PROPICONAZOLE EXPLANATION This chemical has not been previously evaluated by the WHO Expert Group. It is a systemic fungicide with high activity against several fungal pathogens which cause a wide range of problems such as powdery wildrew, rusts and leaf spot disease. The compound can be used for protective, curative and eradicative purposes. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Biochemical aspects Absorption, distribution and excretion Male and female mice were fed a diet containing 5, 100 and 2500 ppm propiconazole for 21 days, followed by a single oral dose of [14C]-phenyl propiconazole at a mean corresponding dose level (0.8/1.0, 16.8/21.5 and 434/475 mg/kg bw for males/females). Urinary excretion accounted for 45-81% of the administered dose after 96 hours and tended to be higher by males than by females. In the faeces 22-43% was excreted. At the lowest dose level (5 ppm propiconazole) the residual radioactivity in blood, liver, kidneys, lungs and in the remaining carcass was below 0.02 mg/kg propiconazole equivalents and accordingly higher at the 100 and 2500 ppm dose level. Residues in female mice were higher than in male mice, except in the kidneys where the males showed higher or equal values. Independent of the dose level and sex of the animals, the highest residues were found in the liver, up to 2.3 and 3.0 mg/kg in males and females of the highest dose level, respectively (Bissig, 1986). Orally administered single doses (0.5 and 25 mg/kg bw) of triazole labelled (3,5-14C)propiconazole to rats were rapidly excreted within 24 hours (74-84%). After 6 days, 0.04-0.15%, 28-46% and 53-67% had been recovered from expired air, faeces and urine respectively. Only about 0.4% of the administered dose remained in the tissues. Highest tissue residues were found in liver, blood and kidneys. No unchanged propiconazole was excreted in the urine (Hambock, 1979). Within 3 days after treatment of male rats with a single oral dose of about 32 mg/kg bw of triazole labelled (3,5-14C) propiconazole or a phenyl-[U-14C] labelled propiconazole, more than 95% of the dose was excreted. Of this, 52% was found in the urine and 43-48% in the faeces. The excretion pattern for both compounds was identical with no administered compound being found in the urine. Approximately 20 metabolic fractions were identified in the urine (Muecke, 1979). Single doses of triazole-14C-propiconazole (1.0 and 10.0 mg/kg bw) applied dermally to rats were absorbed through the skin following first order kinetics with half-lives averaging 24-31 hours for low and high dosed rats, respectively. Equal amounts of the dose were excreted within 72 hours in urine and faeces. The amount of residual radioactivity on the skin averaged 20% of the applied dose (Simoneaux, 1983). Feed consumption, milk production or the general health of a lactating goat were not affected after the daily oral administration of 5 mg triazole-14C-propiconazole for 10 consecutive days (which would correspond to 4.5 ppm in the feed) (Seim & Thomas, 1980). Of the total dose, 89% was excreted within 24 hours after the last administration (68% and 21% in urine and faeces, respectively). All tissues contained less than 0.02 mg/kg propiconazole equivalents, except liver (0.096 mg/kg) and kidney (0.029 mg/kg). The total radioactivity secreted with the milk reached a plateau at day three of 0.013-0.016 mg/kg, representing 0.18% of the total dose (Fischer & Cassidy, 1980). Biotransformation The metabolism of orally administered [14C]-phenyl propiconazole was studied in mice pretreated with unlabeled propiconazole followed by a single oral dose of [14C]-phenyl propiconazole at a corresponding dose level. The urinary metabolite pattern of propiconazole demonstrated a marked sex dependency. In male mice, 60% of the radioactivity in 0-24 hour urine was represented by one metabolite, this metabolite accounted for 30% in the 0-24 hour urine in female mice. This metabolite was identified by spectroscopy as the glucuronic acid conjugate of 1-(2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-yl) ethanol. This demonstrates that the major metabolic pathway in mice involves dioxolane ring cleavage (Bissig, 1986). The metabolism of propiconazole was also investigated in male rats administered a single oral dose of 31.4 mg/kg triazole- [3,5-14C-propiconazole]. Metabolites were isolated from first day urine and faeces excretion representing 44.5% and 36.2% of the applied dose, respectively. A wide array of biotransformations occurred leading to numerous metabolites. The major site of enzymatic attack oxidation of the propyl side chain leading via alcohols and diols to carboxy acids and alpha-hydroxy carboxy acid or cleavage of the dioxolane ring. The majority of the alcoholic and phenolic metabolites are renally excreted as sulfuric acid and glucuronic acid conjugates. In the rat the main metabolite is the alpha hydroxy carboxylic acid of propiconazole (Muecke, 1981; 1983). Comparative TLC studies on urines of propiconazole treated rats and goats revealed that the goat is using similar metabolic pathways for the elimination of propiconazole, except that sulfuric acid conjugation was not evident. The major metabolite in goat urine is less polar than the major metabolite in rat urine. The metabolic patterns in milk and liver of the goat were very similar and many of the individual metabolites are common to those present in the urine. There is evidence that the alkyl chain between the triazole and phenyl ring is cleaved and that most metabolites in milk and liver are associated with the triazole ring. The major metabolite (about 50%) in milk is 1,2,4-triazole (Madrid & Cassidy, 1981; 1983). Effects on enzymes and other biochemical parameters Doses of 0, 20, 80, 160 and 320 mg/kg bw propiconazole were orally administered to groups of male rats and mice for 2 weeks prior to a 24-hour food withdrawal and subsequent examination of their livers for enzymatic activities and protein, DNA, RNA and phospholipid contents. At dose levels of 80 mg/kg and greater, microsomal protein, phospholipid, cytochrome P-450 and the activities for ethoxycoumarin deethylase, epoxide hydrolase, UDP-glucuronosyltransferase and gamma-glutamyl transpeptidase were increased in rat livers. For the mouse a comparable pattern was observed. Cytosolic protein and soluble gluthathion S-transferase were increased from 160 mg/kg onwards. Simultaneous proliferation of smooth-surfaced endoplasmic reticulum was revealed by electron microscopic investigations (Waechter et al., 1984). Toxicological studies Special studies on carcinogenicity (See also under "long term studies"). The promoting action of propiconazole was studied in one day old rats. A group of 45 rats/sex received an initiating dose of 15 mg of N-nitrosodiethylamine (DENA), a known carcinogen, and other groups of 15 rats/sex were placed on a diet containing 2000 ppm propiconazole (purity 89.7%) or 500 ppm phenobarbital. Similar groups of rats, which received only the 0.9% saline solvent, were placed on the same diet. At days 36, 50 and 78, the rats (5/group) were killed, liver sections were prepared and examined for preneoplastic foci. These foci in liver sections were identified by histochemical demonstration of GGT (gamma-glutamyl transpeptidase). Two thousand ppm propiconazole as well as 500 ppm phenobarbital led to a significant increase of preneoplastic foci. The reaction was more pronounced in males. Initiation with DENA resulted in a higher incidence and a larger size of foci. It was concluded that propiconazole acted as a promotor in rat liver comparable to phenobarbital in this respect (Froelich et al., 1984). Special studies on teratogenicity Rats Groups of 25 female albino rats received 0, 30, 100 and 300 mg propiconazole (purity 91.0%)/kg bw by gavage from day 6-15 of gestation. All animals were killed on day 21 of pregnancy. The dams were observed for mortality, food consumption and body weight. The number of implantations, early and late resorptions and corpora lutea were recorded. The fetuses, delivered by caesarian section, were counted and weighed, gross pathology and histopathology (skeletal and visceral) were recorded. At 300 mg/kg bw 3 dams died and growth and food consumption were significantly reduced. No effects were found in the offspring except for one fetus with hydro-cephalus at 100 mg/kg bw and an increased total incidence of delayed ossification at the highest dose group. The delayed ossification at the highest dose level suggests a slight retardation of physiological growth and was considered to be related to maternal toxicity (Fritz et al., 1979a). Groups of 24 Charles River rats received 0, 30, 90, and 360/300 mg technical propiconazole (purity not specified)/kg bw by gavage from day 6-15 of gestation. (Propiconazole was administered as a suspension in 3% aqueous cornstarch containing 0.50% Tween 80.) The high dose level was reduced to 300 mg/kg bw during the first 6 days of treatment due to severe maternal toxicity. All animals were killed on day 20 of pregnancy. The dams were observed for clinical signs, mortality, body weight and food consumption. The number of corpora lutea, implantations, early and late resorptions were recorded. The fetuses, delivered by caesarian section, were counted and weighed, external, visceral and skeletal findings were recorded. The highest dose of 360/300 mg/kg bw and to a lesser extent also 90 mg/kg bw were maternally toxic as shown by clinical signs (lethargy, ataxia and salivation and signs of rales, prostration, hypothermia and bradypnea), decreased body weight gain and food consumption. No effects were observed in the offspring except for what the study authors described as a slight delay in the development of the urinary system (dilated ureters) at the highest dose group and an increased incidence of rudimentary ribs and non ossified sternebrae at 90 and 360/300 mg/kg bw. Cleft palate was observed in 3 fetuses from 3 litters, one (0.33%) at 90 mg/kg and two (0.7%) at 360/300 mg/kg bw, respectively. These findings were not statistically significant, even including one additional fetus at 90 mg/kg bw displaying cleft lip. This indicates embryotoxicity at maternally toxic dose levels. According to the authors, the low incidence of cleft palate may be a consequence of maternal toxicity (Geknis et al., 1987). In order to determine the reproducibility of the incidence of cleft palate in the above study an additional study was conducted. A total of 178 and 189 mated CD rats received 0 and 300 mg propiconazole/kg bw, respectively, by gavage from day 6-15 of gestation. All animals were killed on day 20 of gestation. The dams were observed for clinical signs, mortality, food consumption and body weight. The number of corpora lutea, implantations, live and dead fetuses was recorded. The fetuses, delivered by caesarian section, were sexed, numbered, weighed and examined for external abnormalities and cleft palate. Maternal toxicity was observed in dosed dams. Severe signs of toxicity including ataxia, coma, respiratory difficulties, lethargy, prostration, ptosis, salivation, palor, lacrimation as well as 4 deaths occurred. Bodyweight, bodyweight gain and food consumption were decreased. Mean number of viable fetuses and mean fetal weight were significantly reduced in the treated group. Cleft palate was observed in 2/2064 (0.1%) fetuses from 2/158 litters in the compound treated group but not in the control group. This figure is within the range of the frequency observed at maternally toxic doses in a large number of experiments (0-1.4%) (Mallows et al., 1987). Rabbits Groups of 20 pregnant female chinchilla rabbits were orally administered daily doses of 0, 30, 90 and 180 mg propiconazole (purity 91.1%)/kg bw from day 6-18 of gestation. All animals were killed on day 28 of pregnancy. The dams were observed daily, body weight and food consumption were measured. The number of implantations, early and late resorptions and corpora lutea were recorded. The fetuses were counted and weight and external, skeletal and visceral anomalies were recorded. There were no effects observed on the dams and offspring, except for sedation in high dosed dams and a reduction in food intake in dams (Fritz et al., 1979b). Groups of 19 pregnant New Zealand White rabbits were orally administered daily doses of 0, 100, 250 and 400 mg propiconazole (purity not stated)/kg bw from day 7-19 of gestation. (Propiconazole was administered as a suspension in 3% cornstarch with 0.5% Tween 80.) All animals were killed on day 29 of pregnancy. The dams were observed for clinical signs, mortality, body weight and food consumption. The number of implantations, corpora lutea, early and late resorptions and live and dead fetuses were recorded. The fetuses, delivered by caesarean section, were sexed and weighted and examined for external, visceral and skeletal anomalies. Dams of the high dose group had an increased incidence of stool variations and abortions/early deliveries. Decreased feed consumption and body weight gain were observed at 250 and 400 mg/kg bw and a decreased body weight was observed at 400 mg/kg. The incidence of resorptions was significantly increased at 400 mg/kg bw. No effects were found in the offspring except for a significantly increased incidence of fully formed thirteenth ribs at 400 mg/kg bw (Giknis, 1986). Special studies on eye irritation Propiconazole (0.1 M) was instilled in the left eye of 6 New Zealand white rabbits (3/6 eyes were rinsed). In unrinsed eyes 24 hours after treatment, corneal irritation (score 1-2) was observed in 2/3 eyes ands slight conjunctival irritation (score 1) in 1/3 eyes. Forty eight hours after treatment the corneal irritation was still present in 1/3 animals. Full recovery was observed after 72 hours. The substance is minimal irritating. Rinsing immediately after application alleviated the irritation (Ullmann, 1978b). Special studies on metabolites Investigations of the toxicological properties of triazolyl alanine, a plant metabolite of propiconazole and other triazole fungicides, demonstrates that triazolyl alanine is virtually nontoxic in acute, subchronic, mutagenicity and reproduction studies (Bayer et al., 1986). Special studies on mutagenicity Propiconazole was negative in various mutagenicity assays. See table 1. for a summary of the studies considered. Special studies on reproduction Rats Groups of Tif: RAIf (SPF) albino rats (10 males and 20 females/group) were fed diets containing 0, 400, 2000 and 5000 ppm propiconazole (purity 91.9%) and subjected to a two generation reproduction study of one liter each. F0 rats received the diet from days 28-32 post partum until weaning of the F1 rats (160 days) and the selected F1 rats until weaning of the F2 rats. F0 and selected F1 rats were sacrificed after weaning of F1 and F2 rats, respectively. Not selected F1 rats and F2 rats were sacrificed after weaning (28-30 post partum). Table 1. Special Studies on the Mutagenicity of propiconazole. Type of test Test object Concentration Purity Results References of propiconazole In vitro Ames test Salmonella 25 µg upto 83.9% negative Arni & (with and without typhimurium 2025 µg/0.1 ml (1) Muller, metabolic activation) TA 98, TA100 in DMSO 1979 TA 1535 and Ames test Salmonella 20 µg upto 90.7% negative Deparade & [with and without typhimurium 5120 µg/0.1 ml (1) Arni, 1983 metabolic TA98, TA100, in DMSO activation (2)] TA 1535, TA 1537 and TA 1538 Yeast test Saccharomyces 10, 30, 90 and ? negative Arni & (with and without cerevisiae D7 270/µg/ml in (1) Muller, metabolic activation) DMSO; 90 and 1982 270/µg/ml toxic (1) positive control yielded positive results (2) induction of liver enzyme activity with Aroclor 1254 and propiconazole (3) test results available only in summary form Table 1. cont. Type of test Test object Concentration Purity Results References of propiconazole In vitro Mouse lymphoma mouse L 5178Y7.81, 15.62, 90.7% negative Strasser & forward mutation TK +/- cells 31.25, 62.5 (1) Muller, assay (with and and 125.0 µg/ml 1982a without metabolic in DMSO activation) Chromosomal human 11.25, 22.5, 89.7 negative Strasser & aberration test lymphocytes 45.0, 90.0 and (1) Arni, 1984 (with and without 180 µg/ml in metabolic activation) 1% DMSO 180 µg/ml toxic DNA repair test rat 0.69, 3.44,17.2 90.7% negative Puri & hepatocytes & 86 nl/ml in DMSO (1) (3) Muller, 1982b DNA repair test human 0.077, 0.38, 1.92 90.7% negative Puri & fibroblasts & 9.6 nl/ml (1) Muller, in DMSO 1982a Transformation mouse 1.16, 2.31, 4.63 90.7% negative Strasser & assay fibroblasts 9.25 & 18.50 µg/ml (1) Muller, (BALB/3T3) in DMSO 1982c (1) positive control yielded positive results (2) induction of liver enzyme activity with Aroclor 1254 and propiconazole (3) test results available only in summary form Table 1. cont. Type of test Test object Concentration Purity Results References of propiconazole In vivo Dominant lethal Tif:MAGf single oral dose 90% negative Hool & test (SPF) mice of 165 or Muller, 495 mg/kg in 1979 2% CMC Sister chromatid Chin. hamster single oral dose 90.7% negative Hool & exchange assay bone marrow of 255, 510 or (1) Muller, cells 1020 mg/kg in 1982c arachid oil Host mediated Salmonella 350, 700 and 90.7% negative Arni & assay typhimurium 1400 mg/kg in (4) Muller, TA98, TA100, 2% CMC 1983 TA1535 NMRI mice Host mediated mouse L 5178Y496 mg/kg, 90.7% negative Strasser & assay cells orally in Muller, DBA mice 2% CMC 1982b (1) positive control yielded positive results (4) test was carried out with induced and not induced mice (with propiconazole) Table 1. cont. Type of test Test object Concentration Purity Results References of propiconazole In vivo Nucleus anomaly Chin. hamster 251, 502 and 90% negative Hool et al. test bone marrow 1004 mg/kg (1) 1979 cells orally in PEG twice, 24 hr. apart Chromosomal Mouse 166 or 498 mg/kg 90.7% negative Hool & aberration test spermatogonia orally in 0.5% Muller, CMC once on days 1982a 0, 1, 2, 3 & 4 Chromosomal Mouse 166 or 498 mg/kg 90.7% negative Hool & aberration test spermatocytes orally in 0.5% Muller, CMC once on days 1982b 0, 2, 3, 5 & 9 (1) positive control yielded positive results (4) test was carried out with induced and not induced mice (with propiconazole) Observations were made on the general condition and behaviour. Reproduction parameters such as delivery date, mating and fertility indices, duration of gestation, implantation rate and general condition during weaning, litter size, number and percent of live and dead fetuses, litter and pupweight and abnormalities were recorded. Autopsy and histopathological examinations were performed on a selected number of F1 and F2 weanlings and F1 adults. Bodyweight gain and food consumption was reduced in F0 males at 5000 ppm and in F0 females at 2000 and 5000 ppm. At 5000 ppm all the pregnant females died shortly before or after birth of the F1 generation. For this reason, the study was discontinued for this group. The implantation rate in F0 females was significantly reduced in the 5000 ppm dose group. Body weight gain was reduced in pups of both the dose groups 400 and 2000 ppm. The reproductive parameters were not affected. A slight significant increase of the rel. liver weight accompanied by slight hypertrophy of the centrilobular hepatocytes was noted in the F1 adults of the 2000 ppm group (Fritz et al., 1981). Groups of 15 male and 30 female, 35 days old rats received 0, 100, 500 and 2500 ppm propiconazole (purity 89.7%) in the diet in a two generation (two litters/ generation) study. Diets were maintained during mating, gestation and lactation. Maternal toxicity (significantly decreased, body weight gain and food consumption) was observed at 2500 ppm and to a lesser extent at 500 ppm. F1 males showed a slightly decreased body weight gain at 2500 ppm. Reproductive observations and performance, expressed in indices for mating, male and female fertility and gestation were not affected. F2a litter size and F2b pup survival (during lactation) were significantly reduced at 2500 ppm. At day 0, F2b pup weight was equally but significantly decreased in all dose levels. Pup weight (at day 4-21) was significantly decreased in F1a, F1b, F2a and F2b pups at 2500 ppm and also in F2b pups at 500 ppm (at day 14-21). A significant decrease in mean final body weight, brain weight (F1a only) and testes with epididymus weight was observed in F1a and F2a male pups. F2b pups exhibited significant reductions in final body weight and F2b female pups showed a significantly decrease in absolute brain weight. In F0 and F1 females and F1a, F2a and F2b male pups relative brain weight was significantly increased at 2500 ppm. Other organs (except ovaries) were not weighed. Gross pathology showed no significant changes. At 2500 and 500 ppm, a statistically significant increase of cellular swellings of hepatocytes was observed in the liver of both F0, F1b, F1, F2b male and female rats. The incidence of clear-cell change in the liver was also significantly increased in male F0 rats and male and female F1 rats at 2500 and 500 ppm. The NOAEL in this study is 100 ppm (Salamon et al., 1985). Special studies on skin irritation Treatment of the intact and abraded skin of 6 New Zealand white rabbits with propiconazole produced erythema (score 1-2) and oedema ()score 1) in all animals after after 24, 48 and 72 hours. Full recovery was observed after 7 days. The compound is slightly irritating (Ullmann, 1978c). Special studies on skin sensitization Propiconazole has no sensitizing potential in the guinea-pig when tested by Maurer's optimization test (Ullmann, 1979b). Acute toxicity The acute toxicity of propiconazole to several animal species is given in table 2. Table 2. Acute toxicity of propiconazole in animals species sex route LD50 LC50 references (mg/kg bw) (mg/l) Mouse M&F oral 1490 -- Bathe, 1979a Rat M&F oral 1517 -- Bathe, 1978 M&F oral 2233* -- Bathe, 1979d M&F oral 1211** -- Bathe, 1979e M&F dermal >4000 -- Bathe, 1979b M&F i.p. 508 -- Bathe, 1979c Rabbit M&F oral 1344 -- Ullmann, 1978a M&F dermal >6000 -- Ullmann, 1979a * Cis-isomer ** Trans-isomer Short-term toxicity Rats Groups of RAIf (SPF) rats (10/sex/group) were orally administered 0, 50, 150 and 450 mg propiconazole (purity 91.6%) in 2% CMC/kg bw for 28 days. All animals were observed daily for mortality and signs of toxicity while body weight and food consumption were recorded weekly. Haematology, clinical chemistry and urinalysis were recorded at the end of the test period on 5 rats/sex. All surviving animals were killed and a complete gross and histopathological examination was performed. Selected organs were weighed. There were no effects on body weight. Food consumption was decreased in high dosed females and these animals showed sedation, dyspnoea and ruffled fur during the first week of treatment. One mid and 2 high dose females died from causes which were not related to treatment. Haematological changes were generally unremarkable. Clinical chemistry determinations and urinalysis were within normal biological variation, except for an increased blood glucose concentration and a decreased chloride concentration in females at 450 mg/kg bw. A dose-related increase in absolute as well as relative liver weight was observed in males at 150 and 450 mg/kg bw and in females at all dose levels. Histopathology revealed minimal to moderate hypertrophy of hepatocytes in all rats of the 450 mg/kg dose group and in 4/10 males and 8/10 females of the 150 mg/kg dose. Recent areas of necrosis were observed in the liver parenchyma in 3/10 females of the highest dose group (Basler et al., 1980). Groups of Tif:RAIf SPF rats (20/sex/group) were orally administered 0, 240, 1200 and 6000 ppm propiconazole (purity 90%) in the diet for three months. All animals were observed daily for mortality and clinical signs while body weight and food consumption were observed weekly. Haematology, blood chemistry and urinalysis examinations were recorded at weeks 4, 8 and 13 on all rats. At the termination of the study all animals were killed, selected organ weights and complete gross and histopathological examinations were performed. There were no effects on mortality and appearance. A trend to reduced food consumption was noted in the 6000 ppm group during the first three weeks. Body weights were significantly decreased in males and females at 6000 ppm and in females at 1200 ppm. At the highest dose level Hb, Ht and number of erythrocytes were lower than the controls, in most cases significantly, after 4, 8 and 13 weeks. Alkaline phosphatase activity in female rats at the high dose level was increased and gamma-glutamyl transpeptidase activity was increased in male and female rats. Urea and total protein were increased at 6000 ppm and a tendency for increased urea was present at 1200 ppm. Relative brain, liver, testes and ovaries weight were significantly increased in males and females at 6000 ppm. In high dosed females, relative heart, kidney and adrenal weight were also increased. At 1200 ppm, relative brain, heart, liver, adrenal and ovaries weight were significantly increased in females. In the spleen of all high dosed females a slight increase of haemosiderosis was observed. No adverse effects were observed at 2140 ppm (Sachsse et al., 1979a). Groups of RAIf SPF rats (20/sex/group) were exposed by inhalation to aerosols at 0, 21, 85 and 191 mg technical propiconazole (purity 91.9%)/m3 6 hours/day for 5 days/week for 90 days (head only). No toxic symptoms or treatment related deaths occurred (2 male control rats died and 1 female rat of the lowest dose group died). Food intake, food conversion, opthalmoscopy, haematology and blood chemistry values were within normal ranges. Mean female body weight was decreased in all dose groups (significantly in the high and low dose group)and in males at the 85 mg/m3 dose group. Liver weight was increased in females at the high dose level. Neither gross nor histopathological changes were observed in propiconazole exposed rats (Sachsse et al., 1980a). Rabbits New Zealand white rabbits (10/sex/group) received dermal applications of 0, 200, 1000 and 5000 mg propiconazole (purity 91.9%)/kg bw on the shaven skin of the back. The skin of half the rabbits, at the exposure site, was abraded prior to, and once weekly during the experiment. The rabbits were exposed 6 hours/day, 5 days/week for 3 weeks. High and mid dosed rabbits showed dyspnoea, tremor, ataxia, sedation and ruffled fur starting from day 4. No compound related effects were observed on mortality, food consumption, food conversion, haematology and blood chemistry (except for increased gamma-glutamyl transpeptidase in high dosed males and females). Body weight was decreased in high dose females and relative liver weight was significantly increased in males and females. Slight skin irritation was observed in all treated rabbits. Local dermal changes showing focal acanthosis and hyperkerntosis of the epidermis and chronic inflammatory infiltration in the dermis were observed. The changes were dose related and more pronounced in the highest dose group. Focal necrosis and ulceration of the epidermis was noted in 4/20 rabbits of the highest dose group (Sachsse et al., 1979b). Dogs Beagle dogs (4/sex/group) were administered diet containing 0, 50, 250 and 1250 ppm propiconazole (purity 93%) for three months. No compound-related effects were observed with respect to mortality, clinical signs, food consumption, opthalmoscopy, haematology, urinalysis and blood chemistry (except for an increased activity of alkaline phosphatase in males and females at 1250 ppm). In females of the highest dose group, a tendency for a lower body weight gain was observed. Liver weight was slightly increased in both males and females at 1250 ppm. In 3/6 dogs of the highest dose group a slightly increased amount of lymphoid follicules in the mucous membrane of the stomach was observed. The NOAEL is 250 ppm, equivalent to 7 mg/kg/day (Sachsse et al., 1980b). Beagle dogs (5-7/sex/group) were orally administered 0, 5, 50 and 250 ppm propiconazole (purity 90.2%) in the diet for one year. 2 dogs/sex in the control and high dose group were maintained untreated for a 28 day recovery period. No compound related effects were reported in any of the tested parameters measured: clinical signs, mortality body weight, food consumption, haematology, clinical chemistry, urinalysis, opthalmoscopy, gross and histopathology. Organ weights were not different than those of control animals except for significantly increased relative adrenal weight in females of the 50 and 150 ppm dose group (not dose related) and a decreased relative pituitary weight in males of the highest dose group. The NOAEL was 250 ppm in the diet, equivalent to 7 mg/kg/bw (Johnson et al., 1985). Long term studies Mice Groups of 52 male and 52 female mice (CD) were fed diets containing 0, 100, 500 and 2500 ppm propiconazole (purity 91.9%) for 104 weeks. Satellite groups of 12 male and 12 female mice were fed diets containing propiconazole at the same dietary levels and sacrificed after 53 weeks of treatment. Observations included clinical signs, mortality, body weight, food consumption, food efficiency, water consumption, haematology, clinical chemistry and urinalysis. Surviving mice were sacrified after 104 weeks. Organs were weighed and comprehensive histopathological examinations were made. During the first 26 weeks mortality was significantly increased in males at 2500 ppm. At 2500 ppm, growth rate was reduced significantly throughout the study in male and female mice. In male mice of the same dose group, food consumption was increased during the study and during the first 5 months in females. Ht and Hb were decreased at 2500 ppm in males and females (males only at week 52). ASAT, ALAT and alkaline phosphatase activity was significantly increased in males (week 52 and 104) and to a lesser extent in females (week 52) receiving 2500 ppm. Lower cholesterol levels (statistically significant in males) were observed at week 52 in mice receiving 2500 ppm and in females of the same dose group at termination of the study. Liver weight was significantly increased in male and female mice receiving 2500 ppm and in males (only significantly after 53 weeks) receiving 500 ppm. The gross examination revealed a higher incidence of liver masses and/or enlarged livers in males and females receiving 2500 ppm propiconazole. Histological examination showed an increase in the incidence of benign and malignant liver cell tumors in males at 2500 ppm (see table 3.). In the male animals a trend was present for a shorter latency period for the liver tumours, since at the interim kill (week 53) the incidence of benign liver tumours was 0/11, 0/11, 1/11 and 2/9 for control, 100, 500 and 2500 ppm test groups, respectively. For malignant tumours, the incidences were 1/11, 0/11, 2/11 and 3/9 respectively. The liver tumour incidence in females at 2500 ppm appeared marginally increased: 5/52, 1/52, 2/52 and 8/52 for control, 100, 500 and 2500 ppm, test groups, respectively). The NOAEL for non neoplastic effects was 1000 ppm in the diet, equivalent to 10.04 mg/kg bw in males and 55.60 mg/kg bw in females (Hunter et al., 1982b). The NOEL for neoplasia was 500 ppm. Table 3. Incidence of liver cell tumors in male mice Occurrence Control 100 ppm 500 ppm 2500 ppm Animals with 16/51 11/51 12/50 31/52 preneoplastic foci Animals with liver 12/51 7/51 8/50 21/52 adenomas only Animals with liver 15/51 7/51 14/50 23/52 carcinomas* * including animals with both liver adenomas and carcinomas Rats Groups of 80 male and 80 female CD Sprague-Dawley rats (of which 50 animals/sex/group were for tumorigenic evaluation and 10 animals/sex/dose for interim kills, 10 animals/sex/dose for haematology and 10 animals/sex/dose for blood chemistry and urinalysis) were fed diets containing 0, 100, 500 and 2500 ppm propiconazole (purity 91.9%) for 107-109 weeks. Observations included clinical signs, mortality, body weight, food and water consumption, haematology and urinalysis (10 animals/sex/group), clinical chemistry (10 animals/sex/group) opthalmoscopy and hearing tests, absolute and relative organ weight (interim kill and all surviving animals at the end), gross and histopathology. At 2500 ppm, propiconazole growth, food consumption and food efficiency was reduced. The survival of the rats in this dose group was better (significantly with females), possibly caused by the decreased food consumption. At 500 ppm, growth and food efficiency was decreased in females during the first 26 weeks. At 2500 ppm, numerous changes in haematology (Hb, Ht, MCV and MCH decreased) were observed. At 2500 ppm, the concentrations of urea and cholesterol, were increased and of glucose decreased (to a greater extent in females) and the A/G ratio decreased. At 500 ppm, only in a few cases were changes observed in haematology and blood chemistry which were compound related. At interim kill as well as at the termination of the study, an increased liver weight was observed in males and females at 2500 ppm associated with an increased incidence of foci of enlarged liver cells in females. At 52 weeks, heart and ovaries weight was increased in females at 2500 ppm. No enhanced tumour incidence was observed in treated animals. The NOAEL was 100 ppm (equal to 3.60 mg/kg males - 4.57 mg/kg females) (Hunter et al., 1982a). COMMENTS After oral administration to mice and rats the compound was rapidly excreted via the urine and faeces. Excretion was generally higher in the urine. No unchanged propiconazole was excreted in the urine. The compound is metabolized by oxidation of the propyl side chain, cleavage of the dioxolane ring and oxidation of the triazole and phenyl rings. The alcoholic and phenolic derivatives are excreted as sulphuric and glucuronic acid conjugates. The compound apparently induces drug metabolizing enzymes in the liver of rats and mice. Propiconazole presented low acute toxicity in mice, rats and hamsters. It did not show any effects on reproductive performance. Maternal effects decreased pup growth, swelling of liver hepatocytes and an increased incidence of clear-cell changes in the liver were seen at 500 ppm and above in a two-generation reproduction study in rats. In three rat and two rabbit teratogenicity studies, embryonic effects were found at maternally toxic dose levels, but no teratogenic effects were observed. Subchronic administration of propiconazole to rats, rabbits and dogs revealed body weight reduction and liver changes indicative of increased metabolic activities with necrosis at relatively high doses as the main toxicological effects. Propiconazole was not mutagenic in a battery of mutagenicity tests. In long-term studies the same effects were found as in short-term studies. In the mouse study the highest dose (2500 ppm) was associated with a significant increase in preneoplastic and neoplastic liver changes in males only. In the two year feeding study with rats no indication of carcinogenicity was found. However, propiconazole has enzyme-inducing properties In a separate study in rats, the effect of propiconazole on proliferative liver changes, initiated by N-nitrosodiethylamine, was very similar to that of phenobarbital. An ADI was allocated for propiconazole, on the basis of the toxicological data in rat and dog. The committee noted that application of propiconazole resulted in residues of triazolylalanine as well as propiconazole. The available data on propiconazole cannot be used to assess the toxicity of triazolylalanine since this does not appear to be a metabolite in animal species other than ruminants. While an ADI has been allocated for propiconazole, attention is drawn to the need for an evaluation of triazolylalanine to assess the toxicological significance of this metabolite. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Rat: 100 ppm in the diet, equal to 4 mg/kg bw/day Dog: 250 ppm in the diet, equivalent to 7 mg/kg bw/day ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.04 mg/kg bw. STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED EVALUATION OF THE COMPOUND Observations in man. REFERENCES Arni, P. & Muller, D., 1979. Salmonella/Mammalian-microsome mutagenicity test with CGA 64250. Unpublished report, No. experiment: 78/2577, January 4, 1979 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Arni, P. & Muller, D., 1982. Saccharomyces cerevisae D7/Mammalin-microsome mutagenicity test in vitro with CGA 64250. Unpublished report, No. experiment: 81/1558 d.d. August 19, 1982 from Ciba-Geigy. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Arni, P. & Muller, D., 1983. Intrasanguine host-mediated assay with Salmonella typhimurium. Unpublished report, test No.: 83/0120 d.d. May 10, 1983 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Basler et al., 1980. 28-Days cumulative toxicity study with CGA 64250 techn, on rats. Unpublished report, project No.: 79/1659 d.d. November 11, 1980 from Ciba-Geigy Ltd, Exp. Toxicology Sisseln. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bathe, R., 1978. Acute oral LD50 in the rat of technical CGA 64250. Unpublished report, project No.: 78/5244 d.d. December 7, 1978 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bathe, R., 1979a. Acute oral LD50 in the mouse of technical CGA 64250. Unpublished report, project No.: 78/5243 d.d. May 7, 1979 from Ciba-Geigy Ltd, Exp. Toxicology Sisseln. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bathe, R., 1979b. Acute dermal LD50 in the rat of technical CGA 64250. Unpublished report, project No.: 78/5245 d.d. January 22, 1979 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bathe, R., 1979c. Acute intraperitoneal LD50 in the rat of technical CGA 64250. Unpublished report, project NO.: 78/5246 d.d. March 13, 1979 from Ciba-Geigy Ltd., Exp. Toxicology Sisseln. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bathe, R., 1979d. Acute oral LD50 in the rat of CGA 64250. Unpublished report, project No.: 79/1655 d.d. November 21, 1979 from Ciba-Geigy Ltd., Exp. Toxicology Sisseln. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bathe, R., 1979e. Acute oral LD50 in the rat of CGA 64250. Unpublished report, project No.: 79/1656 d.d. October 12, 1979 from Ciba-Geigy Ltd., Exp. Toxicology Sisseln. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bayer et al., 1986. Properties and safety assessment of triazolyl alanine. Prepared by Bayer, Ciba-Geigy, ICI and Rohm & Haas, November 1986. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Bissig, R., 1986. The metabolism of [U-14C]-phenyl-CGA 64250 in mace after pretreatment with unlabeled CGA 64250. Unpublished report 6/86 d.d. May 20, 1986 from biochemistry department R & D plant protection, agricultural division, Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Deparade, E. & Arni, P., 1983. Salmonella/Mammalian-microsome mutagenicity test. Induction of liver enzyme activity with Aroclor or with the test substance. Unpublished report project hr.: 83/0121, d.d. June 27, 1983 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Fischer, W.C. & Cassidy, J.E., 1980. Balance and metabolism of triazole-14C-CGA 64250 in a lactating goat. Unpublished report ABR-80036 from biochemistry department, agricultural division, Ciba-Geigy Corporation, Greensboro, N.C. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Fritz, H., Becker, H. & Hess, R., 1979a. Report on CGA 64250 techn, teratology study (seg.II) in rats. Unpublished report no 79/0011 d.d. September 17, 1979 from Ciba-Geigy Ltd. reproductive toxicology, GU 2.5/ek. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Fritz, H., Becker, H. & Hess, R., 1979b. Report on CGA 64250 techn, teratology study (seg.II) in rabbits. Unpublished report no 79/0009 d.d. September 10, 1979 from Ciba-Geigy Ltd. reproductive toxicology, GU 2.5/ek. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Fritz, H., Giese, K., Zak, F. & Hess, R., 1981. Report on CGA 64250 techn. 2-generation study in rats. Unpublished report no 79/0010 d.d. June 29, 1981 from Ciba-Geigy Ltd. reproductive toxicology, GU 2.1 Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Froelich, G. et al., 1984. Promotion study with CGA 64250. Unpublished report, GU exploratory research project no.: 83/4015 d.d. December 18, 1984 from Ciba-Geigy, Toxicology GU 2. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Giknis, M.L.A., 1986. A teratology study in rabbits. Unpublished report no.: 86043 d.d. August 1, 1986 from Ciba-Geigy Pharmaceutical division, New Jersey. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Giknis, M.L.A., 1987. A teratology (segment II) study in rats. Unpublished report no.: 86004 d.d. January 28, 1987 from Ciba-Geigy Pharmaceutical division, New Jersey. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hambock, H., 1979. Distribution, degradation and excretion of CGA 64250 in the rat. Unpublished report no 24/79 from Biochemistry department R & D plant protection, Agricultural division, Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hool, G. & Muller, D., 1979. Dominant lethal study CGA 64250 MOUSE. Unpublished report, experiment no.: 79/0034, from Ciba-Geigy, Protection of health and environment. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hool, G. & Muller, D., 1982a. Chromosome studies in male germinal epithelium CGA 64250 Mouse. Unpublished report, experiment no.: 81/1511, from Ciba-Geigy, Protection of health and environment. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hool, G. & Muller, D., 1982b. Chromosome studies in male germinal epithelium CGA 64250 Mouse. Unpublished report, experiment no.: 81/1512, from Ciba-Geigy, Protection of health and environment. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hool, G. & Muller, D., 1982c. Sister chromatid exchange study CGA 64250 Chinese hamster. Unpublished report, experiment no.: 81/1515, d.d. October 18, 1982 from Ciba-Geigy. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hool, G. et al., 1979. Nucleus anomaly test in somatic interphase nuclei CGA 64250 Chinese hamster. Unpublished report, experiment no.: 79-08-05, d.d. September 17, 1979 from Ciba-Geigy Ltd. Protection of health and environment. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hunter, B. Scholey, D. & Heywood, R., 1982a. Potential tumorigenic and toxic effects in prolonged dietary administration to rats (final report). Unpublished report no.: CBG 193/8284 (test no. 78/9023) from Huntingdon research centre, Huntingdon, England. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Hunter, B., Scholey, D. & Heywood, R., 1982b. CGA 64250 long-term feeding study in mice (final report). Unpublished report no. CBG/196/81827 d.d. October 20, 1982 from Huntingdon research centre, Huntingdon, England. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Johnson, W.D., Thompson, S.W. & Becci, P.J., 1985. One-year subchronic oral toxicity study in beagle dogs with CGA 64250 technical (final report). Unpublished report study no.: 7737 d.d. May 28, 1985 from Food & Drug Research Laboratories Inc. Waverly, NY. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Madrid, v. & Cassidy, J.E., 1981. Characterization of metabolites in urine, milk and liver of a goat treated with triazole-14C-CGA-64250. Unpublished report ABR-81007 d.d. March 27, 1981 from Biochemistry department, agricultural division Ciba-Geigy Corporation, Greensboro, N.C. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Madrid, S.O. & Cassidy, J.E., 1983. Structure elucidation of a major metabolite in milk from a goat treated with triazole-14C-CGA-64250 or CGA-64251. Unpublished report ABR-83062 d.d. September 27, 1983 from Biochemistry department, agricultural division Ciba-Geigy Corporation, Greensboro, N.C. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Mallows, S., Levy, E., Giknis, M.L.A. & Yau, E.T., 1987. A modified teratology (segment II) study in albino rats with CGA 64250. Unpublished report no.: 96189 d.d. February 6, 1987 from Ciba-Geigy Pharmaceutical division, New Jersey. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Muecke, W., 1979. Characterization of urinary and faecal metabolites of rats after oral application of CGA 64250. Unpublished report no 356/79 from Biochemistry department R & D plant protection, Agricultural division, Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Muecke, W., 1981. The major metabolic pathways of CGA 64250 in the rat. Unpublished report no 9/81 from Biochemistry department R & D plant protection, Agricultural division. Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Muecke, W., 1983. The metabolism of CGA 64250 in the rat. Unpublished report 245/83 d.d. September 1, 1983 from Biochemistry department R V& D plant protection agricultural division, Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Puri, E. & Muller, D., 1982a. Autoradiographic DNA repair test on human fibroblasts CGA 64250. Unpublished report experiment no.: 81/1655 d.d. August 12, 1982 from Ciba-Geigy. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Puri, E. & Muller, D., 1982b. Autoradiographic DNA repair test on rat hepatocytes CGA 64250. Unpublished report experiment no.: 81/1514 d.d. August 12, 1982 from Ciba-Geigy. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Sachsse, K., Suter, P., Luetkemeier, H., Zak, F. & Hess, R., 1979a. Three months toxicity study on rats of CGA 64250 technical. Unpublished report project nr.: 79/0014 d.d. 30 August, 1979 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Sachsse, K., Ullman, L., Luetkemeier, H., Zak, F. & Hess, R., 1979b. 21-Day percutaneous toxicity study in rabbits with technical CGA 64250. Unpublished report project hr.: 79/0007 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Sachsse, K., Ullman, L., Luetkemeier, H., Zak, F. & Hess, R., 1980a. 90 Days aerosol inhalation study on rats with technical CGA 64250. Unpublished report project hr.: 79/0006 d.d. September 10, 1980 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Sachsse, K., Bathe, R., Luetkemeier, H., Zak, F. & Hess, R., 1980b. 3-Month toxicity study with CGA 64250 on dogs. Unpublished report project nr.: 78/5751 d.d. August 9, 1980 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Salamon, CM., 1985. Two-generation reproduction study in albino rats. Unpublished report study no. 450-1202 d.d. March 12, 1985 from Toxigenics, Inc. Decatur, IL 62526. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Seim, V.W. & Thomas, W.A., 1980. Biological report for the metabolism of triazole-14C-CGA-64250 in a lactating goat. Unpublished report no BIOL-80004 from Biochemistry department, Agricultural division, Ciba-Geigy Corporation, Vero Beach, Florida. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Simoneaux, B., 1983. Dermal absorption of triazole-14C-CGA-64250 by rats. Unpublished report no ABR-82068 from biochemistry department, agricultural division, Ciba-Geigy corporation, Greensboro, N.C. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Strasser, F. & Arni, P., 1984. Chromosome studies on human lymphocytes in vitro. Unpublished report no.: 84/0025 d.d. May 10, 1984 from Ciba-Geigy Protection of health and environment, experimental pathology. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Strasser F.F. & Muller, D., 1982a. L5178Y/TK+/- mouse lymphoma mutagenicity test. CGA 64250. Unpublished report, experiment no.: 81/1516, d.d. August 10, 1982 from Ciba-Geigy, Protection of health and environment. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Strasser F.F. & Muller, D., 1982b. Point mutation assay with mouse lymphoma cells. Host-mediated assay with CGA 64250. Unpublished report, experiment no.: 81/1513, d.d. August 10, 1982 from Ciba-Geigy, Protection of health and environment. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Strasser F.F. & Muller, D., 1982c. BALB/3T3 cell transformation assay CGA 64250. Unpublished report, experiment no.: 79/0806 d.d. August 10, 1982 from Ciba-Geigy. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Ullmann, L., 1978a. Acute oral LD50 in the rabbit of technical CGA 64250. Unpublished report project no.: 78/5247 d.d. November 2, 1978 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Ullmann, L., 1978b. Eye irritation in the rabbit after single application of technical CGA 64250. Unpublished report project nr.: 78/5248 d.d. October 26, 1978b from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Ullmann, L., 1978c. Skin irritation in the rabbit after single application of technical CGA 64250. Unpublished report project nr.: 78/5249 d.d. October 26, 1978 from Ciba-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Ullmann, L., 1979a. Acute dermal LD50 in the rabbit of technical CGA 64250. Unpublished report project nr.: 79/0375 d.d. July 2, 1979 from Ciby-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Ullmann, L., 1979b. Skin sensitizing (contact allergenic) effect in guinea pigs of technical CGA 64250. Unpublished report project nr.: 78/5250 d.d. February 8, 1979 from Ciby-Geigy Ltd. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland. Waechter, F. Bentley, P. & Staubli, W., 1984. The effect of propiconazole on drug metabolizing enzymes in the livers of male rats and mice. Unpublished report d.d. July 1984, submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.
See Also: Toxicological Abbreviations