PESTICIDE RESIDUES IN FOOD - 1981 Sponsored jointly by FAO and WHO EVALUATIONS 1981 Food and Agriculture Organization of the United Nations Rome FAO PLANT PRODUCTION AND PROTECTION PAPER 42 pesticide residues in food: 1981 evaluations the monographs data and recommendations of the joint meeting of the FAO panel of experts on pesticide residues in food and the environment and the WHO expert group on pesticide residues Geneva, 23 November-2 December 1981 FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS Rome 1982 AZOCYCLOTIN Explanation Although this compound was reviewed by the 1979 JMPR*, the toxicological evaluation was not undertaken at that time. DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Uptake, distribution and excretion Studies on rats to investigate uptake, distribution and excretion of azocyclotin were conducted with both the [113Sn]-labelled and [1-14C]-labelled compound (Bayer AG 1981; Grubenbecher and Figge 1979a, b). [113Sn] Azocyclotin was administered orally to rats in a single dose of approximately 8 mg/kg body weight. In the studies with [1-14C] azocyclotin, possible dependence of elimination kinetics on dose level was also investigated by comparing a single dose of 10 mg/kg body weight with a single dose of 1 mg/kg body weight. Labelled azocyclotin was absorbed at a relatively slow rate and in a small amount. Excretion in urine was slight (1.1% of the administered radioactivity for the [113Sn]label; 12.6% for the [1-14C]label. The amount of radioactivity present in the gastrointestinal tract after the first 24h was approximately 60% of the administered radioactivity. Between 24 and 48h, the level of radioactivity decreased quickly owing to excretion in faeces, with the result that after 3 days all radioactivity had been virtually completely eliminated from the animal body. The radioactivity present in the body less gastrointestinal tract (3% of administered radioactivity after 3 days, approximately 1% of administered radioactivity after 10 days) was distributed uniformly among the organs and tissues. No radioactivity levels exceeding approximately 1% of the initial dose were measured in any organ. Somewhat elevated values were measured at 4h after administration in liver and kidney. Thereafter, the values decreased continuously in all organs and tissues (Bayer AG 1981). * See Annex II for FAO and WHO documentation. TOXICOLOGICAL STUDIES The acute toxicity of azocyclotin, which was studied in seven animal species, is reported in Table 1. TABLE 1. Acute toxicity of azocyclotin Species Sex Route of LD50 Reference application (mg/kg) Rat M oral 99 Thyssen and Kimmerle 1974a,b Rat F oral 76 ibid. Rat M oral 180 Iyatomi 1980 Rat F oral 150 ibid. Rat M oral 102 Flucke 1980 Rat* M oral 93 ibid. Rat F oral 118 ibid. Rat* F oral 128 ibid. Mouse M oral 453 Thyssen and Kimmerle 1974a,b Mouse F oral 417 ibid. Mouse M oral 980 Iyatomi 1980 Mouse F oral 870 ibid. Cat F oral > 25 Thyssen and Kimmerle 1974a,b Dog F oral < 50 ibid. Guinea pig M oral 261 Thyssen 1974 Guinea pig F oral 261 ibid. Quail M oral 144 Thyssen 1979 Quail F oral 195 ibid. Quail F oral >175 < 250 Kimmerle 1973 Hen oral 250 - 375 ibid. Rat M intraperitoneal 3.65 Thyssen and Kimmerle 1974a,b Rat F " 3.54 ibid. Rat M " 4.6 Iyatomi 1980 Rat F " 5.9 ibid. Mouse M " 3.6 ibid. Mouse F " 4.0 ibid. TABLE 1. (con't) Species Sex Route of LD50 Reference application (mg/kg) Rat M subcutaneous >1000 Iyatomi 1980 Rat F " >1000 ibid. Mouse M " 250 ibid. Mouse F " 300 ibid. Rat M dermal ca. 1000 Thyssen and Kimmerle 1974a,b Rat F dermal > 1000 ibid. Rat M " > 5000 Iyatomi 1980 Rat F " > 5000 ibid. Mouse M " > 5000 ibid. Mouse F " > 5000 ibid. * = fasted Symptoms seen in rats after both oral and intraperitoneal administration were characterized by impairment of general health, drowsiness and at elevated dose levels, breathing disorders and diarrhoea. Onset of these symptoms at the high dose levels were within one hour of application, and they persisted for up to 14 days. Following dermal application, the effects seen were local irritation, increased blood flow and formation of edoema on the ears resulting in necroses from pressure on the margins of the ears. Subcutaneous application induced ulcers. Symptoms seen in mice and guinea pigs were characterized by depression of the general health, drowsiness and breathing disorders, which persisted for up to 14 and 15 days, respectively after application. Cats and dogs vomited within one hour of oral application (Bayer AG 1981). Single doses of the 25% WP formulation of azocyclotin were also tested for acute toxicity to rats and mice. The results obtained are summarized in Table 2. TABLE 2. Acute toxicity of azocyclotin 25% WP Species Sex Route of LD50 application (mg/kg) Reference Rat M oral 631 Rat F oral 611 Mouse M oral 2451 Thyssen and Kimmerle 1974a,b Mouse F oral 1936 Rat M i.p. 16.7 Rat F i.p. 22.6 The poisoning symptoms seen in the rats following oral and intraperitoneal administrations were characterized by impairment of the general health, breathing disorders and body weight depression. Additional effects observed at the elevated dose levels were diarrhoea and cyanosis. Symptoms seen in the mice were characterized by impairment of the general health and breathing disorders. Short-term studies Rat Groups of 15 male and 15 female Wistar rats were orally dosed with azocyclotin at levels of 0.2, 2 and 20 mg/kg bw, emulsified in distilled water and Cremophor EL, administered by gavage on 30 consecutive days. A similar control group received the vehicle only. Male rats tolerated doses of 0.2 and 2 mg/kg bw without any adverse effects. The female rats tolerated only the lowest dose of 0.2 mg/kg bw without showing any signs of treatment-related effects. Although they also tolerated 2 mg/kg bw without showing any noteworthy clinical symptoms, this dose level caused a slight reduction in their relative thymus and brain weights. At the 20 mg/kg dose level, some male and female mortalities occurred. This dose caused an impairment of the general health and affected the growth rate. Additionally, the haematological tests showed a tendency towards leucopenia. Interference with liver function was indicated by increased alkaline phosphatase activity. Some organ weight alterations were noted at 20 mg/kg, viz. reduction of thymus, heart, lung and kidney weights and an increase in liver, adrenal and brain weights in males; reduction of thymus and brain weights and an increase in liver weight in females. Neither gross pathology or histopathology revealed any variations or alterations from the physiological norm in the tissues of either sex. The wet weight of the brains and the weight of freeze-dried brains provided no indication of the brain having an increased water content (Thyssen and Luckhaus 1974). In another study on Wistar rats, groups of 15 males and 15 females were maintained for 3 months on a diet containing azocyclotin at concentrations of 0, 5, 15, 50 and 150 ppm. Dietary concentrations of 5 and 15 ppm did not affect physical appearance, behavioural patterns, growth rate or survival rate of the males and females. At dietary levels of 50 and 150 ppm, food consumption was less and body weights were lower than in the control group. The dietary level of 150 ppm caused mild drowsiness. Clinical chemical tests, haematological tests and urinalyses performed during and at the end of the study yielded no indication of any damage to body functions at dietary levels of up to and including 150 ppm. Gross pathology and histopathology revealed no indication of any damaging effects from administration of azocyclotin at dietary levels of up to and including 150 ppm. The dietary level of 15 ppm was tolerated by the rats for 3 months without having any damaging effects whatsoever (Löser and Luckhaus 1975). In a subacute inhalational toxicity study, male and female Wistar rats (10 per sex per group) were exposed for 6h daily over a 3-week period (total of fifteen 6h-exposures) to azocyclotin aerosols (ethanol + polyethylene glycol 400; 20 ml/m3) at concentrations averaging 0.0901, 0.275 and 0.961 mg/m3 air. A control group of identical composition was exposed to the solvent mixture only. During the exposure period, the rats were inspected for their behavioural reactions, and their body weights were measured. At the end of the study, haematological tests, clinical chemical tests, urinalyses, macroscopic tissue examinations, organ weight measurements and histopathological examinations of the major tissues were performed. The concentration levels of 0.0901 and 0.275 mg/m3 air had no adverse effects on behavioural patterns, physical appearance and growth rate. Haematology, clinical chemistry and urinalyses did not reveal any signs of damage at these concentration levels. Exposure of the rats to 0.961 mg azocyclotin/m3 air caused poisoning symptoms, reduced weight gain and organ weight alterations. The symptoms were characterized by impairment of the general health and breathing disorders. One male rat died after the seventh exposure. Measurement of the organ weights revealed a reduction of the liver and thymus weights and an increase in the lung weight at the highest concentration level. The histological examinations did not reveal any morphological equivalent of the observed clinical symptoms and organ weight alterations (Kimmerle 1974). Dog In a 13-week feeding experiment, groups of 4 male and 4 female beagle dogs were maintained on a diet containing azocyclotin at concentrations of 0, 5, 50 and 500 ppm. In this study, the no-toxic effect dietary level of azocyclotin was 5 ppm. Higher dietary concentrations caused slow and reduced food intake, slow weight gain, diarrhoea and vomiting, in a dose-related manner. The dogs fed dietary levels of 50 and 500 ppm also had an ungroomed appearance. The dogs of the 500 ppm group had a slightly drowsy appearance, particularly during the first phase of the treatment. This was associated with the depression of their general health. However, all the dogs survived the treatment. Special haematological tests did not provide any indication of treatment-related damage at dietary levels of 5 and 50 ppm. At the dietary concentration of 500 ppm, some male dogs showed signs of anaemia, manifested by a reduction of the erythrocyte count and concomitantly by a reduction of the haemoglobin content and the haematocrit level. Clinical chemistry revealed a slight, treatment- related increase in serum cholesterol in some female dogs of the 50 and 500 ppm groups at the end of the treatment period. The serum calcium values showed a slight reduction in comparison with the initial values in the 50 and 500 ppm groups. One male dog in the 500 ppm group exhibited marked signs of liver damage. The urinalyses and macroscopic examinations performed at the end of the study provided no indication of any damage from azocyclotin administration. Organ weight measurements showed a slight increase in adrenal weights only in females of the 50 and 500 ppm groups. Histopathology did not reveal any treatment-related alterations in any tissue in any treated group (Hoffman and Schilde 1975). Rabbit Groups of 3 male and 3 female White New Zealand rabbits were treated dermally on 5 days per week over a 3-week period (total of 15 applications) with azocyclotin at doses of 0 (vehicle), 5 and 25 mg/kg bw, respectively, applied to either intact or abraded skin areas. Evaluation of the treated skin areas for reaction to azocyclotin revealed severe skin reactions (irritations and corrosions) at both dose levels and on both intact and abraded skin areas, as compared with the controls. Neither male nor female rabbits exposed to azocyclotin applied to intact and abraded skin showed any systematic damage attributable to absorption of azocyclotin. Some of the rabbits in the highest dose group did not exhibit the same weight gains as the controls. Since there were no signs whatsoever of systemic damage, this effect on body weight development was evidently associated with the severe skin injury and the associated pain. Therefore, 25 mg/kg body weight applied dermally to rabbits was a no- effect dose from the systemic toxicity aspect. However, azocyclotin that was applied emulsified in distilled water and Cremophor EL caused local intolerance and had strong skin-irritating and skin-corrosive effects (Thyssen and Kaliner 1978). Long-term studies Rat Azocyclotin was evaluated for potential chronic toxicity and carcinogenicity in a 24-month study on groups of 50 male and 50 female Wistar-TNO W74 rats fed dietary levels of 5, 15 and 50 ppm, respectively. The control group fed a diet without azocyclotin consisted of 100 male and 100 female rats. For clinical laboratory tests (haematology, clinical chemistry, urinalyses, enzyme induction assays) and intermediate necropsies, 10 rats per group and per sex were used additionally. At the end of the 24-month feeding experiment, all survivors were sacrificed and necropsied. All major organs were weighed and histopathologically examined. The tests provided no indication of azocyclotin causing carcinogenic effects in rats. With respect to chronic toxicity, the no-effect dose was 5 ppm for both males and females. Although the two higher dietary levels tested, viz. 15 and 50 ppm, caused retarded growth in both sexes, they did not have any specific effects on organs and organ functions (Bomhard, Löser and Vogel 1979). Mouse Azocyclotin was evaluated for potential chronic toxicity and carcinogenicity on groups of 50 male and 50 female CF 1 mice fed the compound for 24 months at dietary concentrations of 0 (control), 5, 15 and 50 ppm, respectively. For intermediate tests and intermediate necropsies at 6 and 12 months, 10 male and 10 female mice per group were used additionally. Clinical inspections, body weight measurements, food intake measurements, macroscopic examinations and comprehensive histological examinations were performed. The study revealed no indication of carcinogenic effects, as the nature, localization and incidence of tumours, as well as the time of their occurrence, were comparable in all groups. No chronic toxic effects were seen at the two lower dietary levels of 5 and 15 ppm. At the dietary level of 50 ppm, male mice showed less weight gain, particularly in the first half of the feeding experiment, whereas the females showed weight gain similar to that of the controls. However, specific effects on organs or on organ functions were not seen either in female mice or in males at any of the dietary levels up to and including 50 ppm (Krötlinger and Löser 1981). Dog In a chronic toxicity study, azocyclotin was fed to groups of 4 male and 4 female beagle dogs for 104 weeks at dietary levels of 0, 10, 30, 100 (up to week 53), 200 (week 54 to 82) and 400 ppm (week 83 to 104) respectively. Clinical inspections, haematological tests, clinical chemical tests and urinalyses were performed. At the end of the feeding experiment, the dogs were sacrificed and necropsied, organ weights were measured and tissues were histopathologically examined. Azocyclotin at a dietary level of 10 ppm was tolerated by both males and females throughout the two-year period without causing any untoward effects. Dietary levels of 30 ppm, 100 ppm and above caused increased diarrhoea. At the highest concentration, which was raised from 100 ppm through 200 ppm to 400 ppm in order to obtain an effect, body weight gain was also seen to have been affected, especially in the second half of the study. However, clinical laboratory tests, gross pathology and histopathology did not provide any indication of specific damage to tissues (Hoffman and Schilde 1979). Special studies on reproduction Rat Azocyclotin was evaluated for its potential effect on reproduction in a three-generation study on Wistar rats. There were two matings per generation and azocyclotin was fed to groups of 10 male and 20 female rats throughout the study at dietary concentrations of 0 (control), 5, 15 and 50 ppm, respectively. The treated rats were studied for the effects of oral azocyclotin on behavioural pattern, growth rate, mortality, fertility, lactation performance (ability to successfully nourish the resulting offspring) and development of offspring. The F0 generation was about 30 to 35 days old at the start of the study and was treated for 70 days before the first mating. The pups of the F3b generation were sacrificed at an age of 4 weeks, dissected, and 17 major tissues were examined histopathologically. Dietary concentrations of 5 and 15 ppm had no adverse effect on the reproductive performance of the rats, and 50 ppm in the diet resulted in lower fertility rates after only one of six matings and usually caused body weight depressions in the pups during the lactation period and also in the parent rats. Azocyclotin did not cause any malformations in the young at any of the tested dietary levels. Histopathological examination of the major tissues from the 4-week old pups of the F3b generation did not reveal any alterations. Therefore, 15 ppm was tolerated in the three-generation study without having any untoward effects (Löser 1980). Special studies on mutagenicity Microorganisms Azocyclotin was tested for mutagenicity by the Salmonella/microsome test (Ames test) using strains TA 1535, 1537, 100 and 98 and metabolic activation with S-9 microsomal fraction of adult male rat livers. Azocyclotin was tested at doses of 4, 20, 100, 500 and 2 500 µg per plate; four agar plates were used per dose. Doses of up to and including 100 µg per plate did not cause any bacteriotoxic effects, while higher dose levels caused inhibition of bacterial growth. There were no mutagenic effects found in any of the test strains used (Herbold 1979b). In a rec-assay (repair test), azocyclotin was tested for potential DNA-damaging effects on two Bacillus subtilis strains at concentrations ranging up to and including, 5 000 µg per plate. Reversion assays were conducted by the Ames test on the Salmonella typhimurium strains TA 1535, 1537, 1538, 98 and 100 and on Escherichia coli WP 2. In these assays, azocyclotin was tested at concentrations ranging up to and including a maximum of 5 000 µg/plate, with and without metabolic activation. Azocyclotin induced neither DNA-damage nor any point mutations. Azocyclotin was evaluated for potential genetic activity (recombinogenic activity) on two B; subtilis strains and for potential point mutation activity in a reverse mutation induction assay (eukaryotic test) employing two S. cerevisiae strains (S 138 and S 211) in comparison with negative (solvent) and positive controls, with and without metabolic activation. Azocyclotin had no mutagenic activity at concentrations of up to toxic levels (100 µg/plate) (Jagannath and Hoorn 1980). Mouse - micronucleus test Azocyclotin was evaluated for mutagenicity in a micronucleus test using the procedure of Schmid (1973) on groups of 10 NMRI mice dosed orally with the test compound at levels of 2 × 50 mg/kg bw. The study included a negative control group and a positive control group dosed with cyclophosphamide. The two applications of azocyclotin were made at an interval of 24h, and the femoral marrow was prepared 6h after the second application. Polychromatic erythrocytes, 1000 per mouse, were analysed; the number of normochromatic erythrocytes per 1 000 polychromatic erythrocytes was counted. No indication of mutagenicity was found in the mouse at oral doses of up to and including 2 × 100 mg/kg. Erythropoiesis, as measured by the ratio of polychromatic to normochromatic erythrocytes, was not adversely affected (Herbold 1979a). Azocyclotin was tested by the same procedure in male Swiss mice at oral dose levels of 2 × 50 mg/kg, 2 × 100 mg/kg and 2 × 150 mg/kg bw. The control group and the lowest dose group each consisted of 10 mice; the middle dose group comprised 15 mice; the highest dose group consisted of 5 mice. No indication of mutagenicity of azocyclotin was found. However, some of the doses were toxic; 4 of the 15 mice died at an oral dose of 2 × 100 mg/kg bw, and 1 of the 5 mice died in the group dosed orally with 2 × 150 mg/kg bw (Siou 1979). Mouse (male) - Dominant lethal test A group of 50 male NMRI mice each received a single oral dose of 2.5 mg/kg bw; a control group of 50 male mice received the vehicle only. The 2.5 mg/kg dose is within the toxic range (Thyssen and Kimmerle 1974a). The treated mice exhibited transient drowsiness on the day of administration, but they all survived. After administration of the test compound, each male was mated with a fresh untreated virgin female every 4 days, this procedure being repeated for a total of 12 matings. The pre-implantation and post-implantation losses and the fertility data were tested for statistically significant differences between the treated groups and the controls. Azocyclotin was not mutagenic in this test system (Machemer 1977a). Special studies on teratogenicity Rat Azocyclotin was tested on Long Evans rats at oral doses of 3, 10 and 30 mg/kg bw/day and, in another experiment, at oral doses of 0.3, 1.0 and 3.0 mg/kg bw/day. Each experiment included a control group. Twenty fertilized females, which were used per group, were tested daily from day 6 to 15 post coitum. On gestation day 20, the foetuses were removed by caesarean section. Doses of up to and including 3 mg/kg had no damaging effects on the dams. Doses of 10 mg/kg and above depressed dam weight gain. The 30 mg/kg dose level also caused toxic symptoms and the death of 2 dams. Embryonic and foetal development were not affected by doses of up to and including 10 mg/kg. Although the dose level of 30 mg/kg had a marked embryo- lethal effect and caused an increase in the frequency of stunted foetuses, there were no indications of azocyclotin having any teratogenic or primary embryotoxic effects at any of the tested dose levels of up to and including 30 mg/kg; even the maternal toxic dose of 10 mg/kg did not have any damaging effects on embryonic and foetal development. Only the dose level of 30 mg/kg, that was markedly toxic and lethal to dams, increased lethality in embryos (Machemer 1977b). Special studies on liver and kidney function Rats Ten male Wistar rats each received 50 mg azocyclotin/kg bw administered orally in an aqueous formulation. Ten control males were dosed with the formulating aids only. The rats were sacrificed 24h after administration, and blood for tests was obtained by cardiopuncturc. Liver function was assessed by measuring the following parameters: GOT, GPT, alkaline phosphatase, GLDH, SDH and bilirubin. Kidney function was assessed by measuring the urea and creatinine levels in plasma. No evidence was found of liver and kidney function having been adversely affected by administration of azocyclotin (Thyssen 1974). Special studies on haematology Guinea pig Ten male and ten female Pirbright guinea pigs received a single dose of 100 mg azocyclotin/kg bw administered orally in an aqueous formulation. A control group of the same animal composition received the formulating aids only. The guinea pigs were sacrificed 4 days after applications and the blood for the haematological tests was obtained by cardiopuncture. There was no indication of the treatment having had any adverse effects on the red blood cells or the while blood cell differential count (Thyssen 1974). Special studies on effect on liver enzymes Rat Groups of 5 male Wistar rats were treated with a single dose of 25 mg azocyclotin/kg bw administered orally in an aqueous formulation. The groups were then sacrificed at different intervals, viz. at 24h, 48h, 3 days, 5 days and 7 days, respectively, and the activities of the EPN-oxidase (enzyme system which oxidises O-ethyl-O- (4-nitrophenyl)-phenylphonothioate), the O-demethylase and the N-demethylase in the liver tissue of the rats were then measured. The results showed that azocyclotin had an inhibitory effect on the activities of the EPN-oxidase and the N-demethylase in liver tissue. The activity of O-demethylase was only minimally depressed. While the activity of the EPN-oxidase was still inhibited 7 days after administration of azocyclotin, the activity of the O-demethylase was again within the physiological range only 5 days after administration. The activity of the N-demethylase corresponded to the physiological norm at 7 days post-administration (Thyssen 1974). Special studies on blood clotting Rats Azocyclotin applied in an aqueous formulation at a dose of 250 mg/kg bw to the clipped dorsal skin of each of 5 male Wistar rats for a contact time of 7 days had no effect on the thromboplastin time, as compared with the results obtained for a control group of similar composition (Thyssen 1974). EVALUATION COMMENTS Azocyclotin is poorly absorbed from the rat gastro-intestinal tract. The small amount of absorbed material is evenly distributed throughout the body tissues and is excreted relatively slowly. There were no indications of azocyclotin having mutagenic effects, primary embryo-toxic effects, teratogenic effects or adverse effects on reproductive performance. There was no indication that azocyclotin has a cumulative toxic effect of any significance. No histological changes were observed in short-term or long-term studies. The highest no-effect dose in a 30-day oral experiment on rats was 0.2 mg/kg bw/day. In a 2-year feeding experiment on rats, the no-effect dietary level was 5 ppm. The no-effect dietary level in a 2-year feeding experiment on dogs was 10 ppm (0.25 mg/kg bw/day), and the no-effect dietary level in a 2-year feeding study on mice was 15 ppm (2.0 mg/kg bw/day). Two-year feeding studies in rats and mice did not indicate any carcinogenic potential. As it is known that some organic tin compounds affect the immune system, and as thymus weight was decreased in some studies, further investigation of possible immune effects was felt to be desirable. Level causing no toxicological effect Rat : 5 ppm, in the diet equivalent to 0.25 mg/kg bw/day Mouse : 15 ppm, in the diet equivalent to 2.0 mg/kg bw/day Dog : 10 ppm, in the diet equivalent to 0.25 mg/kg bw/day Estimate of acceptable daily intake for man 0 - 0.003 mg/kg bw FURTHER WORK OR INFORMATION Desirable 1. Studies to determine the potential for central nervous system toxicity. 2. Studies to examine the possibility of effects on the immunal system. REFERENCES Ames, B.N. et al. Am improved bacterial test system for the detection 1973 and classification of mutagens and carcinogens. Proceedings of the National Academy of Sciences, 70: 782-786. Bayer AG. Azocyclotin: Monograph. Prepared for FAO/WHO 1981 JMPR. 1981 Report submitted by Bayer AG, September, 1981 (Unpublished). Bomhard, E., Löser, E. and Vogel, O. BUE 1452/chronic toxicity study 1979 on rats (two-year feeding experiment), December 14, Report No 8780, Bayer AG, Institut für Toxikologie. Report submitted by Bayer, AG. (Unpublished) Grubenbecher, F. and Figge, K. BUE 1452 ([1-14C]-Cyclohexyl markiert): 1979a Ausscheidung und Organverteilung an Ratten. September, Report No. Na 760043. Natec, Institut für naturwissenschaftlichtechnische Dienste GmbH. Report submitted by Bayer AG. (Unpublished) 1979b BUE 1452-113Sn: Ausscheidung und Organverteilung an Ratten. September 1979, Report No. Na 760043. Natec, Institut für naturwissenschaftlichtechnische Dienste GmbH. Report submitted by Bayer AG. (Unpublished) Herbold, B. BUE 1452/micronucleus test on mouse to evaluate BUE 1452 1979a for potential mutagenic effects. 26 January 1979, Report No. 8129, Bayer AG, Institut für Toxikologie. Report submitted by Bayer, AG. (Unpublished) 1979b BUE 1452/Salmonella/Microsome test for detection of point- mutagenic effects. 23 February 1979, Report No. 8205, Bayer AG, Institut für Toxikologie. Report submitted by Bayer, AG. (Unpublished) Hoffman, K. and Schilde, B. BUE 1452/subchronic toxicity study on dogs 1975 (Thirteen-week feeding experiment). 2 July 1975, Report No. 5506, Bayer AG, Institut für Toxikologie. Report submitted by Bayer, AG. (Unpublished) 1979 BUE 1452/chronic toxicity study on dogs (two-year feeding experiment). 12 October 1979, Report No. 8680, Bayer AG, Institut für Toxikologie. Report submitted by Bayer, AG, (Unpublished) Iyatomi, A. Report of acute toxicity - A. 19 September 1980. Report 1980 sheet No. A-32, Nitokuno, Agricultural Chemicals Institute, Japan. Report submitted by Bayer AG. (Unpublished) Jagannath, D.R. and Hoorn, A.J.W. Mutagenicity evaluation of BUE 1452 1980 in the rec-assay and the reverse mutation induction assay. January, 1980. KR-Bericht Nr. 1674, Litton Bionetics, Inc., USA. Report submitted by Bayer AG. (Unpublished) Kimmerle, G. BUE 1452/acute oral toxicity study on hens, 22 May 1973. 1973 Bayer AG, Institut für Toxikologie. Report submitted by Bayer, AG. (Unpublished) 1974 BUE 1452/subacute inhalation toxicity study on rats. 12 August, 1974. Report No. 4842, Bayer AG, Institut für Toxikologie. Report submitted by Bayer AG. (Unpublished) Krötlinger, F. and Löser, E. BUE 1452 (Peropal active ingredient, 1981 azocyclotin) chronic toxicity studies on mice (two-year feeding experiment), 7 January 1981, Report No. 9680, Bayer AG, Institut für Toxikologie. Report submitted by Bayer AG. Addendum: Glaister, J.R., Histopathology Hazleton Laboratories Europe Ltd., Harrogate. (Unpublished) Löser, E. BUE 1452/multigeneration reproduction study on rats, 8 1980 April, 1980. Report No. 9387, Bayer AG, Institut für Toxikologie. Report submitted by Bayer AG. (Unpublished) Löser, E. and Luckhaus, G. 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See Also: Toxicological Abbreviations Azocyclotin (Pesticide residues in food: 1979 evaluations) Azocyclotin (Pesticide residues in food: 1983 evaluations) Azocyclotin (Pesticide residues in food: 1989 evaluations Part II Toxicology) Azocyclotin (JMPR Evaluations 2005 Part II Toxicological)