CLOFENTEZINE EXPLANATION Clofentezine is an acaricide used for the residual control of mites. It acts primarily as an ovicide, with some activity on early motile stages. It was considered for the first time by the present meeting. IDENTITY AND PROPERTIES CHEMICAL NAME 3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine (IUPAC) 3,6-bis(0-chlorophenyl)-1,2,4,5-tetrazine SYNONYMS Apollo, Apolo, Acaristop; FBC code number NO 21314 STRUCTURAL FORMULAEMPIRICAL FORMULA C14 H8 Cl2 N4 MOLECULAR MASS 303.15 PHYSICAL STATE Both pure and technical materials are magenta-coloured crystalline solids. MELTING POINT 182 - 186°C (pure compound) 179 - 182°C (technical product) VAPOUR PRESSURE Approximately 10-16 mm Hg = 10-14 Pa at 25°C. SOLUBILITY Solubility (pure a.i.) at 20°C: chloroform 5 % dichloromethane 3.5 % acetone 0.5 % benzene 0.25% ethanol < 0.1 % hexane < 0.1 % solvesso 200 0.25% water < 1 µg/1 OCTANOL/WATER PARTITION COEFFICIENT log P = 3.1 STABILITY (a.i.) The stability in aqueous solutions is pH- and temperature-dependent; at pH 7 and 22°C, the half-life is approximately 35 hours, whereas at pH 5 and 22°C the half-life is approximately 250 hours. STABILITY (formulations) 50% wettable powder: stable under storage conditions at 40°C for 6 months; 50% aqueous suspension concentrate: stable under storage conditions at 12 - 38°C for 12 months. SPECIFICATION OF TECHNICAL MATERIAL The technical material has a purity in excess of 96% w/w, with the main impurities being: (a) 4-amino-3,5-bis(2-chlorophenyl)-4H-1,2,4-triazole <1% (b) 3,6-bis(2-chlorophenyl)-1,2-dihydro-1,2,4,5-tetrazine <1% (c) 2,5-bis(2-chlorophenyl)-1,3,4-oxadiazole <1% (d) total volatiles (water and acetic acid) <1%. FORMULATIONS AVAILABLE COMMERCIALLY 50% wettable powder; 50% aqueous suspension concentrate. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Biochemical aspects Absorption, distribution and excretion Mice 14C-Labelled clofentezine was administered orally at single doses of 10 mg/kg b.w. to 8 male and 8 female mice. Ninety-six hours after dosing, 91 - 95% of the administered dose had been recovered in the excreta, particularly in the faeces. Residues after 96 hours were highest in the liver (0.11 µg/g in males and 0.18 µg/g in females). All other tissues (including plasma) contained substantially lower residues, in most cases below the limit of detection (Campbell & Needham, 1982a). Rats Groups of 5 male and 5 female rats received single oral doses of 0.1, 10, or 1000 mg 14C-clofentezine/kg b.w. or 0.1 mg 14C-clofentezine (in ethanol)/kg b.w. i.v. Eighty-nine hours after dosing, 22 29% of the administered 14C-clofentezine in the low-dose groups had been recovered in the urine. Tissue residues were generally below the detection limit (< 0.01 µg/g), with occasional samples of liver, kidney, spleen, and heart tissues containing measurable residues (0.01 - 0.02 µg/g). Urinary excretion accounted for 19% (males) and 20% (females) of the administered dose after administra- tion of 10 mg 14C-clofentezine/kg b.w., with the highest residues in the liver (0.22 - 0.46 µg/g) and kidneys (0.12-1.28 µg/g). Plasma levels were 0.07 - 0.22 µg/ml, and the remaining tissues contained 0.02 - 0.2 µg/g in the mid-dose group. Urinary excretion fell to only 2.0% (males) and 4.5% (females) after the administration of 1000 mg 14C-clofentezine/kg b.w. In the faeces these percentages amounted to 99% and 96%, respectively. The highest residues were found in plasma (9.2-19.5 µg/ml), adrenals (2.9-17.1 µg/g), liver (2.8-14.0 µg/g), and fat (3.6 - 9.4 µg/g) (Challis & Needham, 1981a; 1982a,b). Ninety-six hours after i.v. administration of 0.1 mg 14C-clofen- tezine/kg b.w., 25 - 29% of the administered dose had been recovered in the urine, while in the faeces the residues were 82-85%. Tissue residues were very low (< 0.01 µg/g) (Challis & Needham, 1983). An examination of the distribution of radioactivity using whole-body autography, 24 hours after the oral administration of 10 mg 14C-clofentezine/kg b.w. to rats, showed that the liver, kidneys, and gut contain significant amounts of radioactivity. The carcass was clear of residues 96 hours after dosing (Needham, 1982). Rats (25/sex) received single oral doses of 10 mg 14C-clofen- tezine/kg b.w. Residues in plasma were measured 5 minutes to 18 hours after dosing. Total radioactivity showed maximum values of 1.3 - 1.6 µg/ml between 4 and 6 hours after dosing, which declined to 0.02 µg/ml at 18 hours after dosing. The concentration of clofentezine reached a maximum at 4 - 6 hours after dosing and then declined, with a half life of 2.5 - 2.7 hours (Campbell & Challis, 1982). Total radioactivity and unchanged clofentezine in plasma of rats dosed with 1000 mg 14C-clofentezine/kg b.w. rose to a maximum of 14-16 mg/l and 6 - 8 mg/l, respectively, between 6 and 8 hours after dosing. Unchanged clofentezine declined, with a half-life of 3.6 hours (Campbell & Needham, 1985b). When rats were fed daily oral doses of 20 mg clofentezine/kg b.w. for 25 days, the highest residues were found in the liver (3.2-4.4 µg/g). After 5 - 10 days a plateau was reached in the liver, kidneys, skin, and ovaries, with residues being 2 - 4 times higher than after 1 day. For residues in the adrenals, muscle, lung, and fat, no definite plateau could be established, but residues in fat were 8 times higher after 25 days than after 1 day. No accumulation occurred in bone, brain, spleen, testes, or blood (Challis & Needham, 1981c). Pre-treatment with clofentezine (27 g/kg diet for 28 days) prior to an i.v. dose of 0.1 mg 14C-clofentezine/kg b.w. resulted in an increase in urinary excretion (34% of the radiolabelled dose in both sexes). Tissue levels were not significantly altered (Challis & Needham, 1981b). Pre-treatment with clofentezine (10 mg/kg diet for 14 days) prior to an oral dose of 10 mg/kg 14C-clofentezine/kg diet did not change the excretion profile nor the residues disposition. The concentration of unchanged clofentezine in plasma reached a maximum of 0.11-0.19 µg/ml and declined, with a half-life of 1.6 hours. These results are consistent with an increase in the rate of metabolism when compared to a single dose (Challis & Needham, 1982c) (Campbell & Needham, 1985a). Pregnant rats received single oral doses of 10 mg 14C-clofen- tezine/kg b.w. on day 20 post-coitum (p.c.) after being orally dosed with 3200 mg clofentezine/kg b.w. from days 7 to 13 p.c., 320 mg/kg b.w. on day 14 p.c., and then remaining untreated from days 15 to 19 p.c. Residue levels were much lower in the fetus (0.7-1.2 µg/g) than in the maternal plasma (3.7 - 6.4 µg/g) 6 hours after dosing, showing that clofentezine and/or its metabolites do not readily cross the placenta. The clearance rate from the fetus appeared to be slower than from the maternal tissues (Needham, 1981). Rabbits Rabbits (3/sex) were orally dosed with 10 mg 14C-clofen- tezine/kg b.w. Urine and faeces were collected over 96 hours. In the first 48 hours, 88% of the dose was excreted (35% in the urine and 53% in the faeces). Residues after 96 hours were highest in the liver and kidneys (0.24 µg/g and 0.90 µg/g, respectively) (Campbell & Needham, 1982b). Dogs After oral administration of 10 mg/kg 14C-clofentezine to dogs (3/sex), 96% of the dose was excreted in the first 48 hours, mainly in the faeces (94%). Nearly complete excretion (99%) was observed after 96 hours, with only 2.0% in the urine. Residues were highest in bile (1.56 µg/ml), liver (0.21 µg/g) and thyroid (0.15 µg/g). All other tissues contained substantially lower residues. Peak plasma concentration (0.06 µg/ml) occurred 4 - 8 hours after dosing and by 72 hours it was reduced to 0.01 µg/ml or less (Campbell & Needham, 1982c). Dogs (2/sex) received single i.v. doses of 0.1 mg 14C-clofen- tezine/kg b.w. The bulk of the dose was excreted in the first 48 hours, mainly in the faeces (69%), and 21% in the urine. Tissue residues measured 144 hours after dosing were, with few exceptions, below the limit of detection (< 0.01 µ/g) (Campbell & Needham, 1981). Baboons A male and a female baboon were each given a single oral dose of 10 mg 14C-clofentezine/kg b.w. Ninety-six hours after dosing 15 - 28% of the administered dose was excreted in the urine and 42 - 44% in the faeces. Cage debris and wash together accounted for 9%. Tissue concentrations of radioactivity 96 hours after a second oral dose of 14C-clofentezine (following 52 daily doses of up to 400 mg unlabelled clofentezine starting 96 hours after the first oral dose) were similar in both baboons. The highest concentrations were detected in fat, liver, and kidneys (0.06 - 0.23% of administered radioactivity/kg wet tissue) while tissue-to-plasma ratios were on the order of 3 - 10 (Sortwell et al., 1983). Biotransformation The metabolism of clofentezine was studied in rats. Urine and faeces were collected 24 hours after dosing in a series of experiments in which rats received 14C-clofentezine orally at 10 mg/kg b.w. Absorbed clofentezine was extensively metabolized, with only 3% of the radioactivity in the urine present as the parent compound. Two major urinary pathways have been identified, one leading to a monochloro sulfur-containing derivative, 3-(2'-methylthio-3'-hydroxyphenyl)- 6-(2'-chlorophenyl)-1,2,4,5-tetrazine (in free and conjugated forms this metabolite accounted for 35% of the urinary radioactivity), and the other involving hydroxylation of clofentezine at the 3, 4, or 5 positions (see Figure 1). At least half of the administered dose was excreted in the faeces unchanged. The remaining clofentezine was extensively metabolized to more than 20 minor metabolites (Challis & Needham, 1985). a figure that could possibly be photocopied is on p. 9 of the summary submitted by FBC Ltd.
Figure 1. The metabolism of clofentizine in animals. Metabolites were also identified in a study with baboons. 4-Hydroxy-clofentezine in free and conjugated (beta-glucuronide conjugate) forms accounted for over 70% of the urinary metabolites. Other minor metabolites included 3-hydroxy-clofentezine (present as phenol and glucuronide conjugates) and a mono-chloro sulfur-containing compound, each accounting for less than 1% of the extractable radioactivity (Sortwell et al., 1983). The metabolism of clofentezine in rats, mice, rabbits, calves, goats, dogs, and baboons was qualitatively similar, with hydroxylation and replacement of chlorine with a methylthio group being the major pathways (see Figure 1). In calves and baboons, hydroxylation and subsequent conjugation were the most important pathways, while methylthiolation was more prominent in rodents and rabbits (Challis, 1985). The chromatographic profiles of liver extracts from rats, goats, and calves following oral administration of 14C-clofentezine were qualitatively similar to that of rat urine, with conjugates of 3-, 4-, and 5-hydroxylated clofentezine and a 3-(methylthio-hydroxyphenyl)-6- (2'-chlorophenyl)-1,2,4,5-tetrazine isomer (Needham & Challis, 1985). Toxicological studies Special studies on the endocrine system After treatment of male rats with 0 or 3% clofentezine for 1 month, a slight decrease in thyroxine (T4) half-life was observed in dosed rats compared to control animals (a slight increase occurred over this time period in the controls). A comparison of the effect of clofentezine treatment (0 and 3% for 4 weeks) in rats and mice (both sexes) showed that in rats there was a significant and rapid increase in thyroid uptake of iodine (compared to control animals) following i.p. dosing with [131I]-sodium iodide. This effect was not observed in mice (Challis & Creedy, 1985). Groups of 10 rats/sex were fed diets containing 0, 400, or 30,000 ppm technical clofentezine for 6 weeks. At 30,000 ppm clofentezine, T4, free T4 index, thyrotropin (TSH), progesterone, dehydroepiandrosterone, and liver weights were significantly increased in both sexes. Triiodothyronine (T3) was significantly increased in males only. Body weights and thyroxine binding capacity were significantly reduced in females. At 400 ppm clofentezine, T4 and liver weight were significantly increased in males and dehydroepi- androsterone was significantly increased in females (Saunders & Mallyon, 1986). Special studies on enzyme induction Mice Groups of 9 - 10 male Charles River CD1 mice received clofentezine at dietary levels of 0, 40, or 27,000 ppm for 8 weeks prior to examination of their livers for aniline hydroxylase and aminopyrine demethylase activities, for levels of cytochromes P-450 and b5, and for microsomal protein concentration. At 27,000 ppm the levels of cytochrome P-450 and b5 were increased 3-fold. The activity of aminopyrine demethylase rose by a factor of 2.2 and the mean liver weights increased by 35%. There was a marginal effect on the enzyme induction system at 40 ppm (Needham et al., 1984). Rats Groups of 6 male Charles River CD rats were fed diets containing clofentezine at levels of 0, 40, or 27,000 ppm for 8 weeks. Twenty-four hours after the final dose, their livers were examined for aniline hydroxylase activity, for levels of cytochromes P-450 and b5, and for microsomal protein concentration. At 27,000 ppm a 50% increase in the level of cytochrome P-450 and 2-fold increases in the level of cytochrome b5 and in the activity of aniline hydroxylase were found. In a subsequent study it was discovered that the effect could be reversed after a 2-week withdrawal period. No induction was observed at 40 ppm (Needham et al., 1983a,b). In a more extensive study, male and female rats were given diets with 0, 10, 40, or 400 ppm clofentezine for 2 weeks. At 400 ppm there was an increase in the level of liver protein (+ 12%), aldrin epoxidase (22 - 32%), ethoxycoumarin deethylase (20 - 49%), and cytochrome P-450 (24 - 26%) in both sexes. Liver weights and cytochrome b5 were increased in males only. At 40 ppm, liver ethoxycoumarin deethylase was slightly increased in males only (Creedy et al., 1985). Special studies on mutagenicity Clofentezine was negative in various mutagenicity assays (Table 1). Table 1: Results of mutagenicity assays on clofentezine Test Concentration Test system Object of clofentezine Results Reference Ames testa Salmonella 10 - 3300 negative McConville, typhimurium µg/plate 1980 TA98, TA100, TA1535, TA1537, and TA1538 Yeast testa,b Saccharomyces 12.5 - 200 negative Riach & cerevisiae D7 µg/ml McGregor, 1983 Mouse lymphoma Mouse L 5178Y 0 - 128 negative Bootman & assaya TK +/- cells µg/ml Rees, 1982 Micronucleus Mouse 2 × 0 to negative Hounsell, 1982 assay (bone 3200 mg/kg marrow) in 0.5% aqueous gum, orally Dominant Rat (males) 0 to 400 negative Jackson, 1983 lethal test mg/kg in the diet for 10 weeks a with and without metabolic activation b gene conversion and mitotic recombination Special study on reproduction Rats Groups of 6-week old Charles River rats (30 - 40/sex) were fed diets containing 0, 4, 40, or 400 ppm clofentezine. After 74 days of treatment the rats were paired for 20 days to start a 2-generation (2 litters/generation) study. Diets were maintained during mating, gestation, and lactation. Weanlings from the second litter were selected to become parents of the next generation. The F2a litters were grown to maturity. In the parental generations clinical signs and food consumption of treated rats were comparable to those of the control rats. Mating performance, pregnancy rate, fertility, and the duration of gestation and parturation were unaffected by clofentezine treatment. Parental toxicity was observed at 400 ppm, which included reduced body-weight gain of F1- and F2-generation females (maturation) and F1-generation females (post-coitum and post-partum), as well as significantly increased liver weights in F1- and F2-generation males. The increased liver weight was associated with minimal centrilobular hepatocyte enlargement and a slight reduction in periportal fat deposition. Toxic effects on litters included significantly reduced F1a and F2a pup weights and significantly smaller F2b litter sizes. The only toxic effect at 40 ppm was a significant increase in liver weights of F2a males. No adverse effects on fertility or reproductive performance were observed at 4 or 40 ppm clofentezine (Jackson & Chambers, 1984). Special studies on skin and eye irritation Application of clofentezine (0.2 ml of 333 mg/ml suspension) to the intact and abraded skin of 6 guinea pigs showed pink staining and very slight edema (in 2 out of 12 treated areas), both receding during observation (Crome et al., 1980b). A dermal irritation study with 6 guinea pigs was conducted with clofentezine using the 50% wettable powder formulation (0.2 ml of 6 or 947 mg/ml suspension). Observations were carried out at 24 hours and then daily for one week. Pink staining and erythema (between moderate and severe) were observed in all animals treated with 947 mg/ml suspension, and slight erythema was observed in 3/6 guinea pigs treated with 6 mg/ml suspension. The erythema regressed in one week. In 2/6 guinea pigs treated with 947 mg/ml suspension, very slight erythema was present when the animals were subjected to post-mortem examination (no abnormalities were observed) (Crome & Sanderson, 1981b). Treatment of the intact and abraded skin of 6 New Zealand white rabbits with clofentezine in 50% aqueous suspension produced very slight edema in 1/6 animals after 24 hours, with full recovery after 72 hours. Erythemal response could not be scored because of the bright pink color of the test substance (Cuthbert et al., 1983). Undiluted clofentezine (50% aqueous suspension) caused mild conjunctival irritation 24 hours after installation; it had disappeared at 48 hours (Cuthbert & Carr, 1983). Special study on skin sensitization Clofentezine had no sensitizing potential in guinea pigs when tested by the Magnusson & Kligman method (Teale, 1982). Special studies on teratogenicity Rats Groups of 34 - 35 pregnant female Sprague-Dawley CD rats received 0, 320, 1280, or 3200 mg clofentezine/kg b.w. by gavage from days 7 to 20 post-coitum (p.c.). The dams were examined twice daily for mortality, appearance, and behaviour. Body weights were recorded on days 1 and 4 and on days 7 to 21 p.c. The dams were killed on day 21 of pregnancy. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, weight and histopathology of the liver of the dams, number of live and dead fetuses, litter and pup weights, sex ratios, gross pathology, and histopathology (skeletal and visceral) of the fetuses. Maternal toxicity was observed at 1280 and 3200 mg/kg b.w. At the highest dose, body weights were significantly decreased (also when corrected for uterine content). Dose-related and significantly increased relative liver weights were observed at all dose levels; when corrected for the uterine contents, the increase was significant only at 1280 and 3200 mg/kg b.w. At histopathology, slight differential staining and enlargement of centrilobular hepatocytes were seen at 3200 mg/kg b.w. Litter size, litter weight, mean placental weight, and post-implantation losses were not affected at any of the treatment levels, although mean fetal weight was increased at 3200 mg/kg b.w. Embryonic and fetal development were unaffected by treatment (Jackson, 1982). Rabbits Groups of 14 - 15 pregnant New Zealand white rabbits were administered daily doses of 0, 250, 1000, or 3000 mg clofentezine/kg b.w. by gavage on days 7 to 28 of gestation. All animals were killed on day 29 of pregnancy. The dams were examined for mortality, appearance, behaviour, body weight, food consumption, serum cholesterol and serum triglyceride (day 29), weight of uterus, number of implantations, resorptions (early and late), and corpora lutea. The fetuses, delivered by caeserean section, were examined for the number alive and dead, litter and pup weight, gross pathology, and histopathology (skeletal and visceral). Maternal body-weight gain was significantly reduced at 3000 mg/kg b.w. (and to a lesser extent at 1000 mg/kg b.w.) initially during treatment, which was associated with reduced food intake. Mean litter and fetal weights were significantly reduced at 3000 mg/kg b.w. No visceral or skeletal anomalies were reported (Cozens et al., 1983). Acute toxicity The acute toxicity of clofentezine to several animal species is given in Table 2. Signs of clofentezine toxicity in rats after oral administration were confined to very slight salivation and slight urinary incontinence. No clinical symptoms after oral administration were observed in hamsters, mice, guinea pigs, or dogs, except for skin reddening in dogs at the highest dose. Short-term studies Mice Groups of mice (20 males and 20 females per group) were administered clofentezine (technical grade) in the diet for 90 days at dose levels of 0, 200, 1000, or 5000 ppm. All animals were observed daily for mortality and signs of toxicity while body weights and food consumption were recorded weekly. Haematology and clinical chemistry were performed at weeks 4 and 12 on 10 mice/sex/group, and urinalysis was performed at weeks 4 and 12 on 20 mice/sex/group. At termination of the study all animals were killed, selected organs were weighed, and complete gross and histopathological examinations were performed. There were no effects on mortality, appearance, body weight, food consumption, or haematology. Significantly increased plasma levels of triglycerides, calcium, and phosphate were observed in mice in the 5000- and 1000-ppm groups. Urinanalysis investigations revealed red stellar crystals in high-dose males. A dose-related urinary colour change from yellow, through orange, to red was observed in female mice. A treatment-related significant increase in liver weight was observed in both sexes of the mid- and high-dose groups, which was associated in males at 5000 ppm with centrilobular hepatocyte enlargement (5/20). The NOEL in this study was 200 ppm (Hounsell et al., 1982). Table 2. Results of acute toxicity assays on clofentezine LD501 LC502 Species Sex Route (mg/kg b.w.) (mg/l) Reference Mouse M+F oral > 3200 - Crome et al., 1980a Rat M+F oral > 3200 - Mallyon & Sanderson, 1980 Rat M+F dermal > > 1332 - Crome et al., 1980c Rat M+F i.p. > 800 - Crome et al., 1981 Rat M inhalation - > 9.08 Mallyon et al., 1981 Hamster M+F oral > 3200 - Crome & Sanderson, 1980 Beagle dog M+F oral > 2000 - Chambers et al., 1981 Guinea pig F oral > 1500 - Crome & Sanderson, 1981a 1 given as a 33% suspension in 0.5% gum tragacanth. 2 6 hours exposure with 80% wettable powder. Rats Groups of Charles River CD rats (20 males and 20 females/group) were fed diets containing 0, 3000, 9000, or 27,000 ppm clofentezine for 90 days. Five rats/sex/group were interim-sacrificed after 64 days and 5 rats/sex/group were maintained untreated for a 28-day recovery period. All animals were observed daily for mortality and physical signs. Body weights, food consumption, and water consumption were recorded weekly. Haematology, clinical chemistry, and urinalysis were performed at weeks 4 and 12 on 10 rats/sex/group. Cholesterol, triglycerides, and alanine aminotransferase were also measured after 6 weeks of treatment and at the end of the 4-week recovery period. Detailed gross and histopathological examinations were performed and selected organs were weighed. Dose-related hair loss was observed in 50% and 40% of the animals of the high- and mid-dose groups, respectively. Six animals died throughout the study, 2/6 of the 27,000 ppm group, probably because of the test substance. Body-weight gain was significantly reduced in males and females of the mid- and high-dose groups. In all dose groups some haematological and clinical chemistry values changed in a dose- related manner (e.g., haemoglobin and packed cell volume decreased, protein and cholesterol increased, and alkaline phosphatase and albumin/globulin ratios decreased in treated groups compared to controls. After the 4-week recovery period, low- and mid-dose values were comparable to controls. Relative liver, kidney, heart, and brain weights were significantly increased at all dose levels. Hepatocyte enlargement was noted at all dose levels. These effects had disappeared after the 4-week recovery period. In this experiment a NOEL could not be established (Ginocchio & Brooks, 1981). In a second 90-day study, groups of Charles River CD rats (25 males and 25 females per group) were fed diets containing 0, 40, 400, or 4000 ppm clofentezine for 90 days. Five males and 5 females per group were maintained untreated for a 6-week recovery period. All animals were observed daily for mortality and clinical signs, while body weights, food consumption, and water consumption were measured weekly. Haematology, clinical chemistry, and urinalysis were performed at 4, 8, and 12 weeks of treatment on 10 rats/sex/group, with subsequent monitoring of the regression of treatment-related effects. Organ weights and detailed gross and histopathological examinations were performed on 20 male and 20 female rats after 90 days of treatment and on the remaining animals at the end of the 6-week regression period. There were no effects on mortality or clinical signs. Body-weight gain was significantly decreased in females of the 4000 ppm group. A statistically-significant decrease in the haemoglobin concentration in the 4000 ppm group was observed after 4 (females only), 8, and 12 weeks of treatment. This decrease was also observed in the 400 ppm group after 12 weeks. Plasma cholesterol was significantly increased in both sexes in the high- and mid-dose groups after 4, 8, and 12 weeks of treatment; protein and albumin levels were increased in the same dose groups at the same times in males. All these effects had regressed after the recovery period. A dose-related colouration from orange to red in the urine was observed at all dose levels. Relative liver, kidney, and spleen weights were significantly increased in both sexes of the high-dose group and the relative liver weight was also increased at 400 ppm. Centrilobular hepatocyte enlargement was observed among male rats receiving 400 and 4000 ppm and among female rats receiving 4000 ppm clofentezine. There was evidence of slight, localized hepatocyte enlargement in males at 40 ppm. Retrospective examination of liver tissue by electron microscopy indicated moderate proliferation of smooth endoplasmic reticulum in centrilobular hepatocytes of males and females treated at 4000, but not at 40 ppm, clofentezine. These changes (but not the increase in liver weight) were completely reversible during the 6-week recovery period. The authors concluded that the NOEL in this study was 40 ppm clofentezine (Brooks & Turnbull, 1983). Dogs Beagle dogs (4/sex/group) were fed diets containing 0, 3200, 8000, or 20,000 ppm clofentezine for 90 days. Two dogs were killed for humane reasons in week 6 of the study (no relation to treatment: polyarteritis). Except for pink coloration of the faeces and an increased liver weight in all treated groups, no compound-related effects were reported on any of the tested parameters measured: body weight, food and water consumption, haematology, clinical chemistry, urinalysis, ophthalmoscopy, electrocardiography, organ weights, gross pathology, or histopathology (Hounsell et al., 1981). Beagle dogs (6/sex/group) were fed diets containing 0, 50, 1000, or 20,000 ppm clofentezine for 52 weeks. No mortality occurred. Apart from reddish-pink coloured faeces in high-dose dogs, no effects of treatment were observed on clinical signs, body weight, food and water consumption, ophthalmoscopy, electrocardiography, blood pressure measurements, or urinalysis. The highest dose was associated with moderate hepatotoxicity consisting of significantly-increased relative liver weights, enlargement of periportal hepatocytes with cytoplasmic eosinophilia, hepatomegaly, and increased plasma cholesterol triglycerides and alkaline phosphatase. Adrenal and thyroid weights were also significantly increased in males and females, respectively. At 1000 ppm clofentezine, minimal hepatotoxicity was observed, with increased liver weights in females only. The authors concluded that the NOEL was 50 ppm clofentezine in the diet (equal to 1.72 mg/kg b.w./day) (Chesterman et al., 1984). Long term studies Mice Groups of 52 male and 52 female CD mice were fed diets containing 0, 50, 500, or 5000 ppm clofentezine for 105 weeks. Observations included clinical signs, mortality, body weight, food consumption, haematological determinations (weeks 52 and 104) and organ weights and comprehensive histopathological examinations at the end of the experiment. At 5000 ppm clofentezine, increased mortality attributed to amyloidosis was observed in females. Growth was decreased during the first 52 weeks in males at the high-dose level and after 52 weeks decreases were also found in haemoglobin, haematocrit, and the number of red blood cells, especially in males. Total white blood cells were decreased in males after 52 and 105 weeks. Liver weights were increased in both sexes (significantly in females) at the high-dose level. Testes weights were significantly increased in males and an increased incidence of magenta-discoloured forestomach epithelium was noted in both sexes of the high-dose group. A higher number of benign liver cell tumours was observed in female mice dosed with 5000 ppm clofentezine, but the incidence was not significantly above that of the controls. At 5000 and 500 ppm an increased incidence of focal eosinophilic/basophilic hepatocytes was observed in females. The authors concluded that the NOEL was 50 ppm clofentezine (equivalent to 5 mg/kg b.w./day) (Lloyd et al., 1985). Rats Groups of 50 male and 50 female CD rats were fed diets containing 0, 10, 40, or 400 ppm clofentezine (technical) for 118 weeks (27 months). Additional supplementary groups of 20 male and 20 female rats were fed diets containing clofentezine at the same dietary levels and sacrificed after 12 months of treatment. Observations included clinical signs, mortality, body weight, food consumption, water consumption, haematology, clinical chemistry, urinalysis, ophthal- moscopy, and assays for thyroid function and sex hormones. At termination all surviving rats were killed, organs were weighed, and comprehensive histopathological examinations were made of tissues from each of these animals as well as from those dying during the study. The only treatment-related effects found after haematology and clinical chemistry analyses were decreased haemoglobin in females after 18 and 27 months and an increase in free T4 in males at 400 ppm. However, other parameters of thyroid function were not affected. There was no evidence of chronic toxicity in any tissues other than the liver and the thyroid. Increased relative liver weights and liver cell hypertrophy, characterized by centrilobular hepatocyte enlargement and by vacuolisation and fat deposits, were observed at 400 ppm in males (in females in a few cases). There was a slight increase in the number of follicular cell tumours in the thyroid at 400 ppm in males. This is considered of doubtful biological significance since a comparable incidence was observed in control males in a parallel study. The authors concluded that the NOEL was 40 ppm clofentezine in the diet (equivalent to 2 mg/kg b.w./day) (Ginocchio & Mallyon, 1985). Observations in humans Information useful for evaluation is not available. COMMENTS Clofentezine is an acaricide with low mammalian toxicity. Its mode of action is not understood. At high doses clofentezine exerts an effect on the liver (enzyme induction). Pretreatment with high dietary levels of clofentezine increases the rate of metabolism. It also affects thyroid function and impairs steroid hormone regulation. After oral administration of clofentezine to rats, it was excreted predominantly in the faeces. Low levels of residues were found in organs and tissues. The levels in plasma reached a maximum 4 to 6 hours after an oral dose of 10 mg/kg b.w. after which the level decreased, with a half-life of 2 - 3 hours. When clofentezine was given to rats during 25 days, a plateau was reached after 5 - 10 days in various organs, with the highest residues in the liver. The concentration in the liver after 25 days was 2 - 4 times higher than after 1 day, while fat residues were about 8 times higher. The material excreted in rat urine consisted mainly of metabolites. The two major pathways were hydroxylation of clofentezine and formation of a monochlorosulfur derivative. In the faeces 50% was excreted unchanged; the rest was metabolized to more that 20 minor metabolites. The metabolic pattern in other species (rabbits, dogs, baboons) was similar to the rat, with a higher excretion in the faeces than in the urine. The same metabolites were formed in rats, mice, calves, dogs, goats, and baboons, with methylthiolation being more prominent in rodents. In calves and baboons, hydroxylation was more prominent. Clofentezine has a low acute toxicity in rats, mice, hamsters, guinea pigs, and dogs. Clofentezine did not affect fertility or reproductive performance. Maternal effects (decreased growth, liver enlargement) were seen in all generations at 400 ppm. There were no indications of a teratogenic effect in rats or rabbits. A battery of mutagenicity tests did not indicate mutagenic potential. Short-term oral administration to mice, rats, and dogs produced liver enlargement as the main toxicological effect. In rats, decreased growth and decreased haemoglobin were observed at high-dose levels, as well as effects on biochemical parameters. Histopathological liver changes were in all cases associated with liver enlargement and liver enzyme induction. In addition, changes in thyroid function and steroid hormone regulation were observed (tested in special studies with rats). In long-term studies the same effects were found as in short-term studies. In mice a non-significant increase in benign liver tumours was found in females. In the rat study with relatively low dose levels a slight increase of thyroid follicular cell tumours was observed. Neither effect was considered to be an indication of carcinogenicity. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Mouse: 50 ppm in the diet, equal to 5 mg/kg b.w./day. Rat: 40 ppm in the diet, equivalent to 2 mg/kg b.w./day. Dog: 50 ppm in the diet, equal to 1.72 mg/kg b.w./day. ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0 - 0.02 mg/kg b.w. FURTHER WORK OR INFORMATION STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED EVALUATION OF THE COMPOUND 1. Observations in man. 2. Studies on the possible mode of action on the thyroid. 3. Information on possible enterohepatic recirculation. REFERENCES Bootman, J. & Rees, R. Technical NC 21314: Investigation of mutagenic 1982 activity in the TK +/- mouse lymphoma cell mutation system. Unpublished report No. TOX/82/167-38 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Brooks, P.M. & Turnbull, G.J. Technical NC 21314: 90-Day dietary 1983 toxicity study in the rat - additional examination of the liver histology. Unpublished report No. TOX/83/167-44 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Campbell, J.K. & Needham, D. Excretion and tissue residues of 1981 (14C) NC 21314 in male and female dogs following a single intravenous dose at 0.1 mg/kg. Unpublished report No. METAB/81/37 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Campbell, J.K. & Challis, I.R. Concentration of (14C) NC 21314 and 1982 its metabolites in the plasma of rats doses orally with NC 21314 at the rate of 10 mg/kg body weight. Unpublished report No. METAB/82/39 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Campbell, J.K. & Needham, D. Excretion and residues of (14C) 1982a NC 21314 in male and female mice given a single oral dose of 10 mg/kg. Unpublished report No. METAB/82/11 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Campbell, J.K. & Needham, D. Excretion and residues of (14C) 1982b NC 21314 in male and female rabbits following a single oral dose of 10 mg/kg. Unpublished report No. METAB/82/21 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Campbell, J.K. & Needham, D. Excretion and residues of (14C) 1982c NC 21314 in male and female dogs following a single oral dose of 10 mg/kg. Unpublished report No. METAB/82/6 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Campbell, J.K. & Needham, D. Concentration of (14C)-clofentezine and 1985a its metabolites in the plasma of rats given fourteen daily doses of clofentezine followed by a single oral dose of (14C)-clofentezine at 14 mg/kg bodyweight. Unpublished report No. METAB/85/6 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Campbell, J.K. & Needham, D. Concentration of (14C)-Clofentezine and 1985b its metabolites in the plasma of rats dosed orally with clofentezine at the rate of 1000 mg/kg bodyweight. Unpublished report No. METAB/85/2 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The excretion and distribution of 1981a radiolabelled residues in male and female rats dosed orally at 0.1 mg/kg with NC 21314. Unpublished report No. METAB/81/26 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The excretion and distribution of 1981b radiolabelled residues following a single intravenous dose of 0.1 mg/kg (14C)-NC 21314. Unpublished report No. METAB/81/38 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The distribution and level of 1981c radiolabelled residues in rats following repeat oral dosing with (14C)-NC 21314 at 20 mg/kg/day. Unpublished report No. METAB/81/32 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The excretion and distribution of 1982a radiolabelled residues in male and female rats dosed orally at 10 mg/kg with NC 21314. Unpublished report No. METAB/82/1 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The excretion and distribution of 1982b radiolabelled residues in male and female rats dosed orally at 1000 mg/kg with NC 21314. Unpublished report No. METAB/82/22 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The excretion and distribution of 1982c radiolabelled residues in male and female rats dosed orally at 10 mg/kg with (14C)-NC 21314 following 14 days pre-treatment by dosing with unlabelled NC 21314 at 10 mg/kg/day. Unpublished report No. METAB/82/37 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The excretion and distribution of 1983 radiolabelled residues in male and female rats dosed intravenously at 0.1 mg/kg with (14C)-NC 21314. Unpublished report No. METAB/83/14 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. A comparison of the metabolism of clofentezine in rat, 1985 mouse, rabbit, calf, dog and baboon. Unpublished report No. METAB/85/9 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Creedy, C.L. The effects of clofentezine on thyroid 1985 function. Unpublished report No. METAB/85/36 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Challis, I.R. & Needham, D. The metabolism of clofentezine in the rat. 1985 Unpublished report No. METAB/85/5 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Chambers, P.R., Sanderson, D.M., & Brooks, P.N. The acute oral 1981 toxicity of technical (pilot plant) NC 21314 to the male and female beagle dog. Unpublished report No. TOX/80/167-10 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Chesterman, H., Massey, J.E., Heywood, R., Buist, D., Street, A.E., 1984 Gopinath, C., & Rupanagudi, S. Rao. NC 21314 oral toxicity study in dogs (final report: repeated dietary administration for 52 weeks). Unpublished report No. TOX/84/167-68 from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England, and FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Cozens, D.D., Perkin, C.J., Barton, S.J., Clark, R., Offer, J.M., 1983 Gibson, W.A., & Street, A.E. Effect of technical NC 21314 on pregnancy of the rabbit (teratology study). Unpublished report No. FBC TOX/83/167-42 from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England and from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Creedy, C.L., Hemmings, P.A., & Needham, D. The effect of clofentezine 1985 on the hepatic mixed-function oxidase system of the male and female rat following dietary administration at 10, 40, or 400 ppm diet for two weeks. Unpublished report No. METAB/ 85/34 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Crome, S.J. & Sanderson, D.M. The acute oral toxicity of unformulated 1980 NC 21314 (CR 20099) to the hamster. Unpublished report No. TOX/80/167-8 from Fisons Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Crome, S.J., Sanderson, D.M., & Brooks, P.N. The acute oral toxicity 1980a of unformulated (CR 20099/4) to the male & female mouse. Unpublished report No. TOX/80/167-7 from Fisons Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Crome, S.J., Sanderson, D.M., & Brooks, P.N. The primary skin 1980b irritancy of unformulated NC 21314 (CR 20099/5) to the guinea pig. Unpublished report No. TOX/80/167-6 from Fisons Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Crome, S.J., Sanderson, D.M., & Brooks, P.N. The acute dermal toxicity 1980c of unformulated NC 21314 (CR 20099/5) to the male and female rat. Unpublished report No. TOX/80/167-4 from Fisons Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Crome, S.J. & Sanderson, D.M. The acute oral toxicity of technical 1981a (pilot plant) NC 21314 to the guinea pig (CR 20099). Unpublished report No. TOX/81/167-16 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Crome, S.J. & Sanderson, D.M. The primary skin irritancy of NC 21314 1981b 50WP to the guinea pig. Unpublished report No. TOX/81/167-13 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Crome, S.J., Sanderson, D.M., & Brooks, P.N. Acute intraperitoneal 1981 toxicity of pilot plant technical NC 21314 to the rat. Unpublished report No. TOX/80/167-5 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Cuthbert, J.A. & Carr, S.M.A. NC 21314 50 SC formulation primary eye 1983 irritancy study in rabbits. Unpublished report No. TOX/83/ 167-46 from Inveresk Research International, Musselburgh, Scotland, and from FBC, Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Cuthbert, J.A., Carr, S.M.A., & D'Arcy-Burt, K.J. NC 21314 50 SC 1983 formulation primary skin irritancy study in rabbits. Unpublished report No. TOX/83/167-47 from Inveresk Research International, Musselburgh, Scotland, and from FBC, Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Ginocchio, A.V. & Brooks, P.N. Technical NC 21314 (pilot plant, CR 1981 20099/5): the 90-day dietary toxicity study in the rat. Unpublished report No. TOX/81/167-23/1 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Ginocchio, A.V. & Mallyon, B.A. The oncogenicity and chronic toxicity 1985 of technical NC 21314 (clofentezine) in the diet to the rat. Unpublished report No. TOX/84/167-70 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Hounsell, I.A., Chambers, P.R., & Brooks, P.N. The 90-day subchronic 1981 oral toxicity of technical (CR 20099/8) NC 21314 in the diet to the dog. Unpublished report No. TOX/81/167-21/1 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Hounsell, I.A. A micronucleus study in mice using technical NC 21314. 1982 Unpublished report No. TOX/82/167-32 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Hounsell, I.A., Chambers, P.R., & Brooks, P.N. The 90-day subchronic 1982 oral toxicity of technical (pilot plant) NC 21314 in the diet to the mouse. Unpublished report NO. TOX/82/167-33 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Jackson, C.M. Technical NC 21314: Teratogenicity study in the rat 1982 (plus addendum). Unpublished report No. TOX/82/167-34 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Jackson, C.M. Technical NC 21314: dominant lethal mustation assay in 1983 male rats. Unpublished report No. TOX/83/167-45 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Jackson, C.M. & Chambers, P.R. Technical clofentezine: a dietary 1984 multigeneration study in the rat. Unpublished report No. TOX/84/167-66 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Lloyd, G.K., Spencer-Briggs, D.J., Heywood, R., Gopinath, C., & 1985 Cherry, C.P. Technical NC 21314: oncogenicity in the diet to the mouse (final report). Unpublished report No. TOX/85/ 167-80 from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England, and from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Mallyon, B.A. & Sanderson, D.M. The acute oral toxicity of 1980 unformulated NC 21314 (NC 21314/4, 99% pure) to the male and female rat. Unpublished report No. TOX/80/167-2 from Fisons Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Mallyon, B.A., Sanderson, D.M., & Brooks, P.N. The acute inhalational 1982 toxicity of NC 21314 80WP CR 15569, to the rat. Unpublished report No. TOX/81/167-24 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. McConville, M. Ames test for mutagenic activity carried out with 1980 technical NC 21314 (CR 20099/4). Unpublished report No. TOX/80/167-3 from Inveresk Research International, Musselburgh, Scotland, and from Fisons Ltd, Saffron Walden, Essex, England. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Needham, D. The distribution of radioactivity in the maternal tissues 1981 and foetuses of rats after an oral dose of (14C)-NC 21314. Unpublished report No. METAB/81/19 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Needham, D. The whole-body autography of (14C)-NC 21314 in rats 1982 following oral administration at 10 mg/kg body weight. Unpublished report No. METAB/82/23 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Needham, D., Challis, I., & Campbell, J. The effect of eight weeks 1983a dietary administration of NC 21314 at 40 and 27,000 mg/kg on the hepatic mixed function oxidase system of the male rat. Unpublished report No. METAB/81/31 (2nd Edn.) from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Needham, D., Challis, I., & Campbell, J. The effect of a two week 1983b withdrawal period on the induction of hepatic microsomal mixed function oxidases caused by dietary administration of NC 21314 at 27,000 mg/kg diet. Unpublished report No. METAB/82/2 (2nd Edn.) from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Needham, D., Campbell, J., & Challis, I. The effect of eight weeks 1984 dietary administration of NC 21314 at 27,000 and 400 mg/kg diet on the hepatic mixed-function oxidase system of the male mouse. Unpublished report No. METAB/82/20 (2nd Edn.) from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Needham, D. & Challis, I.R. An investigation into the nature of the 1985 residues present in the liver of the rat, goat and calf following the oral administration of clofentezine. Unpublished report No. METAB/85/8 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Riach, C.G. & McGregor, D.B. Technical NC 21314: induction of gene 1983 conversion and mitotic recombination in yeast. Unpublished report No. TOX/83/167-56 from Inveresk Research International, Musselburgh, Scotland, and from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Saunders, P.C. & Mallyon, B.A. Technical clofentezine: 6 week dietary 1986 investigation of thyroid function in the rat. Unpublished report No. TOX/85/167-77 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Sortwell, R.J., Richmond, G.P., Kirkpatrick, D., Finn, C.M., & Conway, 1983 B. Excretion and tissue distribution of radioactivity after oral administration of (14C)-NC 21314 to a male and female baboon. Unpublished report No. METAB/83/26 from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England, and from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England. Teale, H.J. Delayed dermal sensitisation study in the guinea pig, 1982 NC 21314 technical. Unpublished report No. TOX/82/167-36 from FBC Ltd. Submitted to WHO by FBC Ltd., Hauxton, Cambridge, England.
See Also: Toxicological Abbreviations Clofentezine (JMPR Evaluations 2005 Part II Toxicological)