ETOFENPROX First draft prepared by P.J.C.M. Janssen, P.H. Arentzen, E.M. den Tonkelaar National Institute of Public Health and Environmental Protection, Bilthoven, Netherlands EXPLANATION Etofenprox is an insecticide with an action similar to the pyrethroids. It is active against a wide range of insect pests and is effective against strains of rice green leafhopper and planthoppers resistant to organophosphorus and carbamate insecticides. It is also used to control public health pests, and on livestock (Agrochemicals Handbook, 1991). Etofenprox was considered for the first time by the present Meeting. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOLOGICAL DATA Biochemical aspects Absorption, distribution and excretion Rats Groups of 5 Charles River CD rats/sex received a single oral dose by intubation of 30 or 180 mg/kg bw of 14C-etofenprox (a 1:1 mixture of [1-14C-propyl] etofenprox and [alpha-14C- benzyl]etofenprox dissolved in PEG 400). Separate groups were used to determine excretion of radioactivity in urine and faeces, excretion in bile (bile-cannulated rats) and concentrations in blood. Tissue radioactivity concentrations were measured in all groups. Excretion in faeces over the 5 days post-dosing period were about 87% and 90%, and in urine 9% and 7% at the low and high dose, respectively. No radioactivity was found in expired air. Mean plasma radioactivity concentrations reached peak levels (5.1 mg/litre at the low dose and 16.9 mg/litre at the high dose) after 3 to 5 hours. Elimination from plasma was biphasic with half-lives of 7-8 hours for the rapid phase (for both dose levels) and 18 hours and 35 hours for the slow phase, for the low and high dose, respectively. Total retention in the tissues at 5 days from treatment was 3-4% for both doses with highest concentrations being present in fat (mean of 14 mg/kg at the low dose and 92 mg/kg at the high dose). Concentrations in other tissues were markedly lower (0.04-1.7 mg/kg). In rats with cannulated bile ducts, mean excretion in bile amounted to 15-30% (low dose) and 10% (high dose). Based on the study results and the biotransformation pattern identified in excreta, total estimated gastrointestinal absorption was between 65-93% (low dose) and 48-77% (high dose) (Hawkins et al., 1985a). A group of 25 Charles River CD rats/sex was dosed orally with 14C-etofenprox (the same mixture as above) at a dose level of 30 mg/kg bw/day for 7 days. At 4 hours, 1, 2, 5 and 10 days after the last dose, 5 rats/sex were killed and tissue concentrations were determined. At 4 hours from the last dose, highest mean tissue concentrations were present in fat (98 mg/kg), adrenals (42 mg/kg), ovaries (24 mg/kg), liver (26 mg/kg), thyroid (16 mg/kg) and kidneys (8.8 mg/kg). Tissue concentrations declined progressively with time, but fat concentrations declined relatively slowly in a linear fashion with approximate half-lives of 5 days for males and 8.5 days for females (Hawkins et al., 1985a). A further part of the study of Hawkins et al. (1985a) was focused on transplacental transfer and transfer into milk. This involved oral dosing with 14C-etofenprox (mixture as above) at 30 mg/kg bw/day to pregnant Charles River CD rats from day 10 through day 16 of gestation and to pregnant/nursing rats (same strain) from day 18 of pregnancy until about day 9 after parturition. Groups of 2 pregnant rats were killed before parturition at 4 hours, 1, 2, 3 or 5 days after the final dose. Pups were allowed to suckle the nursing rats for 1 hour, at which time the pups were killed and their stomach content was analyzed for radioactivity. Total radioactivity and elimination patterns in tissues of pregnant rats were similar to those seen in non-pregnant rats. At 4 hours after the final dose, radioactivity concentrations were low in placentae (4.7 mg/kg) and fetuses (1.6 mg/kg) compared to other tissues such as adrenals (62 mg/kg) and liver (27 mg/kg). Highest maternal tissue concentrations were present in mammary glands (87 mg/kg); this level declined with a half-life of about 3.5 days. Secretion of the test compound into milk was observed. Pup stomach contents contained radioactivity concentrations of 41-88 mg/kg (compared to maternal plasma concentrations of 1.9-3.6 mg/litre). After cessation of exposure this secretion dropped markedly (Hawkins et al., 1985a). Dogs Groups of 2 beagle dogs/sex received a single oral dose by intubation of 30 mg/kg bw of 14C-etofenprox (a 1:1 mixture of [1- 14C-propyl]etofenprox and [alpha-14C-benzyl]etofenprox dissolved in PEG 400). Radioactivity in blood, urine and faeces was monitored up to day 5 after treatment. Concentrations in tissues and bile were determined in two additional groups (2 dogs/sex) given the same dose and sacrificed after 2 or 4 hours. Total excretion in faeces and urine was about 90% and 6% of the dose, respectively. In blood plasma, peak concentrations of 4.4-7.2 mg/litre were reached at 0.25-3 hours after dosing. Blood levels showed absorption to be more rapid in females. After reaching the peak, radioactivity concentrations declined with half-lives in the range of 8.6-17 hours. In tissues, highest concentrations were found in liver (3.1-9.6 mg/kg), followed by kidneys (1.0-3.3 mg/kg) and fat (0.4-4.1 mg/kg); lowest levels were found in muscle (0.3-0.6 mg/kg). Concentrations in bile were very high (815-1036 mg/kg), indicating that this is an important excretion route of absorbed radioactivity. Based on the study results the pattern of metabolites identified in excreta, the total estimated gastrointestinal absorption was 14-51% (Hawkins et al., 1985b). Biotransformation Rats Hawkins et al. (1985a) identified metabolites in their oral study in Charles River CD rats. Metabolite identification was carried out in faeces and urine in the single dose groups, in bile in the bile-cannulated rats (given a single dose of 30 mg/kg bw), in liver and fat in the repeated-dose group (at 4 hours after the last dose) and in pup stomach contents in the group dosed during lactation. Faecal radioactivity was present as unchanged etofenprox (7-30% of the dose), 2-(4-hydroxyphenyl)-2-methylpropyl-3- phenoxybenzyl ether (19-25%) and 2-(4-ethoxyphenyl)-2-methylpropyl- 3-(4-hydroxyphenoxy)benzyl ether (7.7-13%). The percentage that was present as unchanged compound was slightly higher in the high-dose group compared to the low-dose group and in females compared to males. The same metabolites were present (as glucuronide or sulfate conjugates) in liver, bile and, in small amounts (< 2% of the dose), in urine. No unchanged compound was present in bile. In fat and milk, radioactivity was almost entirely present as unchanged etofenprox. In an additional study, the presence or absence in rats (SD strain) of 2-(4-ethoxyphenyl)-2-methylpropyl-3-phenoxybenzoate (MTI- 500 alpha-CO, a major metabolite in plants and soil and a photodegradation product) was determined after administration of a single dose of 30 mg/kg bw [alpha-14C-benzyl]etofenprox. The metabolite MTI-500 alpha-CO could be detected in faeces and urine in trace amounts only (< 0.002% of the dose). The metabolite 3- phenoxybenzoic acid, the hydrolysis product of MTI-500 alpha-CO, was found in faeces in larger amounts (4% of the dose). In addition 3- (4-hydroxyphenoxy)benzoic acid was present (as conjugate) in faeces (0.47%) and urine (0.006%) (Tomoda et al., 1986). From these studies in rats the proposed metabolism scheme may be derived by combining the results of Hawkins et al. (1985a) with the scheme as proposed by Tomoda et al. (1986). The resulting metabolism scheme is presented in Figure 1. The metabolite MTI-500 alpha-CO is probably only formed in rats as an intermediate which is rapidly metabolized further into 3-phenoxybenzoic acid. Dogs Hawkins et al. (1985b) identified metabolites in their oral study in beagle dogs. In blood plasma radioactivity was present as unchanged etofenprox, 2-(4-hydroxyphenyl)-2-methylpropyl-3- phenoxybenzyl ether and as 2-(4-ethoxyphenyl)-2-methylpropyl-3-(4- hydroxyphenoxy)benzyl ether. Faecal radioactivity was present as unchanged etofenprox (48 or 59% of the dose) and as the two above metabolites (together 2.9 or 3.5% of the dose). These metabolites were also present (as glucuronide or sulphate conjugates) in liver, bile and, in small amounts (together 1.6% of the dose), in urine. Unchanged compound was also found in the liver. No unchanged compound was present in bile. Radioactivity in fat was almost entirely in the form of unchanged etofenprox. The major pathways of etofenprox biotransformation in dogs derived from these studies is given in Figure 1. Toxicological studies Acute toxicity studies Results of acute toxicity studies for etofenprox are given in Table 1. WHO has classified etofenprox as unlikely to present acute hazard in normal use (WHO, 1992). Additional acute studies were carried out with Trebon 20 EC, an emulsifiable concentrate containing 20% etofenprox (+ 6.5% emulsifier + 73.5% organic solvent). In both mice and rats the oral LD50 value was > 5 g/kg bw (Kashima, 1985a,b). The dermal LD50 in rats was > 2 g/kg bw (Kashima, 1985c). The results of a series of acute studies to determine the general pharmacological/toxicological action of etofenprox at high dose levels are given in Table 2 (Kamiya et al. (1985). Short-term toxicity studies Mice Groups of 20 CD-1 mice/sex were fed diets containing 0, 50, 500, 3000 or 15 000 ppm etofenprox (purity 96%) for 13 weeks. These dose levels were equal to 6.1, 60, 375 or 1975 mg/kg bw/day in males and 6.9, 71, 390 or 2192 mg/kg bw/day in females. Observations included clinical signs, mortality, food consumption, body weight, haematology, clinical chemistry and urinalysis. The weights of 10 organs/animal were recorded. Gross pathology and histopathology (about 27 tissues/animal) were carried out. At 15 000 ppm the main effects were: clinical signs (including hunched posture, lethargy, body tremors, emaciated appearance, respiratory distress), increased mortality, growth retardation, decreased RBC, Hb, PCV and MCHC, increased liver weight with hepatocyte enlargement, increased kidney weight with tubular basophilia and dilatation and microscopic changes in the lymphoreticular system (increased cellularity of splenic white pulp, reactive changes in lymph nodes, reduced thymic cellularity). At 3000 ppm a slight decrease in PCV, Hb and RBC occurred in males. The effects at 3000 ppm were consideredTable 1. Acute toxicity of etofenprox Species Sex Route LD50 LC50 Purity Reference (g/kg bw) (g/m3) Mouse M&F oral > 107.2 96%a Hashimoto et al., 1982a M&F dermalb > 2.14 96%a Hashimoto et al., 1982a M i.p. > 53.6 96%a Hashimoto et al., 1982a F i.p. 13.4 96%a Hashimoto et al., 1982a M&F s.c. > 53.6 96%a Hashimoto et al., 1982a Rat M&F oral > 42.88 96%a Hashimoto et al., 1982b M&F dermalb > 2.14 96%a Hashimoto et al., 1982b M&F i.p. > 42.88 96%a Hashimoto et al., 1982b M&F s.c. > 32.16 96%a Hashimoto et al., 1982b M&F inhalc > 5.9 96%d Jackson et al., 1983 Dog M&F oral > 5.0 96.3%e Harling et al., 1985a a compound given as undiluted molten solution (40 °C) b exposure for 24 hours c exposure for 4 hours d compound given as aerosol in acetone e compound given in gelatine capsules Table 2. Study results - pharmacological/toxicological action (Kamiya et al., 1985) Parameter Species (sex) Route Result Central nervous system - spontaneous motor activity DDY mouse (M) oral dose-related decrease at 25 & 50 g/kg bw (no other levels tested) - thiopental-induced sleeping time DDY mouse (M) oral dose-related increase at 25 & 50 g/kg bw; no effect at 12.5 g/kg bw - muscle relaxation actiona DDY mouse (M) oral affected at 50 g/kg bw; no effect at 5 g/kg bw - body (rectum) temperature DDY mouse (M) oral no effect at 25 and 50 g/kg bw - induced tonic and clonic DDY mouse (M) oral no effect at 5 & 50 g/kg bw convulsionsb - general behaviour Wistar rat (M) oral no effect at 1 & 10 g/kg bw - EEG of frontal lobe Wistar rat (M) oral dose-related effect at 1 & 10 g/kg bw (no other levels tested) - EEG of hippocampus Wistar rat (M) oral effect at 10 g/kg bw; no effect at 1 g/kg bw & parietal lobe - conscious reaction induced Wistar rat (M) oral no effect at 1 & 10 g/kg bw by sound stimulation - spinal reflex potential mongrel cat (M/F) i.d.c no effect at 0.125-1 g/kg bw (cumulative administration) Effect on smooth muscle - intestinal charcoal propulsion DDY mouse (M) oral dose-related increase at 25 & 50 g/kg bw; no effect at 12.5 g/kg bw - normal movement and contractile rat, in vitro - 0.01-1.0 mmol/l (cumulative administration) - responsed of vas deferens produced no effect - autonomous movement of gravid rat. in vitro - 0.001-1.0 mmol/l (cumulative administration) or non-gravid uteruse produced no effect - uterus contractabilityf rat, in vitro - no effect at 0.1 mmol/l - spontaneous movement rabbit, in vitro - 0.01-1.0 mmol/l (cumulative administration) & contraction of ileum produced no effect - spontaneous movement of ileum guinea-pig, - 0.001-1.0 mmol/l (cumulative administration) in vitro produced no effect Table 2 (contd) Parameter Species (sex) Route Result neuro-muscular junction - contraction of musculus Wistar rat (M) i.v. no effect at 12.5-100 mg/kg bw gastrocnemiusg autonomic ganglia - contractions of nictitating mongrel cat (M/F) i.v. no effect at 10-100 mg/kg bw membraneh respiratory and circulatory system - respiration rate, blood pressure mongrel dog (M/F) i.v. decreased respiration rate (followed by increased rate) and ECG in combination with increased blood pressure & heart rate at > 30 mg/kg bw; at 100 mg/kg bw severer effects; no effect at 10 mg/kg bw - cardiovascular response as mongrel dog (M/F) i.v. no effect at 100 mg/kg bw induced by NE, ISP, AC, HIi & bilateral carotid occlusion - contractility of isolated atrium guinea-pig, in vitro -0.01-1.0 mmol/l (cumulative administration) produced no effect - positive & negative inotropic guinea-pig, in vitro -0.01-1.0 mmol/l (cumulative administration) reaction of isolated atrium produced no effect on induced neg. as induced by ISP & HI (+) or inotropy; effect on pos. inotropy AC (-) at 1.0 mmol/l only (no effect at 0.01-0.1 mmol/l) urinary volume & components - measured: volume, Cl-, Na+ & K+ Wistar rat (M) oral dose-related decrease in volume, Cl- & Na+ at 10 & 20 g/kg bw (no other dose levels tested), no effect on K+ Table 2 (contd) Parameter Species (sex) Route Result serum components - standard blood biochemistry Wistar rat (M) oral increased glucose (after 1 h only) and GOT and GPT after 1, 2, 6 & 24 hours (all sampling times) at 10 & 20 g/kg bw (no other levels tested) blood coagulation - prothrombin time, partial Wistar rat (M) oral no effect at 10 & 20 g/kg bw thromboplastin time & fibrinogen after 1, 2, 6 & 24 hours a measured as incidence of slipping down a smooth slope b induced by pentetrazol, strychnine or electro-shock c i.d. = intraduodenal d contractile response induced by di-norepinephrine e from rats in estrus and diestrus cycle or in pregnant stage f induced by oxytocin g induced by electrical stimulation of sciatic nerve and muscle h as induced by pre- and post-ganglionic nerve stimulation i NE, norepinephrine; ISP, isoproterenol; AC, acetylcholine; HI, histamine compound-related since the same effects were also seen (more severe in degree) at 15 000 ppm (the observed decreases were 8.5-11% at 15 000 ppm and 6% in males at 3000 ppm). The NOAEL in this study was 500 ppm (equal to 60 mg/kg bw/day) (Green et al., 1985a). Rats Groups of 20 Sprague-Dawley rats/sex were fed diets containing 0, 50, 300, 1800 or 10 800 ppm etofenprox (purity 96%) for 13 weeks. These dose levels were equal to 3.3, 20, 120 or 734 mg/kg bw/day in males and 3.8, 23, 142 or 820 mg/kg bw/day in females. Clinical signs, mortality, food consumption and body weight were recorded. Haematology, clinical chemistry (including T3 and T4) and urinalysis were done in all groups at weeks 6 and 12. Additional haematology consisted of the determination of PT and PTT in the 0 and 10 800 ppm groups at weeks 0 and 13. The weights of 10 organs/animal were recorded. Gross pathology and histopathology (about 27 tissues/animal) were carried out. At 10 800 ppm the following effects were observed: slight growth retardation, decreased food utilization, increased thrombin time, PT and PTT, decreased T4, increased cholesterol, increased ASAT, ALAT and LDH (at week 6 only), increased liver weight with slight hepatocyte enlargement and increased thyroid weight with increased incidence of microfollicles in thyroids. These effects, except for the increase in thrombin time (PTT and PT not determined), were also present to a slight degree at 1800 ppm. The NOAEL in this study was 300 ppm (equal to 20 mg/kg bw/day) (Green et al., 1985b). Dogs Groups of 6 beagle dogs/sex were given diets containing 0 or 10 000 ppm etofenprox (purity 96.3%) for 52 weeks. Two additional groups of 4 dogs/sex received dietary dose levels of 100 or 1000 ppm for 52 weeks. These dose levels were equal to 3.5, 33, or 352 mg/kg bw/day in males and 3.2, 32 or 339 mg/kg bw/day in females. After 52 weeks, 4 dogs/sex/group were killed. The remaining dogs in the 0 and 10 000 ppm groups were killed after a recovery period of 8 weeks. Observations included clinical signs, mortality, food consumption, body weight, haematology (including PT and PTT), clinical chemistry and urinalysis. The weights of 10 organs/animal were recorded. Gross pathology and histopathology (about 33 tissues/animal) were carried out. Effects observed at 10 000 ppm were decreased PCV, Hb and RBC, increased SAP, decreased total protein and albumin, increased kidney weight and increased liver weight with minimal swelling of hepatocytes. After 8 weeks of recovery none of these effects were found to persist. The NOAEL in this study was 1000 ppm (equal to 32 mg/kg bw/day) (Harling et al., 1985b). Long-term toxicity/carcinogenicity studies Mice Groups of 52 CD-1 mice/sex were fed diets containing 0, 30, 100, 700 or 4900 ppm etofenprox (purity 96.3%) for 2 years. These dose levels were equal to 3.1, 10, 75 or 550 mg/kg bw/day in males and 3.6, 12, 81 or 615 mg/kg bw/day in females. Satellite groups of 24 mice/sex/group received the same dose levels and were used for interim sacrifices after 26 weeks (10 animals/sex per group) and 52 weeks (remaining satellite animals). Observations included clinical signs, mortality, food consumption, body weight, haematology, clinical chemistry and urinalysis. Ophthalmoscopy was done in the 0 and 4900 ppm groups. The weights of 10 organs/animal were recorded. Gross pathology and histopathology (about 30 tissues/animal) were carried out. At 4900 ppm the following effects were seen: increased mortality in males (survival at test end 10/52 versus 24/52 in controls; renal lesions were considered contributory to death), growth retardation, decreased Hb, RBC, MCHC and PCV in combination with increased MCV (first year only), increased platelet counts (second year), decreased urine specific gravity, and increased weights of liver and spleen. Decreased MCHC and increased MCV were seen at 700 ppm also. Histopathology showed an increased incidence of renal changes in treated animals, mainly in males. The renal changes were mostly tubular lesions appearing as groups of basophilic or dilated tubules, sometimes associated with focal loss of tubules. These lesions were scored on a grade 1 to 5 scale. The incidences are presented in Table 3. At 30 ppm the increase in the incidence of renal lesions was considered marginal. No increase in tumour incidence was found. The NOAEL in this study was 30 ppm (equal to 3.1 mg/kg bw/day) (Green et al., 1986a). Rats Groups of 70 Sprague-Dawley rats/sex were fed diets containing 0, 30, 100, 700 or 4900 ppm etofenprox (purity 96.3%) for 2 years. These dose levels were equal to 1.1, 3.7, 26 or 187 mg/kg bw/day in males and 1.4, 4.8, 34 or 249 mg/kg bw/day in females. Interim sacrifices were made after 26 or 52 weeks (10 animals/sex/group on both occasions). Observations included clinical signs, mortality, food consumption, body weight, haematology, clinical chemistry (including T3 and T4) and urinalysis. The weights of 10 organs/animal were recorded. Gross pathology and histopathology (about 30 tissues/animal) were carried out. At 4900 ppm, the following effects were seen: decreased food intake or utilization, decreased growth, slightly increased thrombin time, increased urinary protein, increased liver weight with hepatocyte enlargement (sometimes with vacuolization), slightly increased kidney weight and increased thyroid weight with increased incidence of cystic follicles in thyroid. At 700 ppm, decreased food intake, increased thyroid weight, slightly increased kidney weight and presence of eosinophilic hepatocytes (sometimes with vacuolization) were noted. At 100 ppm no toxic effects were observed. Increased incidence of thyroid follicular tumours was found (Table 4). No changes in concentrations of T3 and T4 were found. Statistical analysis of these incidences showed that for thyroid follicular cell carcinomas the trend test was negative and the intergroup comparison showed no significant effect. Intergroup comparison showed a statistically significant increase in adenomas at 4900 ppm in females only. For adenomas and carcinomas, the trend test was positive in males and females. The NOAEL in this study was 100 ppm (equal to 3.7 mg/kg bw/day) (Green et al., 1986b). Reproduction studies Rats In a two-generation study, groups of 24 or 28 Sprague-Dawley rats/sex were used as parent animals, receiving dietary concentrations of 0, 100, 700 or 4900 ppm etofenprox (purity 96.3%). Two litters per generation were produced. Parent animals were killed at day 21 after birth of the Fb litters. Pups were also sacrificed at day 21 after birth except for selected F1a pups (maintained on test diets up to day 21 after birth of F1b litters), selected F1b pups (used as F1 parents) and selected F2b pups (maintained on test diets up to week 13 after birth). Gross pathology was done and the weights of selected organs were measured. Histopathology was done in F1 parents (kidneys, thyroids, liver), F0 parents (kidneys) and F2b adult animals (thyroid). At 4900 ppm, the main effects were: decreased growth and increased water consumption (parent animals), increased kidney weights with presence of cysts, deposits, congestion, haemorrhages or inflammation in collecting ducts or medulla (parents and young), increased liver weights with hepatocyte enlargement (parents and young), decreased pup weights, clinical signs (tremors, abnormal gait) in pups and increased thyroid weight with slight increase in height of follicular epithelium (F1 parents). At 700 ppm the effects were: increased kidney weights in F2b adult females and increased liver weights in the young of both generations. No effect on reproduction parameters were observed. The NOAEL in this study was 100 ppm (equivalent to 5 mg/kg bw/day) (Cozens et al., 1985a). Table 3. Number of mice showing renal lesions (Green et al., 1986a) Dilated/basophilic Control 30 ppm 100 ppm 700 ppm 4900 ppm cortical tubules Malesa grade 1 7 8 6 9 5 grade 2 0 3 4 6 4 grade 3 0 0 1 1 11 grade 4 0 0 1 1 6 grade 5 0 0 0 0 4 Femalesa grade 1 3 0 5 6 7 grade 2 1 1 1 1 6 grade 3 0 0 0 2 6 grade 4 0 0 1 0 1 grade 5 0 0 0 0 0 a number of animals examined: 52 in all groups Table 4. Number of rats with thyroid follicular tumours (Green et al., 1986b) Tumour type Control 30 ppm 100 ppm 700 ppm 4900 ppm Malesa adenomas 6 6 4 5 11 carcinomas 0 0 1 3 2 adenomas and/or 6 6 5 8 13 carcinomas Femalesa adenomas 0 3 2 0 9 carcinomas 0 0 0 2 1 adenomas and/or 0 3 2 2 9 carcinomas a number of animals examined: 50 in all groups Special studies on embryo/fetotoxicity Rats In a segment I study, groups of 24 Sprague-Dawley rats/sex were given oral doses (by gavage) of 0, 12.5, 250 or 5000 mg/kg bw/day etofenprox (purity 96.3%) and were mated during a 14-day mating period. The male animals were treated for 9 weeks prior to mating up to termination (autopsy) at week 15. Female animals were dosed for 2 weeks prior to mating up to day 7 of gestation. At day 20 of gestation females were sacrificed, standard litter data were recorded and fetuses were monitored for abnormalities (externally and standard soft tissue and skeletal examinations). No effects on mating performance, litter parameters, incidences of soft tissue or skeletal abnormalities were found. In parent animals at 5000 mg/kg bw/day salivation with brown staining around the mouth, staining/wetness around the anogenital region, crystalline appearance of the faeces, unkempt hair coat (males only) and skin lesions (males only) were present. Salivation with brown staining around the mouth was also observed occasionally at 250 mg/kg bw/day and, in a few animals, at 12.5 mg/kg bw/day. Increased salivation is frequently observed in gavage studies and is probably due to the method of application rather than representing a compound-related toxic effect. The NOAEL for reproductive performance and fetotoxicity was 5000 mg/kg bw/day. The NOAEL for parental toxicity was 250 mg/kg bw/day (Cozens et al., 1985c). In a segment II study, groups of 35 pregnant Sprague-Dawley rats were given oral doses (by gavage) of 0, 12.5, 250 or 5000 mg/kg bw/day etofenprox (purity 96.3%) from days 6 through 17 of pregnancy. No test compound was administered at later stages of the study. On day 20 of gestation, 21-24 dams/group were sacrificed for a standard teratogenicity evaluation (i.e. number of corpora lutea, number and distribution of live and dead fetuses, fetal weights, external abnormalities, soft tissue examination, skeletal examination). The remaining dams were allowed to deliver F1 pups. Litter data were recorded at birth. In the 4-21 days period after birth, a number of neuromotor parameters (including several reflexes and eye opening) were determined. On day 21, one pup/sex/litter was selected for use as F1 parents; pups not selected for later mating were killed and examined internally and externally for abnormalities. Mating was done when these animals were 12 weeks old. Behavioural tests were performed prior to mating. At day 21 after birth of F2 pups all animals were killed and examined internally and externally for abnormalities. At 5000 mg/kg bw/day maternal growth was retarded. Salivation, red/brown staining around the mouth, wet and yellow staining of the fur in the anogenital region were seen in the 5000 mg/kg bw/day dams during the treatment period. At 250 and 12.5 mg/kg bw/day salivation and red/brown staining around the mouth occurred in lesser incidences; these effects are not considered as compound-related adverse effects. No effects on mating performance, litter parameters, incidences of soft tissue or skeletal abnormalities were found in any group. The NOAEL for fetotoxicity was 5000 mg/kg bw/day and the NOAEL for maternal toxicity was 250 mg/kg bw/day (Cozens et al., 1985b). In a segment III study, groups of 25 pregnant Sprague-Dawley rats were given oral doses (by gavage) of 0, 12.5, 250 or 5000 mg/kg bw/day etofenprox (purity 96.3%) from day 17 of pregnancy through day 21 after birth of the F1 pups. No test compound was administered at later stages of the study. Litter data were recorded at birth of the F1 pups. On day 4, pups were culled to 8/litter (pups not selected were discarded). In the 4-21 days period after birth a number of neuromotor parameters (including several reflexes and eye opening) were determined. On day 21, one pup/sex/litter was selected for later mating (parent animals and pups not selected were killed and examined internally and externally). Mating was done when these animals were about 12 weeks old. Behavioural tests were performed prior to mating (i.e. general aspects of behaviour, hole board test for mobility and inquisitivity, inclined-plane test for motor coordination and a one- trial avoidance test). At day 21 after birth of F2 pups all animals were killed and examined internally and externally for abnormalities. In dams at 5000 mg/kg bw/day, decreased growth during the treatment phase and clinical signs (salivation, occasional brown staining around the mouth, staining around the urogenital region) were observed. Only salivation and brown staining were observed at 250 mg/kg bw/day; these effects are not considered as compound-related adverse effects. At 12.5 mg/kg bw/day no effects in dams were found. At 5000 mg/kg bw/day only, in F1 pups increased mortality (preceding symptoms: body tremors and haemorrhages around the nose) and decreased growth were found in the period up to day 21 after birth. Also at 5000 mg/kg bw/day, only in F1 weanlings and F1 adults, enlarged kidneys and histopathological kidney changes were observed. The NOAEL for neonatal effects and maternal toxicity was 250 mg/kg bw/day (Cozens et al., 1985d). Rabbits Groups of 16 or 17 mated New Zeeland white rabbits were given oral doses (by gavage) of 0, 10, 50 or 250 mg/kg bw/day etofenprox (purity 96.3%) from day 6 through 18 of gestation. On day 29 all dams were sacrificed and examined according to standard procedures (litter data, soft tissue examination, skeletal examination). Slight body-weight loss was seen in dams at 250 mg/kg bw/day and growth retardation at 50 mg/kg bw/day. At 250 mg/kg bw/day, the incidences of late abortions and early embryonic deaths were increased. At 50 mg/kg bw/day no effect on fetuses was found. The NOAEL for embryo/fetotoxicity was 50 mg/kg bw/day. The NOAEL for maternal toxicity was 10 mg/kg bw/day (Bottomley et al., 1985). Special studies on genotoxicity Etofenprox has been examined for genotoxicity in bacteria, mammalian cells in vitro and in mice in vivo (micronucleus test). In addition a test for UDS in human HeLa cells in vitro has been carried out. The results are presented in Table 5. The results were negative in all test systems. Special studies on the metabolite 2-(4-ethoxyphenyl)- 2-methylpropyl-3-phenoxybenzoate (MTI-500 alpha-CO) The oral LD50 of MTI-500 alpha-CO in male and female Charles River CD rats was >5000 mg/kg bw (Cummins & Gardner, 1985). Groups of 10 Sprague-Dawley rats/sex were fed diets containing 0, 50, 700 or 10 000 ppm MTI-500 alpha-CO (purity 97.6%) for 13 weeks. These dose levels were equal to 3.8, 54 or 800 mg/kg bw/day in males and 4.7, 64 or 930 mg/kg bw/day in females. Clinical signs, mortality, food consumption and body weights were recorded. Haematology, clinical chemistry, T3, T4 and urinalysis were done in all groups at week 13. At termination the weights of 10 organs/animal were recorded. Gross pathology was done in all animals. Histopathology was done in about 27 tissues/animal in the 0 and 10 000 ppm groups and in lungs, liver and kidneys of the intermediate groups. At 10 000 ppm the following effects were observed: growth retardation, increased total WBC (females only), increased SAP and SGOT, decreases in T4, serum cholesterol and serum globulin, increased relative weights of liver (females only), kidneys and thymus (females only), histopathological changes in kidneys (hypertrophy of the tubular epithelium of the pars recta) in 4/10 females. At the lower dose levels no effects were observed. The NOAEL in this study was 700 ppm (equal to 54 mg/kg bw/day) (Powell et al., 1988). The mutagenic potential of MTI-500 alpha-CO (purity 99.6%) was examined in the Ames test using Salmonella typhimurium tester strains TA 98, 100, 97a, 1535, 1537 and 102 without and with metabolic activation. In addition, Escherichia coli strain WP2 uvra was also used as test organism (without and with activation). The concentration range was 50-5000 µg/plate. The results were negative in all test organisms (Bootman & May, 1985). Table 5. Results of genotoxicity assays with etofenprox Test system Test object Concentration Purity Results References of etofenprox (%) In vitro Ames test, without S. typhimurium 200-3200 µg/plate; 96.3 negative Foster, 1985 and with activation TA100, TA98, TA1535, DMSO as solvent TA1537, TA1538 HGPRT (gene Chinese hamster 9.75-156 µg/ml; 96.3 negative Seeberg, 1985a mutations), without V79 cells DMSO as solvent and with activation Chromosome aberrations human lymphocytes 12.5-50 µg/ml; 96.3 negativea Bootman et al., test, without and with DMSO as solvent 1985a activation Unscheduled DNA human cells HeLa S3 9.75-156 µg/ml 96.3 negative Seeberg, 1985b synthesis, without (without act.) or and with activation 2.44-39 µg/ml (with act.); solvent DMSO In vivo Bone marrow CD-1 mouse 80, 400 and 2000 96.3 negative Bootman et al., micronucleus test mg/kg bw, p.o. (single 1985b dose); sacrifice at 24, 48 and 72 h a Both the test without activation and the test with activation showed a treatment-related reduction in mitotic index. Special study on sensitization Etofenprox (purity not reported) was tested for sensitizing potential in a group of 20 male English Hartley guinea-pigs using the maximization test according to Magnusson & Kligman. Treatment in the induction phase was done with a 20% solution in corn oil. The second induction application was preceded by a treatment with 10% sodium lauryl sulphate in petrolatum ointment to produce an irritative response in the induction phase. Etofenprox did not produce sensitization (Kobayashi, 1985). Special studies on skin and eye irritation Skin irritation of etofenprox was studied using a group of 6 Japanese white rabbits. A quantity of 0.5 ml of undiluted etofenprox (purity 96.3%) was applied as a molten solution (melting point of compound: 35-38 °C) to the shaven intact skin under occlusion for 4 hours. Skin observations were made up to day 14 after treatment. Very slight erythema was seen in 1/6 animals up to day 7. The classification (Draize) based on this result is not irritating (Kashima, 1985d, 1991a). Eye irritation of etofenprox was studied using a group of 6 Japanese white rabbits. A quantity of 0.1 ml of undiluted etofenprox (purity 96.3%) was applied as a molten solution (melting point of compound: 35-38 °C) through instillation into the conjunctival sac of the right eye. No washing was done. Observations were made up to 72 hours after treatment. Mild conjunctival redness was observed in 6/6 animals; after 72 hours this effect was no longer present. Mild conjunctival edema was seen in 1/6 animals, which disappeared after 24 hours. The classification (Draize) based on this result is not irritating (Kashima, 1985e; 1991b). Observation in humans Health assessments were carried out once or twice each year on a group of 21 operators engaged in the production of technical etofenprox for periods ranging from 1.5 to 5.5 years. The examinations included determination of blood pressure, X-ray examination, haematology, blood biochemistry, limited urinalysis, electrocardiography and interview for subjective complaints. No compound-related effects were observed. The report did not include data on the exposure concentrations (Yamazaki, 1992). COMMENTS After oral administration to rats, total excretion in faeces was 85-90% and 7-9% in urine. Excretion in bile was found to be 10% to 30%. Unchanged etofenprox was not found in the bile. Total retention in the body after 5 days was 3-4%. In the gastrointestinal tract from 48 to 93% was absorbed. Absorption tended to be dose-dependent. Tissue concentrations were highest in fat; this residue was present as unchanged parent compound. Etofenprox was secreted (as the unchanged compound) in milk. The major biotransformation routes involve O-de-ethylation of the ethylphenyl moiety and hydroxylation of the phenoxybenzyl moiety followed by conjugation with glucuronide or sulfate. Oxidation of the alpha-CH2 group followed by hydrolysis represents an additional route. The available results for dogs indicate a lower gastrointestinal absorption rate than in rats. The major biotransformation routes were the same as in rats. Etofenprox has a low acute oral toxicity in mice, rats and dogs. WHO has classified etofenprox as unlikely to present acute hazard in normal use. In a 13-week study in mice, using dietary concentrations of 0, 50, 500, 3000 or 15 000 ppm, the NOAEL was 500 ppm, equal to 60 mg/kg bw/day. The main effects seen were mortality, growth retardation, increased weights of liver (with enlarged hepatocytes) and kidneys (with tubular basophilia and dilatation) and decreases in red blood cell parameters. In a 13-week study in rats using dietary concentrations of 0, 50, 300, 1800 or 10 800 ppm, the NOAEL was 300 ppm, equal to 20 mg/kg bw/day, based on effects on growth and the liver. In addition, increased thyroid weight with increased incidence of microfollicles in this organ was observed. In a 52-week study in dogs using dietary concentrations of 0, 100, 1000 or 10 000 ppm, the NOAEL was 1000 ppm (equal to 32 mg/kg bw/day) based on decreased red blood cell parameters, increased serum alkaline phosphatase and increased liver weight (with swelling of hepatocytes). In a two-year toxicity/carcinogenicity study in mice using dietary concentrations of 0, 30, 100, 700 or 4900 ppm, the NOAEL was 30 ppm (equal to 3.1 mg/kg bw/day) based on an increased incidence of tubular lesions in the kidneys at > 100 ppm. There was no evidence of carcinogenicity. A two-year toxicity/carcinogenicity study in rats also used dietary concentrations of 0, 30, 100, 700 or 4900 ppm. The NOAEL was 100 ppm (equal to 3.7 mg/kg bw/day), based on increased weights of thyroid and kidneys and microscopic liver changes at >700 ppm. The incidence of cystic follicles in the thyroid was increased at 4900 ppm only. There was an increased incidence of thyroid follicular adenomas among the 4900 ppm animals which was statistically significantly increased in females only. The absence of genotoxicity of etofenprox (see below) in combination with the observed activation of the thyroid gland, which might be related to the effects on the liver (the latter probably leading to increased breakdown of thyroid hormones), is a strong indication for a non- genotoxic mechanism of induction of the thyroid tumours. In a two-generation study in rats using dietary concentrations of 0, 100, 700 or 4900 ppm, the NOAEL was 100 ppm (equivalent to 5 mg/kg bw/day). No effects on reproduction were observed in this study. Main effects seen in parents as well as young were decreased growth and effects on the weights and histopathology of liver and kidneys. The effects on the offspring were consistent with exposure to unchanged etofenprox via milk. Embryo/fetotoxicity and teratogenicity were studied in rats (3 studies, segment I, II & III, respectively) and rabbits (1 study). In the three studies in the rat, etofenprox was administered by gavage at dose levels of 0, 12.5, 250 or 5000 mg/kg bw/day. In each of the studies, dose-related maternal toxicity (clinical signs, growth retardation) was observed at 5000 mg/kg bw/day. In the two studies in rats with dosing before or during pregnancy, no effects on offspring/fetuses were seen. In the study in rats with dosing during lactation (segment III), toxic effects developed in the offspring, most likely as a result of exposure to etofenprox via milk. In none of the studies in rats were irreversible structural malformations found. The NOAEL for maternal or parental toxicity in each of these studies was 250 mg/kg bw/day. For fetotoxicity, the NOAEL was 5000 mg/kg bw/day in the segment I and II studies. The NOAEL for neonatal effects in the segment III study was 250 mg/kg bw/day. In the rabbit study, the NOAEL for maternal toxicity was 10 mg/kg bw/day, based on decreased growth at 50 and 250 mg/kg bw/day. Incidences of late abortions and early-embryonal mortality were increased at 250 mg/kg bw/day only. The NOAEL for embryo/ fetotoxicity was 50 mg/kg bw/day. No irreversible structural malformations were noted in this study. Based on the results of the available in vitro and in vivo genotoxicity data there was no evidence that etofenprox is genotoxic. The most sensitive species in the animal studies presently available appear to be rodents, with NOAELs of 3.1 and 3.7 mg/kg bw/day for mice and rats, respectively, in the long-term studies. The ADI was based on the long-term study in mice, using a 100-fold safety factor. TOXICOLOGICAL EVALUATION Level causing no toxicological effects Mouse: 30 ppm, equal to 3.1 mg/kg bw/day (two-year study) Rat: 100 ppm, equal to 3.7 mg/kg bw/day (two-year study) Rabbit: 10 mg/kg bw/day (maternal toxicity in a teratogenicity study) Dog: 1000 ppm, equal to 32 mg/kg bw/day (52-week study). Estimate of acceptable daily intake for humans 0-0.03 mg/kg bw. Studies which will provide information valuable in the continued evaluation of the compound Clarification of the dose-response for thyroid effects in the rat, including evaluation of T3, T4, TSH and other relevant parameters. Observations in humans with adequate information on exposure levels. REFERENCES Agrochemicals Handbook (1991) The Agrochemicals Handbook - Third Edition. Royal Society of Chemistry -Information Services, Cambridge, England. Bootman, J., Hodson-Walker, G. & Dance, C.A. (1985a). In vitro assessment of the clastogenic activity of MTI-500, ethofenprox, in cultured human peripheral lymphocytes. Life Science Research Limited, England; report no. 85/MT0017/430, dated 17 July 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Bootman, J., Hodson-Walker, G. & Dance, C.A. (1985b). MTI-500, etofenprox: assessment of clastogenic action on bone marrow erythrocytes in the micronucleus test. Life Science Research Limited, England; report no. 85/MT0016/406, dated 3 July 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Bootman, J. & May, K. (1985). MTI-500alpha-CO: assessment of its mutagenic potential using amino-acid auxotrophs of Salmonella typhimurium and Escherichia coli. Life Science Research Limited, England; report no. 85/MT0020/433, dated 19 July 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Bottomley, A.M., Barton, S.J., Masters, R.E., Offer, J.M., Parker, C.A., Anderson, A. & Dawe, I.S. (1985). Effect of etofenprox (MTI- 500) on pregnancy of the rabbit. Huntingdon Research Centre Ltd., England; report no. MTC 85(84)/85444, dated 20 December 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Cozens, D.D., Barton, S.J., Offer, J.M., Parker, C.A. & Anderson, A. (1985a). Effect of etofenprox (MTI-500) on multiple generations of the rat. Huntingdon Research Centre Ltd., England; report no. MTC 67/85706, dated 29 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Cozens, D.D., Hughes, E.W. & Anderson, A. (1985b). Effect of etofenprox (MTI-500) on pregnancy of the rat with rearing to maturation of the F1 generation. Huntingdon Research Centre Ltd., England; report no. MTC 64/85422, dated 28 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Cozens, D.D., Hughes, E.W., Clark, R. & Anderson, A. (1985c). Effect of etofenprox (MTI-500) on fertility and pregnancy of the rat. Huntingdon Research Centre Ltd., England; report no. MTC 66/84668, dated 29 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Cozens, D.D., Hughes, E.W., Offer, J. & Anderson, A. (1985d). Effect of etofenprox (MTI-500) on the peri and post natal period of the rat with rearing to maturation of the F1 offspring. Huntingdon Research Centre Ltd., England; report no. MTC 65/85423, dated 29 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Cummins, H.A. & Gardner, J.R. (1985) MTI-500 alpha-CO: Acute oral toxicity in the rat. Life Science Research Ltd., England - study no. 85/MT0018/474; report dated 2 August 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Foster, R. (1985). Reverse mutation in Salmonella typhimurium. Test substance MTI-500. Life Science Research Roma Toxicology Centre, Italy; report no. 162001-M-06185, dated 22/8/1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Green, O.P., Heywood, R., Street, A.E., Gopinath, & Almond, R.H. (1985a). Assessment of the toxicity of MTI-500 to mice by dietary administration for 13 weeks. Huntingdon Research Centre Ltd., England; report no. MTC 55/821112, dated 8 July 1983, re-issued 31 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Green, O.P., Street, A.E., Heywood, R., Gopinath, C. & Almond, R.H. (1985b). Assessment of the toxicity of MTI-500 in rats during dietary administration for 13 weeks. Huntingdon Research Centre Ltd., England; report no. MTC 56/821067, dated 7 July 1983, re- issued 18 December 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Green, O.P., Heaps, C.J., Heywood, R., Street, A.E., Gopinath, C., Imm, S. & Gibson, W.A. (1986a). Ethofenprox (MTI-500) potential tumorigenic and toxic effects in prolonged dietary administration to mice. Huntingdon Research Centre Ltd., England; report no. MTC 58/85582, dated 6 January 1986, re-issued 24 February 1986. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Green, O.P., Heaps, C.J., Heywood, R., Street, A.E., Gopinath, C., Sing, H. & Gibson, W.A. (1986b). Ethofenprox (MTI-500) potential tumorigenic and toxic effects in prolonged dietary administration to rats. Huntingdon Research Centre Ltd., England; report no. MTC 59/85581, dated 24 January 1986. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Harling, R.J., Burford, P. & Heywood, R. (1985a) Ethofenprox (MTI- 500) Acute limit test of toxicity to dogs following a single oral administration. Huntingdon Research Centre Ltd., England; report no. MTC 101/851185, dated 24 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Harling, R.J., Burford, P., Street, A.E., Heywood, R., Majeed, S.R. & Gopinath, C. (1985b). Ethofenprox (MTI-500) toxicity to dogs by repeated dietary administration for 52 weeks followed by a recovery period of 8 weeks. Huntingdon Research Centre Ltd., England; report no. MTC 71/85234, dated 25 October 1985, re-issued 8 November 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Hashimoto, K., Ohtaki, T., Yamaguchi, K., Nishijima, Y., Imai, K. & Azegami, J. (1982a). Report on acute toxicity study of MTI-500 (ethofenprox) in mice. Hatano Research Institute, Japan; report no. A-82-35~42, dated 9 November 1982. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Hashimoto, K., Ohtaki, T., Yamada, S., Watanabe, C., Imai, K. & Azegami, J. (1982b). Report on acute toxicity study of MTI-500 (ethofenprox) in rats. Hatano Research Institute, Japan; report no. A-82-27~34, dated 9 November 1982. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Hawkins, D.R., Kirkpatrick, D., Ewen, B., Midgley, I., Biggs, S.R. & Whitby, B.R. (1985a). The biokinetics and metabolism of 14C- ethofenprox in the rat. Huntingdon Research Centre Ltd., England; report no. HRC/MTC 68/84610, dated 1 August 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Hawkins, D.R., Kirkpatrick, D., Ewen, B., Midgley, I. & Biggs, S.R. (1985b). The metabolism of 14C-ethofenprox in dogs. Huntingdon Research Centre Ltd., England; report no. HRC/MTC 69/84583, dated 11 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Jackson, G.C., Hardy, C.J., Clark, G.C., Gregson, R.L., Lewis, D.J. & Gopinath, C. (1983). MTI-500 acute inhalation toxicity in rats 4 hour exposure. Huntingdon Research Centre Ltd., England; report no. MTC 60/821079, dated 19 April 1983 Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kamiya, J., Yoshiwara, K., Saito, S., Takahashi, Y. Oseki, K., Shimizu, H., Kawazura, H., Shiga, Y., Yoshida, M., Hayakawa, M. & Tanaka Y. (1985). General pharmacology of MTI-500. Institute of Biological Sciences - Mitsui Pharmaceuticals Inc., [A translation of an original Japanese report published in Japanese, in: Pharmacology and Therapeutics, vol.13 no.11, pp. 229-244, November 1985]. Translated by T. Hirakawa. Kashima, M. (1985a). Acute oral toxicity of MTI-500 emulsion in mice. Nippon Experimental Medical Research Institute, Ltd., Japan; report no. NEMRI-H-85-50, dated 2 September 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kashima, M. (1985b). Acute oral toxicity of MTI-500 emulsion in rats. Nippon Experimental Medical Research Institute, Ltd., Japan; report no. NEMRI-H-85-48, dated 2 September 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kashima, M. (1985c). Acute dermal toxicity of MTI-500 emulsion in rats. Nippon Experimental Medical Research Institute, Ltd., Japan; report no. NEMRI-H-85-49, dated 2 September 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kashima, M. (1985d). MTI-500 primary skin stimulation test in rabbits. Nippon Experimental Medical Research Institute, Ltd, Japan; report no. NEMRI-H-85-5, dated 23 August 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kashima, M. (1985e). MTI-500 primary ophthalmic stimulation test in rabbits. Nippon Experimental Medical Research Institute, Ltd, Japan; report no. NEMRI-H-85-55, dated 24 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kashima (1991a) Final report modification (I) - study name: MTI-500 primary skin stimulation test in rabbits. Nippon Experimental Medical Research Institute, Ltd, Japan; project no. NEMRI-H-85-5. Modification d.d. 28 October 1991. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kashima (1991b) Final report modification (I) - study name: MTI-500 primary ophthalmic stimulation test in rabbits. Nippon Experimental Medical Research Institute, Ltd, Japan; project no. NEMRI-H-85-55. Modification d.d. 28 October 1991. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Kobayashi, K. (1985). MTI-500 skin sensitization test in guinea- pigs. Nippon Experimental Medical Research Institute, Ltd, Japan; report dated 31 October 1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Powell, A.J., Coleman, M., Crook, D., Gopinath, C., Gobson, W.A., Read, R.M. & Anderson, A. (1988) MTI-500 alpha-CO: Toxicity to rats by dietary administration for 13 weeks (Final report). Huntingdon Research Centre Ltd., England; report no. MTC 141/871448, dated 15 March 1988. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Seeberg, A.H. (1985a). Gene mutation in Chinese Hamster V79 cells. Test substance MTI-500. Life Science Research Roma Toxicology Centre, Italy; report no. 162002-M-06985, dated 22/8/1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Seeberg, A.H. (1985b). Unscheduled DNA synthesis in human cells, cell line: Hela S3. Test substance MTI-500. Life Science Research Roma Toxicology Centre, Italy; report no. 162003-M-05785, dated 30/7/1985. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. Tomoda, K., Arai, M. & Ohnuma, K. (1986). Metabolism study of ethofenprox (MTI-500). 6. Metabolism in rat. Chiba Branch Laboratory, Agrochemicals Laboratory - Mitsui Toatsu Chemicals, Inc., Japan; report dated July 1986. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan. WHO (1992). The WHO recommended classification of pesticides by hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14). Available from the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland. Yamazaki, Y. (1992). Health report from the Industrial Hygiene Section, Ohmuta Factory - Mitsui Toatsu Chemicals, Inc., dated 17 April 1992. Submitted to WHO by Mitsui Toatsu Chemicals, Inc., Tokyo, Japan.
See Also: Toxicological Abbreviations