TOLYLFLUANID EXPLANATION Tolylfluanid, a broad spectrum fungicide, is considered for the first time by the present Meeting. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Biochemical aspects Absorption, distribution, and excretion Single doses of tolylfluanid, 14C-labelled at the fluorodichloromethylsulfenyl group, were orally administered to rats. In the dose range of 0.1-20 mg/kg, 50-60% and 20-30% of the administered activity was eliminated by the urine and the faeces, respectively, within 48 hours from administration. Urinary elimination took place with a half-life of 2-3 hours during the first 24 hours and then more slowly with a half-life of about 40 hours from the third day. Experiments in rats with biliary fistula showed that, after intraduodenal administration of 0.5 mg/kg, about 6% of total radioactivity was eliminated via the bile. However, when 5 mg/kg bw of tolylfluanid were administered, approximately 16% of the activity was exhaled in 48 hours. After oral administration of 5 mg/kg bw, maximal plasma concentration (about 1.5 ppm) was attained after two hours. While plasma half-life was 2-3 hours during the first 6-8 hours, elimination slowed to about 40 hours after 3 days. Of the administered activity, 6%, 2%, 1% and 0.5% was retained (excluding gastrointestinal tract) 8 hours, 48 hours, 6 and 12 days after administration, respectively. The highest concentrations were found in the thyroid gland: 5 ppm and 1 ppm, 1 and 10 days after the administration of 5 mg/kg, respectively. Whole-body autoradiography (after i.v. injection of 10 mg/kg bw of tolylfluanid) confirmed this observation (Weber et al., 1977). In another study, doses of 2 or 20 mg/kg bw of 14C-ring- labelled tolylfluanid were orally administered to male and female Wistar rats. A group of rats of both sexes were also pretreated for 14 days with daily doses of 2 mg/kg bw of non-radioactive tolylfluanid before receiving the radioactive compound. Tolylfluanid was quickly and almost completely absorbed (>95%). The peak plasma concentration was reached within 1.5 hours. Within 48 hours, 75-80% of radioactivity was excreted in urine (half-life of 4-8 hours), 14-25% with faeces, and 0.06% in expired air. An experiment in animals with biliary fistulae showed that biliary secretion accounted for about 14% of total elimination. Total residual radioactivity was 0.07-0.20% of the total administered dose. Higher concentrations of radioactivity were found in liver and kidney (3 to 7 times the mean body concentration). Lesser concentrations were found in perirenal fat, brain, gonads and thyroid (3 to 9 times less than the mean body concentration). Renal clearance was 3.1-4.0 ml/min, which correspond to normal renal plasma flow in rats. No influence of dose was observed on pharmacokinetics (Abbink & Weber, 1988). An autoradiographic study showed a difference between i.v. and oral administration. Intravenous injection is characterized by a great uniformity of distribution with relatively high concentration in almost all body tissues (including highly lipophilic tissues). After oral administration, radioactivity in lipophilic tissues was very low. It may therefore be assumed that after oral administration tolylfluanid is rapidly metabolized prior to or during the absorption and distribution process (Weber, 1988). Biotransformation A single dose of fluorodichloromethyl-14C-labelled tolylfluanid was administered orally or intravenously to rats (5 or 10 mg/kg bw). The main radioactive metabolite in the urine of treated rats was found to be thiazolidine-2-thione-4-carbonic acid (TTC). TTC accounted for 74% of radioactivity contained in the urine 8 hours after intravenous administration and for 50-63% after oral administration. Tolylfluanid was not detected in urine (Ecker, 1978). A single oral dose of 20 mg/kg bw of C14-benzene ring- tolylfluanid was administered to male Wistar rats. 90% of urine radioactivity and 70% of faecal radioactivity was due to one metabolite which was found to be 4-dimethylamino-sulphonylamino- benzoic acid. A minor metabolite (6% of total radioactivity) could not be identified (Ecker & Brauner, 1987). The degradation pathway of tolylfluanid in the rat is described in Figure 1.Toxicological Studies Special studies on carcinogenicity Mice Groups of NMRI mice (50/sex/group) were given tolylfluanid technical (99.1% purity in a 90% pre-mix) in the diet (0, 200, 1000, 5000 ppm) for 104 weeks. In relation to body weight, the males were given 32.6, 161.8 or 768.9 mg/kg bw and the females 45.6, 202.4 or 952.3 mg/kg bw on average. Animals were observed twice a day for mortality or adverse physical/behavioural signs. Body weights were recorded weekly and food consumption of each animal was determined twice a week. Routine haematological and clinical chemistry examinations were performed before the start of the study and after 12 and 24 months. All animals, including those which died or were sacrificed before the end of the study, were dissected, their organs weighed and tissues prepared for microscopic examination. For technical reasons the treated groups started 4 months after the control group. This discrepancy in time was considered by the author to be the cause of the higher body weight gain (+55% and +10/12% of the starting weight in controls and treated males, respectively; +64% and +18/24% in control and treated females, respectively) and food consumption (about 30% higher) found in control animals and of the differences between control and study groups in the haematological and clinical laboratory examinations. No dose-related difference in any of these parameters was, however, found in animals of the treated groups. The mortality rate was higher in female groups but a dose-related effect was not evident. At necropsy, hepatocellular adenomas and pulmonary adenomas were found in all control and treated groups. The incidence of liver rumours was higher in male groups, but no treatment-related effect was evident (10/51, 7/50, 13/50 and 9/50 in control, 200, 1000 and 5000 ppm groups, respectively). The incidence of lung adenomas was 17/51, 17/50, 20/50 and 20/50 in males and 9/49, 6/50, 14/50 and 7/51 in females of control, 200, 1000 and 5000 ppm groups, respectively. Incidence, latency, variety and organ distribution of rumours did not indicate any dose-related effect of tolylfluanid (Mohr, 1982). Rats (See "Long-term studies".) Special studies on embryotoxicity and teratogenicity Groups (n=22-24) of fertilized female rats (75-95 day-old Long Evans FB 30) were given oral daily doses (0, 100, 300, 1000 mg/kg bw) of tolylfluanid (99.9% purity) from day 6 through day 15 of gestation. Animals were observed routinely for physical appearance, behaviour and body weight gain. At day 20 of gestation pups were delivered by caesarean section. Foetuses were weighed, sexed, inspected for external abnormalities and examined for visceral and bone malformations. No alteration of physical appearance and behaviour was observed in any group. Two dams of the mid-dose group died of effects unrelated to treatment. Body weight gains were reduced in a dose-dependent manner in the mid- and high-dose groups. However, dams compensated after end of treatment. The average foetal weight was reduced by treatment of the dams with 300 or 1000 mg/kg bw. The resorption ratio in the high-dose group was slightly, not statistically significantly, higher than in the control group, because of complete loss of embryos by one female. There was no evidence of teratogenicity at any of the doses used. The dose of 100 mg/kg bw had no toxic effect to dams and foetuses (Machemer, 1976). Acute toxicity of metabolites 4-dimethylamino-sulftoluidine, a metabolite of tolylfluanid, was tested for acute toxicity. After single administration, LD50s were as follows (Kimmerle & Solmecke, 1971b). Species Route mg/kg bw Rat (male) p.o. >2500 Mouse (male) p.o. >1000 Rabbit (male) p.o. >1000 Rat (male) i.p. 551 Special studies on mutagenicity Tolylfluanid was variably active in a range of in vitro assays. In vivo, however, tolylfluanid was inactive. Results are summarized in Table 1. Table 1. Results of Mutagenicity assays on tolylfluanid Test system Test Object Concentration of tolylfluanid Purity Results References Ames test (with and S. typhimurium 3.15-1000 µg/plate 100% weakly Oesch, 1977 without activation) TA-98,100,1537 dissolved in DMSO positive 1/ Ames test (with and S. typhimurium 4-2500 µg/plate 100% weakly Herbold, 1979 without activation) TA-98,100,1535, dissolved in DMSO positive 2/ 1537 Reverse mutation Saccharomyces Nonactivated: 1-200 µg/ml 99.1% negative Hoorn, 1984 in vitro cervisiae Activated: 1-100 µg/ml (S138, S211alfa) Gene mutation Somatic Nonactivated: 4-40 µg/ml 98.5% negative 3/ Heidemann,1987 (HGPRT-test) mammalian cells Activated: 300-3000 µg/ml in vitro (V79) Gene mutation Chinese hamster Nonactivated: 0.5-6 µg/ml 98.5% negative 4/ den Boer, 1987 (HGPRT-test) ovary cells Activated: 3-30 µg/ml in vitro Forward mutation Mouse lymphoma Nonactivated: 25-300 µg/ml 99.1% positive Hoorn, 1985 in vitro cells (L5178Y) Activated: 500-7500 µg/ml Cytogenetic assay Human lymphocytes 0.1-10 µg/ml (activated 99.2% positive 5/ Herbold, 1984b in vitro and nonactivated) Micronucleus test Mice (NMRI strain) 2x250 and 2x500 mg/kg 98.8% negative 6/ Herbold, 1980 (p.o. 24 h apart) Table 1. (cont'd) Test system Test object Concentration of tolylfluanid Purity Results References Dominant lethal test Mice (NMRI strain) 4000 mg/kg p.o.(mortality:5/50) 98.8% negative Herbold, 1986 8000 mg/kg p.o.(mortality:12/50) Cytogenetic assay Chinese hamster 4000 mg/kg p.o. 99.7% negative 6/ Herbold, 1983 in vivo bone marrow Cytogenetic assay Chinese hamster 2x250 and 2x500 mg/kg 93.1% inconclusive Herbold, 1984a in vivo spermatogonia (p.o. 24 h apart) 7/ Cytogenetic assay Mice (NMRI strain) 500-5000 mg/kg bw p.o. 97.9% negative 8/ Voelkner,1988b in vivo germ cells Sister chromatide Mice (NMRI strain) 500-5000 mg/kg bw p.o. 97.9% negative 7/ Voelkner,1988a exchange bone marrow Mammalian Mice C5781/6JxT 1750-7000 mg/kg bw p.o. 98.4% negative 9/ Herbold, 1988 Spot test 1/ With S-9 mix only; positive controls (benzo(a)pyrene 4,5-oxide, N-methyl-N'-nitro-N-nitrosoguanidine, 3,methylcholanthrene, 2-aminoanthracene) yielded expected positive results. 2/ TA-100 only; positive controls (endoxan, trypaflavin) yielded expected positive results. 3/ Positive controls (ethyl-methane sulfonate (EMS), 9,10-dimethyl-1,2-benzanthracene (DMBA) yielded expected positive results. 4/ Positive controls (5-bromodeoxyuridine and 3-methylcholanthrene) yielded expected positive results. 5/ At cytotoxic concentrations; positive controls (mitomycin c, endoxan) yielded expected positive results. 6/ Positive controls (endoxan) yielded expected positive results. 7/ Positive controls (doxorubicin) yielded expected positive results. 8/ Positive controls (cyclophosphamide) yielded expected positive results. 9/ Positive controls (1-ethyl-1-nitrosourea) yielded expected positive results. Special study on potentiating effects Equitoxic doses of tolylfluanid (purity not reported) and triadimefon (89.5% purity) were given in combination to rats. No potentiating effect was noted (Flucke & Kimmerle, 1978). Special study on reproduction Groups of Long Evans FB30 rats (30 animals/dose, 10 males and 20 females) were fed diets containing tolylfluanid (technical grade, 98.8% purity in a 90% pre-mix) at levels of of 0, 300, 1500 or 7500 ppm. After 70 days of treatment F0 animals were mated on a 2-female-to-1-male basis. After delivery (F1a) and a 4-week lactation and a 2-week waiting period, F0 rats were mated again. After delivery (F1b) lactation lasted for 4 weeks and then F0 animals were sacrificed. F1b animals (20 females-10 males/dose) were then mated and F1a and F1b generations were obtained. The study was ended when F1b generation reached 4 weeks of age. Rats were weighed weekly and pups were weighed at birth, 5 and 7 days after birth, and weekly thereafter. Pups were also observed immediately after birth and during lactation. F0 generation: Appearance and behaviour of all treated animals did not differ from controls throughout the study. Body weight was reduced in a dose-related manner in male rats treated with 1500 or 7500 ppm; only the dose of 7500 ppm was associated with reduced body weight in female rats. Fertility indices and litter sizes of first and second matings were not reduced by any of the treatments. Survival rate was slightly reduced in F1b generation of the high-dose group. Lactation index (% of pups surviving 4 weeks) was reduced in the F1a generation of the 7500 ppm group, but in the F1b generation of the same group was significantly higher than controls. Body weight of pups at birth and body weight gain were significantly lower in both F1a and F1b generations of the 7500 ppm group. None of the pups showed malformations. F1b generation: Appearance and behaviour of all treated animals did not differ from controls throughout the study. Body weight was reduced in the 7500 ppm group. Fertility indices and litter sizes of first and second matings were not reduced by any of the treatments. Survival rate was reduced in F2b generation of the high-dose group. Lactation index (% of pups surviving 4 weeks) was reduced in F2a and F2b generations of the 7500 ppm group and in the F2b generation of the 1500 ppm group. In the latter group, however, the number of pups surviving four weeks was the same as in the control group and the lower lactation index was due to a higher number of pups at 5 days when all litters were reduced to a maximum of 10 pups rearing. Body weight of pups at birth and body weight gain was lower in both F2a and F2b generations of the 7500 ppm group. None of the pups showed malformations. In summary, this study shows that tolylfluanid at doses up to 1500 ppm did not affect the reproduction of rats. The NOAEL in this study was found to be 300 ppm (Loser, 1980). Special study on skin and eye irritation A 90% pre-mix with 99.2% active ingredient was applied to rabbit skin for 24 hours under semi-occlusive conditions. Tolylfluanid did not show skin irritant properties. The test compound dust (0.1 g), however, when placed on the conjuntival sac of rabbit eyes, displayed a strong irritant potential (redness and swelling of the conjuntivae). The effect was reversible within 14 days (Helmann & Pauluhn, 1983). A further study was conducted on irritant and corrosive effects on the skin and eyes. Tolylfluanid (99.1% purity) did not show irritant effect on the skin (4 hours' exposure). However, 70 mg of a.i. placed in the conjuntival sac produced redness and swelling of the conjuntivae which were completely reversible within 21 days. No cornea or iris lesions were found at any time (Pauluhn, 1984). Special study on subacute cutaneous toxicity in rabbits Rabbits (5 males and 5 females) received daily dermal doses of 500 mg/kg bw of tolylfluanid (98.9% purity) for fourteen days. Each exposure lasted 24 hours. Before and immediately after the end of treatment, and 2 weeks later, clinical-chemical tests were performed, including blood tests (erythrocyte, leucocyte and thrombocyte count, haemoglobin determination, etc.), liver function tests, serum transaminases, sorbitol dehydrogenase, bilirubin and albumin) and kidney function tests (urinanalysis and serum urea concentration). No variation was found between control and treated animals (Kimmerle & Solmecke, 1971a). Acute toxicity Table 2 reports the LD50 values for tolylfluanid and metabolites as determined in different studies and animal species. In rats, signs of toxicity observed after oral administration were altered behaviour, disturbed motility and dyspnoea. In mice, guinea pigs, rabbits and cats tolylfluanid caused deterioration of general conditions and (in cats only) vomiting. In sheep, tolylfluanid, orally administered, caused anorexia, weakness of extremities and loose faeces. Intraperitoneal injection to rats caused disturbed motility, staggering, spastic gait, distention of abdomen, narrowed eyelids, a specific disturbed behaviour. Irritation of abdominal organs was found at autopsy. The dermal application of tolylfluanid at doses up to 5000 mg/kg bw was tolerated without signs of toxicity or skin alterations. The skin-sensitising potential of tolylfluanid was assessed by the Magnusson and Klingman's maximization test on guinea pigs (n=15). The concentration of tolylfluanid (99.2% purity in a 90% pre-mix) used were 1% for the intradermal induction, 0.6% for the topical induction, and 0.3% for the topical challenge. The results indicate that tolylfluanid has a skin-sensitising potential (Heimann, 1983). Short-term studies Rats 0, 150, 500, 1500 or 4500 ppm of tolylfluanid (99% purity) were given to rats (15 males and 15 females) in the diet for 3 months. All dose-regimens were tolerated without alteration of behaviour, weight, mortality or clinical chemistry tests. Morphological examination of organs and tissues did not reveal any treatment-induced alterations (Bomhard and Schilde, 1976). Dogs Beagle dogs (4 males and 4 females/group) were administered 0, 330, 1000 or 3000 ppm of tolylfluanid (99.7% purity) in diet for 3 months. Animals of the high-dose group showed poor general condition and 6/8 animals had a reduced food intake and weight gain. In this group an increased serum alkaline phosphatase activity and a retardation of its age-related decrease as compared to controls was found. Increased liver relative weight and increased PAS histological reaction were also found in these animals. Doses up to 1000 ppm did not induce any detectable adverse effect (Hoffmann & Mirea, 1974). Table 2. Acute toxicity of tolylfluanid (mg/kg bw) Species Sex Route LD50 LC50 Reference Mouse M oral >1000 1/ - Kimmerle, 1968 Rat M oral >2500 2/ - Kimmerle & Lorke, 1967. Rat M inhalation* - 265 2/ Kimmerle & Lorke, 1967 (4-hr exp.) Rat M i.p. 20.2 1/ - Kimmerle, 1968 Rat F i.p. 25.6 1/ - Kimmerle, 1968 Rat F oral >5000 3/ - Heimann & Pauluhn, 1983 Rat M i.p. 14.7 3/ - " Rat F i.p. 15.9 3/ - " Rat M&F dermal >5000 3/ - " (24-hr exp.) Guinea pig F oral 250-500 1/ - Kimmerle, 1968 Rabbit M oral 250-500 1/ - Kimmerle, 1968 Cat M&F oral >500 1/ - Kimmerle, 1968 Sheep M&F oral 625-1250 3/ - Hoffmann, 1983 1/ 99.6% purity 2/ 98.7% purity 3/ 99.2% purity in a 90% pre-mix * Dynamic spraying with Lutrol/ethanol. In static spraying experiments, mice, guinea pigs and rabbits were found to be more sensitive than rats to tolylfluanid. In another study, groups (4 male/4 female) of beagle dogs were orally treated for 12 months with tolylfluanid (99.2% purity in a 90% pre-mix) 0, 2.5, 12.5 or 62.5 (let to 33rd week) and 125 (34th to 52nd week) mg/kg bw. The test compound was administered in gelatin capsules. All animals survived the study and did not show any treatment-related effect on appearance or behaviour. Body weight development in male control animals (+4.4 kg in 12 months) was above the average of the historical controls (+2.8 kg in 12 months), while it was significantly reduced in the animals of the high-dose group. The females in the high-dose group also had lower body weight gain. Animals of the high-dose group vomited quite frequently after administration of the compound. They also had a significant increase of serum alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH), and a retarding of the physiological age-related decrease of the alkaline phosphatase activity. No liver alteration was found, however, at histology. An effect on renal function was also evident in the high-dose group. Urea and creatinine concentrations were significantly increased and in two dogs glycosuria and proteinuria were found. Histology revealed slight alterations of cortical tubules (dilation, epithelial flattening, focal hypertrophy and/or desquamation of the epithelia) in all dogs of the high-dose group. Slightly lower serum potassium concentrations were found in the high-dose group animals as compared to control values, possibly as a result of the frequent vomiting. No treatment-related effect was evident on blood, blood coagulation and transparent media and fundus of the eye. Oral doses of tolylfluanid up to 12.5 mg/kg bw were therefore tolerated by dogs for 12 months without detectable adverse effects (von Keutz & Nash, 1986). Long-term studies Rats Wistar rats (50 males and 50 females/group; 100 male and 100 females, controls) were fed for 2 years with tolylfluanid (98.9% purity in 90% pre-mix) at concentrations of 0, 300, 1500, 7500 ppm. Toxicity following chronic administration and carcinogenic potential of tolylfluanid were evaluated. The animals in the high-dose group had a reduced food consumption (-10%) and a reduced (about 10%) body weight gain; appearance, behaviour and mortality were not affected by the treatment. Clinical laboratory tests showed random alteration of some blood parameters (mean corpuscular volume, mean corpuscular haemoglobin, reticulocyte count, polymorphonuclear cells and lymphocytes). Plasma alkaline phosphatase (AP), transaminases (ALT and AST), bilirubin and total protein were measured as indices of liver function. No dose-related alteration of these parameters was found. Gross pathological and histological examinations did not detect any indication of liver damage. Urinanalysis did not indicate any dose-related kidney alteration. Blood sugar and cholesterol were within normal range in all groups. On autopsy, bone alterations (diffuse hyperostosis of the rib bones, hardened cranial bones, focal hyperostosis of the skull caps) in both sexes, and a faster growth of the incisors of the upper jaw in males only, were found in the 1500 and 7500 ppm groups. These effects were presumably due to an increased fluorine intake from the active ingredient. Tumours of endocrine and reproductive system accounted for about 80% of the rumours seen in the study. Only malignant uterine tumours appeared higher in all treated groups as compared to controls. The incidence was 3/50, 8/50, 12/50 and 13/50 in the 0, 300, 1500 and 7500 ppm groups, respectively. An unusually low incidence of these fairly con, non tumours was found in control animals. Therefore, a second, concurrent group of 50 controls was studied in which the incidence of malignant uterine rumours was similar (9/50) to that of the treated groups. The test, therefore, did not provide indications of carcinogenic potential for tolylfluanid. The concentration of tolylfluanid without detectable adverse effect was 300 ppm (equivalent to 15 mg/kg bw) (Krötlinger & Loser, 1982). Observations in humans Small cottonwool pads on which an unknown concentration of tolylfluanid was applied, were placed on the forearm of 10 male volunteers for 24 hours. Subjects were observed for 10 days; no skin-irritant effects were noted (Kimmerle, 1968). COMMENTS Following oral administration to rats, tolylfluanid was rapidly absorbed, metabolized and eliminated in urine and faeces. When using 14C-ring-labelled tolylfluanid (2 or 20 mg/kg bw), less than 0.2% of the administered radioactivity was detectable in the body 2 days after administration. The highest concentrations were found in liver and kidney. When using 14C-tolylfluanid (0.1-20 mg/kg bw) labelled at the fluorodichloronenthyl group instead, accumulation of radioactivity was evident in the thyroid. The major urinary metabolites were thiazolidine- 2-thione-4-carboxylic acid and 4-dimethylaminosulphonyl-amino-benzoic acid. The oral LD50 is greater than 5000 mg/kg bw in rats and 250-500 mg/kg bw in guinea pigs and rabbits. The oral LD50 of a major plant metabolite, DMST (N,N-dimethyl-N'-p-tolylsulphamide), exceeds 2500 mg/kg in rats and 1000 mg/kg in mice and rabbits. In one study in rats, tolylfluanid was found to be maternally toxic and embryotoxic at doses above 100 mg/kg bw/day but not teratogenic at doses up to and including 1000 mg/kg bw/day. In a two-generation two-litter-per-generation reproduction study, dietary levels up to and including 1500 ppm did not affect rat reproduction. No malformations were observed at dietary levels up to and including 7500 ppm. In a short-term toxicity study with beagle dogs, tolylfluanid did not cause adverse effects for 12 months at doses up to and including 12.5 mg/kg bw/day. Tolylfluanid was mutagenic in prokaryotes and eukaryotes in four of seven in vitro assays. In vivo tests, however, did not indicate a mutagenic potential. In a long-term study in Wistar rats, a higher incidence of malignant uterine tumours was found in the treated groups as compared to controls, but no statistically significant dose-related pattern was evident. Moreover in a second, concurrent, group of controls the incidence was comparable to that in treated groups. In animals treated with 1500 or 7500 ppm tolylfluanid, bone alterations were also found which were suggested to be due to the fluorine constituent of tolylfluanid. No alterations were found in the thyroid or in other organs. The Meeting noted that in the NMRI mouse study, the control animals were four months older than the treated groups, thus compromising the design of the study. Lung and liver adenomas occurred at similar frequency in all treated groups, but because of their known occurrence in mice they were not considered to be biologically relevant. The Meeting therefore concluded that the results of this study did not indicate an oncogenic potential. The Meeting did not request a special study on thyroid function because the dichlorofluorometylthio group is common to dichlofluanid, for which a NOAEL for the thyroid has been demonstrated to be greater than 1500 ppm. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Rat: 300 ppm in the diet, equal to 15 mg/kg bw/day Dog: 12.5 mg/kg bw/day ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.1 mg/kg bw STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED EVALUATION OF THE COMPOUND Observations in man. 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KUE 13183b / Cytogenetic study with human lymphocyte cultures in vitro to evaluate for harmful effect on chromosomes. Institute of Toxicology, Bayer AG. Unpublished report No. 12836. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Herbold, B. 1986. KUE 13183b / Dominant lethal test on the male mouse to evaluate for mutagenic effect. Institute of Toxicology, Bayer AG. Unpublished report No. 15017. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Herbold, B. 1988. Spot test on cross-bred C57B1/6J × T stock mouse fetuses to evaluate for induced somatic changes in the genes of the coat pigment cells. Institute of Toxicology, Bayer AG. Unpublished report No. 16752. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Hoffmann, K. 1983. KUE 13183b / Acute toxicity to the sheep after oral administration. Institute of Toxicology, Bayer AG. Unpublished report No. 11975. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Hoffmann, K. & Mirea, D. 1974. KUE 13183b / Subchronic toxicity study on dogs (13-week feeding experiment). Institute of Toxicology, Bayer AG. Unpublished report No. 4957. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Hoorn, A.J.W. 1984. KUE 13183b / Mutagenicity evaluation of KUE 13183b in the reverse mutation induction assay with saccharomyces cerevisiae strains S138 and S211a. Litton Bionetics, The Netherlands. Unpublished report No. 3060. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Hoorn, A.J.W. 1985. KUE 13183b / Mutagenicity evaluation of KUE 13183b in the mouse lymphoma forward mutation assay. Litton Bionetics, The Netherlands. Unpublished report No. R 3192. Submitted to WHO by Bayer AG, Bayerwerk, FRG. von Keutz, E. & Nash, G. 1986. KUE 13183b / Chronic toxicity to dogs after oral administration (12-month capsule study). Institute of Toxicology, Bayer AG. Unpublished report No. 12999. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Kimmerle, G. 1968. BAY 49854 / Toxicological studies. Institute of Toxicology, Bayer AG. Unpublished report No. 832. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Kimmerle, G. & Lorke, D. 1967. Toxicological studies on the active ingredient BAY 49854. Institute of Toxicology, Bayer AG. Unpublished report No. 323. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Kimmerle, G. & Solmecke, B. 1971a. Methyl-Euparen / Subacute cutaneous application to rabbits. Institute of Toxicology, Bayer AG. Unpublished report No. 2619. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Kimmerle, G. & Solmecke, B. 1971b. DMST / Toxicological Study. Institute of Toxicology, Bayer AG. Unpublished report No. 2681. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Krötlinger, F. & Loser, E. 1982. KUE 13183b / Chronic toxicological study in rats (feeding for 2 years). Institute of Toxicology, Bayer AG. Unpublished report No. 10978. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Loser, E. 1980. KUE 13183b / Generation study with rats. Institute of Toxicology, Bayer AG. Unpublished report No. 9419. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Machemer, L. 1976. KUE 13183b / Studies on embryotoxic and teratogenic effects on rats after oral administration. Institute of Toxicology, Bayer AG. Unpublished report No. 5888. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Mohr, U. 1982. KUE 13183b / Study for cancerogenic effect on NMRI-mice (feeding study for 104 weeks). Appendix: Histopathological Individual Findings. Medizinische Hochshule, Hannover. Unpublished report No. R 2225. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Oesch, F. 1977. Kue 13183b / Ames Test for guparen M. Institute of Biochemical Pharmacology, University of Mainz. Unpublished report from November 10. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Pauluhn, J. 1984. KUE 13183b / Study for irritant/corrosive effect on skin and eye (rabbit). Institute of Toxicology, Bayer AG. Unpublished report No. 12362. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Voelkner, W. 1988a. Sister chromatide exchange assay in bone marrow cells of the mouse. Cytotest Cell Research GmbH, Darmstadt, FRG. Unpublished report No. 4422. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Voelkner, W. 1988b. Mouse germ-cell cytogenetic assay. Cytotest Cell Research GmbH, Darmstadt, FRG. Unpublished report No. 4485. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Weber, H. et al. 1977. KUE 13183b / Biokinetic Investigations of Rats. Institute for Pharmacokinetics, Bayer AG. Unpublished report No. 1165. Submitted to WHO by Bayer AG, Bayerwerk, FRG. Weber, H. 1988. Phenyl-UL-14C-tolylfluanid: whole body autoradiographic distribution of the radioactivity in the rat. Institute for Metabolism Research, Bayer AG. Unpublished report No. 181080-8. Submitted to WHO by Bayer AG, Bayerwerk, FRG.
See Also: Toxicological Abbreviations