bw and above; the threshold was calculated as being 360 mg/kg bw. Fusion of vertebral arches, vertebral bodies and ribs was increased at 240 mg/kg bw and above. Other malformations were not consistently increased. There were no treatment-related effects at 30 mg/kg bw/day (Ogata et al., 1984). Follow-up developmental studies were carried out in groups of 16 to 20 pregnant female Jcl:ICR mice. Tiabendazole (purity 98.5%) was given by gavage in olive oil at doses of 0, 250, 500 or 1000 mg/kg bw/day on gestation day 9. Females were killed on gestation day 18. Treatment at the two highest doses produced similar effects to the previous mouse studies. Pretreatment with SKF-525A (inhibitor of cytochrome P-450) enhanced the rate of resorptions and the incidence of fetal malformations. Sodium phenobarbital pretreatment, on the other hand, resulted in decreases in the resorption rate and reduced fetal abnormalities to control levels. Pretreatment with glutathione, cysteine or diethyl maleate (a glutathione-depleting substance) had no effect on resorptions. However, the incidence of fetal malformations was increased with glutathione or cysteine and reduced to control levels by diethyl maleate. Graphs of tissue concentrations of tiabendazole against time showed the AUC for both maternal blood and fetal tissue was increased by glutathione and reduced by diethyl maleate. The overall conclusion was that the developmental effects appear to be due to unchanged tiabendazole and not to its degradation products (Ogata et al., 1987; 1989). 2.2.5.2 Rats Two groups of rats (20 male and 20 female) were placed on a diet containing 0 or 500 ppm tiabendazole. There were no abnormalities among the young from either mating attributable to tiabendazole at 500 ppm. It was concluded that these data presented no evidence of teratogenecity (FAO/WHO, 1971). In a preliminary teratology study, Charles River SD rats (8 pregnant females per group) were given gavage doses of 0 or 80 mg/kg bw/day tiabendazole (purity unknown) on gestation days 8 to 15. Dams were killed on gestation day 21. There were no effects on resorption rate or on fetal survival, growth or development (Delatour et al., 1974). Groups of 20 pregnant female Wistar rats were administered gavage doses of 0, 125, 250 or 500 mg/kg bw/day of a commercial formulation containing 45% tiabendazole and 55% unknown ingredients. Dosing was on gestation days 6-15 and dams were killed on gestation day 22. No adverse effects were apparent in females and no meaningful effects were reported on the resorption rate, fetal viability, growth or development (Khera et al., 1979). In a range-finding study, Sprague-Dawley Crl:CD(SD)BR rats were given gavage doses of 0, 50, 100, 200 or 400 mg/kg bw/day tiabendazole (purity 99.4%). Groups of 10 pregnant females were treated on gestation days 6 to 17 and were killed on gestation day 20. There were no deaths or abortions but all 200 and 400 mg/kg bw/day females were killed due to severe body-weight effects. Maternal weight gain was also depressed at 50 and 100 mg/kg bw/day. Other toxic signs were lethargy and ptosis at 100 mg/kg bw/day and above and reduced faeces at 200 mg/kg bw/day and above. Increased protein, albumin and cholesterol were observed at the higher doses with decreased triglycerides at all dose levels. Resorptions and fetal morphology were unaffected but fetal weight was reduced at all treatment levels (Lankas & Wise, 1990a). Groups of 25 pregnant female Sprague-Dawley Crl:CD(SD)BR rats were given gavage doses of 0, 10, 40 or 80 mg/kg bw/day tiabendazole (purity 98.9%) suspended in 0.5% methyl cellulose. Drug administration was on gestation days 6 to 17 and the dams were killed on gestation day 20. At 80 mg/kg bw/day, rats showed ptosis and a few animals regurgitated a portion of the dose. Food intake and body-weight gain were depressed at 40 and 80 mg/kg bw/day. There was no mortality or abortions nor were there increases in the resorption rate or in dead fetuses. Fetal abnormalities were not produced, but statistically significantly decreased fetal weight was noted at 40 and 80 mg/kg bw/day. The NOEL was 10 mg/kg bw/day (Lankas & Wise, 1990b). 2.2.5.3 Rabbits Groups of 10 to 32 pregnant female New Zeeland white rabbits were dosed by gavage with 0, 100, 200, 400 or 800 mg/kg bw/day tiabendazole (purity unknown) suspended in 1% carboxymethyl cellulose. Treatment was on gestation days 8 to 16 and does were killed on gestation day 29 or 30. At 200 mg/kg bw/day and above, does lost weight and the resorption rate was increased (not dose-related). Fetal weight was decreased at 400 and 800 mg/kg bw/day but fetal morphology was unaltered. The NOEL was 100 mg/kg bw/day (Peck, 1966a). In a range-finding study New Zeeland white rabbits were given gavage doses of 0, 100, 200, 400 or 800 mg/kg bw/day tiabendazole (purity 98.9%). Groups of 8 pregnant females were dosed on gestation days 6 to 18 and does were killed on gestation day 29. At 800 mg/kg bw/day, abnormal faeces were seen and weight loss necessitated early sacrifice of this group. Food intake and weight gain were lower at 200 and 400 mg/kg bw/day. The implantation rate was lower at 400 mg/kg bw/day but resorptions were not increased. External fetal examinations were unremarkable (Christian et al., 1989). Groups of 18 pregnant female New Zeeland white rabbits were administered 0, 24, 120 or 600 mg/kg bw/day tiabendazole (purity 98.9%) suspended in 0.5% methyl cellulose. The gavage doses were given on gestation days 6 to 18 and females were killed on gestation day 29. At 600 mg/kg bw/day one doe died, four aborted, abnormal faeces were increased, food consumption was lower and body weight was lost. Weight gain was slightly depressed at 120 mg/kg bw/day. There were increased resorptions at 120 and 600 mg/kg bw/day, including total resorption of conceptuses in 4 females at 120 mg/kg bw/day. Domed head, hydrocephaly and enlarged fontanelles were seen in one fetus at 120 mg/kg bw/day and two fetuses at 600 mg/kg bw/day. The NOEL was 24 mg/kg bw/day (Hoberman & Lankas, 1989). Groups of 18 pregnant female New Zeeland white rabbits were given gavage doses of 0, 50, 150 or 600 mg/kg bw/day tiabendazole (purity 98.6%) suspended in 0.5% methylcellulose. Treatment was on gestation days 6 to 18 and dams were killed on gestation day 28. There were no deaths or abortions related to treatment. Food intake and body weight gain were reduced at 600 mg/kg bw/day during the dosing period only. Resorptions were increased slightly but significantly at 600 mg/kg bw/day. At 600 mg/kg bw/day, there were increases in the incidences of variation in lung lobation and incompletely ossified metacarpals. The NOEL was 150 mg/kg bw/day (Lankas & Wise, 1991). 2.2.5.4 Sheep Pregnant ewes tolerated a single dose of 400 mg/kg bw tiabendazole at 2.5 to 8 weeks prior to lambing without any effect on the birth rate, growth or viability of the lambs. This dose had no effect on the ewes throughout the test interval or on viability of the lambs to six weeks of age. Miscellaneous tests using 39 ewes produced 29 weanling lambs after treatment with tiabendazole at 400 mg/kg bw, whereas, from a control group of 22 ewes, 13 lambs were weaned. Ewes tolerated a single dose of 18 g tiabendazole per animal (equal to 235 to 335 mg/kg bw), three to ten days after lambing, without any effect on the weight or food intake of the ewes or survival and growth of the lambs up to the weaning time of six weeks (FAO/WHO, 1971). 2.2.6 Special studies on genotoxicity The results of genotoxicity studies with tiabendazole are summarized in Table 2. Table 2. Results of genotoxicity studies on tiabendazole1 Test system Test object Treatment Results Reference Reverse S.typhimurium 10-5000 negative MacGregor, 1976 mutation TA98, TA100, µg/plate TA1535, TA1537 (+&-S9)2 Reverse S.typhimurium 100-2500 negative Shirasu et al., mutation TA1535, TA1537, µg/plate (-S9) 1976a. TA1538, TA98, 10-1000 TA100, E.coli µg/plate (+S9)2 WP2 hcr- Reverse S.typhimurium 10-2000 negative Peck, 1977 mutation TA98, TA100, µg/plate TA1538 (+&-S9)2 TA100, TA1538 10-2000 negative µg/plate (+S9)3 TA98 10-500 negative µg/plate (+S9)3 1000-2000 positive µg/plate (+S9)3 1000-2000 negative µg/plate (+S9)3 pure tiabendazole 20-1000 positive µg/plate (+S9)3 concentrated impurities Host ICR mice, 300-1000 negative Shirasu et al., mediated S.typhimurium mg/kg bw/day for 1976a G46. 5 days, po Rec. assay B.subtilis 2-1000 negative Shirasu et al., H17, M45 µg/disc (-S9) 1976a DNA Rat 60-262 negative Lankas, 1989 damage hepatocytes µg/ml Anaphase- CHO cells 0.06-0.12 negative Mudry de telophase µg/ml (-S9) Pargament test 0.24-0.6 positive et al., 1987 µg/ml (-S9) Table 2. cont'd Test system Test object Treatment Results Reference Sister Mouse bone 50-200 negative Mudry de chromatid marrow mg/kg bw, ip Pargament exchange et al., 1987 Chromosome Human 2-50 negative Shirasu et al., aberration fibroblasts µg/ml (-S9) 1976c Chromosome Rat bone 100-1000 negative Shirasu et al., aberration marrow mg/kg bw, po 1976d 30-300 negative mg/kg bw/day for 5 days, po Micronucleus Mouse bone 125-500 negative Peck, 1977. test marrow mg/kg bw, po Micronucleus Mouse bone 50-200 positive Mudry de test marrow mg/kg bw, ip Pargament et al., 1987 Dominant Mice 200-600 negative Shirasu et al., lethal mg/kg bw/day 1976b, test for 5 days, po Dominant Mice 125-500 negative Peck, 1977. lethal mg/kg bw/day test for 5 days, po 1 Appropriate positive controls were used. 2 Liver microsomes obtained from Aroclor 1254 pretreated rats. 3 Liver microsomes obtained from phenobarbital pretreated rats. 2.2.7 Special studies on irritation and sensitization 2.2.7.1 Guinea-pigs Male albino guinea-pigs received 10 intracutaneous injections of a 0.1% suspension of tiabendazole in 0.9% saline. Two weeks after the induction period an intracutaneous challenge dose failed to exacerbate reactions at the injection site (Peck, 1966b). 2.2.7.2 Rabbits There was no evidence of a significant degree of irritation when 0.5 g tiabendazole was applied in cold cream at concentrations of 10 and 50% (w/w) for 24 h to intact rabbit skin (FAO/WHO, 1971). No evidence of irritation was noted other than a very slight erythema observed for approximately one hour after application of 1 ml of tiabendazole as a 12% suspension in sodium carboxymethyl cellulose or 10 mg of the dry powder to the conjunctival sac of two rabbits (FAO/WHO, 1971). Male and female New Zeeland white rabbits received 100 mg of tiabendazole powder instilled into the conjunctival sac of the eye. At 15 min, there was slight conjunctival injection with a clear discharge which returned to normal within 24 h (Merck, Sharp & Dohme, undated). 2.2.8 Special studies on pharmacology Oral doses of tiabendazole (4000 mg/kg bw) produced no striking acute pharmacological effects on blood pressure or respiration in either cats or dogs. Similarly, there were no alterations in the electrocardiogram (FAO/WHO, 1971). 2.3 Observations in humans A double blind study was carried out with 100 male volunteers, half of them receiving 250 mg tiabendazole/day for 24 weeks and half of them a placebo. Each subject was interviewed weekly and any potential side effect was recorded. General physical examination and laboratory examinations (haematology, cholesterol, glucose, urea, alkaline phosphatase, thymol turbidity, bilirubin in serum and urinalysis) were carried out before the test and after 4, 12 and 24 weeks. PBI in serum and ECGs were carried out only at the beginning and after 24 weeks. Thirty-six subjects on tiabendazole and 41 on placebo completed the study. As tiabendazole has a possible influence on the thyroid the values for PBI were evaluated carefully. No indication, however, was found of a decrease or increase in PBI values due to tiabendazole. Under the conditions of the study, tiabendazole was well tolerated at a dosage of 250 mg/day during 24 weeks. No effect on any of the parameters studied could be clearly ascribed to the drug. The NOEL was 3-4 mg/kg bw/day (Colmore, 1965; FAO/WHO, 1978). Twenty-three patients with trichinosis received 50 mg/kg bw/day up to 3 g daily tiabendoazole for 10 days (total dose 25 to 30 g tiabendazole), which was administered twice a day (after breakfast and after evening meal). Symptoms of muscle pain and fever subsided 1 to 3 days after commencing tiabendazole. One woman withdrew due to drug-induced rash, fever and proteinuria. Side-effects occurred in 14/23 treated patients - the most common effects being nausea, retching and vomiting in 11/23 subjects, aversion to tablets (3/23), exanthema (3/23), impotence (2/23), diarrhoea (1/23), liver damage (1/23), fever (1/23) and dizziness (1/23) (Hennekeuser et al., 1969). 3. COMMENTS Information from a range of studies on thiabendazole was available for assessment, including data on kinetics and metabolism, acute toxicity, short-term and long-term toxicity, reproductive and developmental toxicity, and genotoxicity and observations in humans. Toxicokinetic studies revealed rapid absorption after oral dosing in mice, rats, dogs, and humans, peak plasma levels occurring within 3 h of drug administration. The drug was excreted in the urine and faeces. Elimination of tiabendazole and its degradation products appeared more rapid in humans than in mice, rats, and dogs, but metabolism was similar in mice, rats, and humans. The main urinary metabolites were the glucuronide and sulfate conjugates of 5-hydroxytiabendazole; there were also small amounts of unconjugated tiabendazole and the 5-hydroxy derivative. At very high doses, other minor metabolites were detected in rat and mouse urine. Single oral doses of tiabendazole were slightly toxic (LD50 > 2000 mg/kg bw) in mice, rats, rabbits, sheep and goats. Where deaths occurred, they appeared to be due to respiratory failure. Following repeated oral administration of tiabendiazole to mice, rats, dogs, chickens, sheep, pigs, and cattle, the most common finding was a reduction in food consumption and in body-weight gain. The effects on weight gain appeared to be greater than could be accounted for by the depressed food intake. Anaemia was seen in rats and dogs, and to some extent may have been related to poor nutrition. However, the presence of increased haemosiderosis in lymphoid tissues and reticulocytosis in some studies was suggestive of red cell destruction. The haematological changes occurred at dose levels of 100 mg/kg bw/day and above for 3 months in rats and 150 mg/kg bw/day and above for 3 months in dogs. The major target organs for toxicity were the hepatic system, thyroid gland, and lymphoid organs. Liver hypertrophy was seen in a 3-month study in rats at doses of 37 mg/kg bw/day and above, and in a 2-year study in dogs minor hepatobiliary changes were observed at 50 mg/kg bw/day and above. Thyroid follicular cell hyperplasia and colloid depletion were noted in a 3-month study in rats at 37 mg/kg bw/day and above and in a 16-week study in sheep at 800 mg/kg bw/day. The thymus, spleen, lymph nodes, and/or bone marrow exhibited lymphoid depletion or atrophy in a 28-day study in rats at 100 mg/kg bw/day and above and in a 16-week study in sheep at 800 mg/kg bw/day. Effects on blood cells, the liver, and lymphoid organs are commonly observed with benzimidazoles. Less common observations included both renal tubular degeneration and hyperplasia in one 7-day study in mice at 250 mg/kg bw/day and above and in one 3-month study in rats at 100 mg/kg bw/day and above. Gastric changes, including mucosal degeneration, cytoplasmic rarefaction, and/or necrosis, were produced in a 3-month study in rats at 100 mg/kg bw/day and above. Atrial thrombosis was present at high incidence in a two-year study in mice at doses of 200 mg/kg bw/day and above that resulted in the death of the affected animals. Tumour incidences were not increased in a two-year carcinogenicity study in mice. The NOEL was 6 mg/kg bw/day, and there was increased mortality at the next highest level, 60 mg/kg bw/day. The incidence of preputial or clitoral gland adenomas was increased at doses above 200 mg/kg bw/day in one of two 2-year studies in rats. Statistical significance was achieved only in males; the animals also displayed poor development due to severe effects on weight gain which suggests that the maximum tolerated dose was exceeded. The relevance of these tumours to low-dose exposure of humans to tiabendiazole is questionable. The NOEL was 10 mg/kg bw/day based on depressed weight gain at the next highest level, 40 mg/kg bw/day. Genotoxicity tests were generally negative. In one of three Salmonella typhimurium reverse-mutation assays, positive results were obtained in strain TA98 only. Further investigation showed that an impurity in some batches was responsible for the mutagenic activity. The manufacturer indicated that no positive results had been obtained in tests on several hundred further batches. In one laboratory, micronuclei were induced in mouse bone marrow and abnormal anaphase-telophase figures were increased in cultured Chinese hamster ovary cells. The effects were seen only at relatively high levels and may be indicative of the tubulin-binding activity characteristic of benzimidazoles (Annex 1, reference 97, section 3.2.4). A range of other assays for mutation, DNA damage, and cytogenetic activity were clearly negative. A multigeneration reproduction study in rats showed no adverse effects on reproduction parameters up to the highest dose tested, 80 mg/kg bw/day. In mice, litter size and survival during the lactation period were reduced at 750 mg/kg bw/day, but reproduction was unaffected at lower doses in a five-generation study. The NOEL was 30 mg/kg bw/day. Developmental toxicity was examined in mice, rats, rabbits, and sheep. In a series of studies in mice, embryotoxicity was observed at 1300 mg/kg bw/day and above, a dose that also resulted in the death of 5 of 39 females. Fetal malformations were produced at 240 mg/kg bw/day and above, the main abnormalities being a reduction deformity of the limbs, cleft palate, and fusion of vertebral arches and vertebral bodies. Unchanged tiabendazole was implicated as the probable embryotoxic and teratogenic agent. The only finding in several rat developmental studies was a reduction in fetal weight at 40 mg/kg bw/day and above. The NOEL was 10 mg/kg bw/day. In rabbits, abortions occurred at 600 mg/kg bw/day in one study on developmental toxicity, but not in the prior range-finding study at higher doses or in a repeat experiment in which similar treatment levels were used. Embryotoxicity and low incidences of domed head, hydrocephaly, and enlarged fontanelles were seen at 120 mg/kg bw/day and above in one study, but not in the repeat study at similar dose levels. All effects in rabbits were seen only at maternally toxic dose levels. The NOEL was 24 mg/kg bw/day. No adverse reproductive effects were observed in pregnant ewes given doses of 400 mg/kg bw/day. In a 24-week study in humans, male volunteers received 250 mg of tiabendazole/day; there were no treatment-related effects on a range of physical and biochemical parameters. The NOEL was 3-4 mg/kg bw/day. In another study, patients with trichinosis were given up to 3 g of tiabendazole daily for 10 days. Side-effects occurred in 14 of 23 patients, the most common being nausea, retching, and vomiting. 4. EVALUATION The Committee noted the availability of extensive data in support of the safety evaluation of tiabendazole and the manufacturer indicated that further studies had been completed or were under way. At the 1977 joint FAO/WHO meeting on pesticide residues, the study in human volunteers was used to establish an ADI of 0-0.3 mg/kg bw. The Committee considered that the investigations undertaken as part of this human study were limited in nature, and that in view of the availability of a number of recent well conducted animal studies, the NOEL should be derived from the animal data. The overall NOEL was 10 mg/kg bw/day based on reduced weight gain in a 2-year dietary study in rats and decreased fetal weight in a developmental study in rats. The Committee decided not to use the NOEL of 6 mg/kg bw/day from the 2-year study in mice as the next administered dose was considerably higher at 60 mg/kg bw/day. Using a safety factor of 100, the Committee established an ADI of 0-100 µg/kg bw for tiabendazole. The Committee noted that the ADI provided a safety margin corresponding to a factor of over 1000 with respect to the dose required for fetal malformations in mice. The Committee asked to see the results from recently completed and ongoing toxicological studies in order to update the database on tiabendazole. 5. 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See Also: Toxicological Abbreviations