(±)-5-amino-l-(2,6-dichloro-a,a,a -trifluoro-p-tolyl)-4-trifluoromethylsulfinylpyrazole-3-carbonitrile
Fipronil was considered for the first time by the present Meeting. It has been proposed for indoor and outdoor use in the control of the mosquito that carries the malaria parasite.
Fipronil is a member of a new class of pesticide chemicals, the phenylpyrazoles. Its putative mode of insecticidal action is interference with the passage of chloride ions through the gamma-aminobutyric acid (GABA)-regulated chloride ion channel, which results in uncontrolled central nervous system activity and subsequent death of the insect. Although fipronil is selectively toxic to insects, some of the toxicity of fipronil observed in mammals also appears to involve interference with the normal functioning of the GABA receptor.
TOXICOLOGY
The toxicological profiles of fipronil, its mammalian metabolites, and two photodegradation products were considered. The Meeting concluded that the mammalian metabolites and one of the photodegradation products have similar toxicological potencies to fipronil, so they are not considered further in this report. Because the other photodegradation product, desulfinylated fipronil, appears to be more toxic than the parent compound, available data on this substance are reviewed here. The chemical structures of fipronil and the photodegradation product of toxicological concern are shown in Figure 1. The photodegradation product is designated as fipronil-desulfinyl.
Fipronil
In a study of dermal absorption in rats, the quantity of [14C] fipronil absorbed was less than 1% of the applied dose at all doses tested (0.88-48 mg fipronil/rat) and all times up to 24 h. In vitro, the relative extent of absorption of a formulation of [14C] fipronil across rat, rabbit, or human epidermal membranes depended on the concentration of the material used. At the lowest concentration tested (0.2 g/litre), the extent of penetration was greatest for all three species, and the percentage of the dose absorbed across human and rat membranes was similar. At higher concentrations (4 and 200 g/litre), penetration was greater through rat and rabbit skin than through human skin.
Figure 1. Chemical structures of fipronil and its photodegradation product fipronil-desulfinyl
There was no appreciable difference between male and female rats in the absorption, distribution, metabolism, or excretion of fipronil after oral administration. The proportion of the dose absorbed appeared to depend on the treatment regimen, being greatest with a single dose of 4 mg/kg bw of [14C] fipronil (minimum absorption, 50%), intermediate with a repeated dose regimen of 4 mg/kg bw per day for 14 days followed by a single, oral labelled dose of 4 mg/kg bw (minimum absorption, 40%), and lowest (minimum absorption, about 30%) with a single dose of 150 mg/kg bw of [14C] fipronil (presumably due to saturation of absorption at the high dose). Once absorbed, fipronil was rapidly metabolized and the residues widely distributed in the tissues where significant amounts of residues remained, particularly in fat and fatty tissues, one week after treatment. The levels of residues in fat and other tissues were greater with repeated low doses or a single high dose than with a single low dose. The long half-life (150-245 h in some cases) of fipronil in blood may reflect slow release of residues from fat and might suggest potential bioaccumulation of metabolic products of fipronil.
Faeces, followed by urine, were the major routes of elimination of fipronil in the rat. Its biotransformation largely involved changes in the functional groups attached to the pyrazole ring. The compounds identified in faeces and urine were the parent compound and the sulfone, the amide derived from the nitrile group, a reduction product, and a cleavage product of the sulfone and its derivatives formed by further cleavage. The sulfone was the major metabolite in fat and tissues.
Fipronil was moderately hazardous to rats (LD50 = 92 mg/kg bw) and mice (LD50 = 91 mg/kg bw) after oral administration of single doses and to rats after single exposure by inhalation (LC50 = 0.36 mg/litre). After a single dermal exposure, fipronil was relatively non-hazardous to rats (LD50 >2000 mg/kg bw) but was moderately hazardous to rabbits (LD50 = 354 mg/kg bw). In rats, signs of toxicity and death were delayed for up to four days after either a single oral dose or repeated oral doses of 75 mg/kg bw per day for up to five days. WHO has not yet classified fipronil for acute toxicity.
In a 13-week study of toxicity, mice were fed diets containing fipronil at doses of 0, 1, 3, 10, or 25 ppm. A dose-related increase in the incidence of liver-cell periacinar hypertrophy with cytoplasmic vacuolation was observed in males at doses of 1 ppm (equal to 0.13 mg/kg bw per day) and above. An NOAEL was not identified.
Rats were fed diets containing 0, 25, 50, 100, 200, or 400 ppm fipronil for four weeks. At 25 ppm (equal to 3.4 mg/kg bw per day), liver weights and plasma cholesterol were increased in females and thyroid follicular-cell hypertrophy of minimal severity was observed in animals of each sex. The levels of total protein and globulin were also increased in both males and females, although the changes at this and higher doses were generally small and poorly correlated with the dose. An NOAEL was not identified.
In a 13-week study of toxicity, fipronil was administered in the diet to rats at doses of 0, 1, 5, 30, or 300 ppm. At 30 ppm and above, relatively small, sometimes inconsistent changes in haematological parameters (decreased packed cell volume, mean cell volume, haemoglobin concentration and prothrombin time, increased platelet count) and clinical chemical parameters (increased total protein and globulins, decreased albumin: globulin ratio and alanine aminotransferase and aspartate aminotransferase activities) were observed, mostly in females. Some alterations were seen in plasma glucose and urea concentrations at 30 ppm; also at 30 ppm, the absolute and/or relative weights of the liver and thyroid were increased in either males or females or both, and there was evidence of thyroid follicular cell epithelial hypertrophy in males. The NOAEL was 5 ppm, equal to 0.33 mg/kg bw per day.
Fipronil was administered in gelatin capsules to dogs for 13 weeks in a study of toxicity at doses of 0, 0.5, 2, or 10 mg/kg bw per day. Inappetence and decreased body-weight gain and food consumption were noted in females at 2 and 10 mg/kg bw per day. The NOAEL was 0.5 mg/kg bw per day.
Fipronil was administered to dogs in gelatin capsules for one year in a study of toxicity at doses of 0, 0.2, 2, or 5 mg/kg bw per day. At 2 mg/kg bw per day and above, clinical signs of neurotoxicity (convulsions, twitching, tremors, ataxia, unsteady gait, rigidity of limbs, nervous behaviour, hyper- or hypoactivity, vocalization, nodding, aggression, resistance to dosing and inappetence, and abnormal neurological responses) were observed in animals of each sex. One animal at 2 mg/kg bw per day was killed because of poor condition related to treatment. The NOAEL was 0.2 mg/kg bw per day.
In a second one-year toxicity study in dogs, fipronil was administered in the diet at doses of 0, 0.075, 0.3, 1, or 3 mg/kg bw per day. The highest dose was reduced to 2 mg/kg bw per day after 38 days because of toxicity. At 1 mg/kg bw per day, clinical signs of neurotoxicity (whole body twitching, and extensor rigidity of limbs) were noted in females. There were no effects on tri-iodothyronine or thyroxine levels. The NOAEL was 0.3 mg/kg bw per day.
In a study of carcinogenicity, fipronil was administered for 78 weeks in the diet to mice at doses of 0, 0.1, 0.5, 10, 30, or 60 ppm. Additional groups of animals were fed the same doses for 52-53 weeks and then killed. Survival was greater than or comparable to that of the control group at doses below 60 ppm. At week 10, all surviving animals at 60 ppm were killed because of excessive mortality. In animals at 10 ppm, some decrease in body-weight gain was noted in males and females, and efficiency of food utilization was decreased in males. At 53 and 78 weeks, the absolute and/or relative liver weights of males were increased, with an increased incidence of liver periacinar microvesicular vacuolation. There was no evidence of carcinogenicity at doses considered to be sufficient to measure such potential. The NOAEL for systemic effects was 0.5 ppm, equal to 0.055 mg/kg bw per day.
In a study of toxicity and carcinogenicity in rats, fipronil was administered in the diet at doses of 0, 0.5, 1.5, 30, or 300 ppm. For the carcinogenicity phase of the study, it was originally planned that the test material should be administered for two years, but excessive mortality resulted in early termination of this phase at week 89 in males and week 91 in females. This was not thought to compromise the study. For the toxicity phase and a reversibility phase of the study, additional groups of animals were fed the same doses of fipronil for one year, when some animals were killed and others were allowed to recover for 13 weeks. Some of the effects noted at the higher doses persisted into the reversibility phase of the study. During treatment, convulsive episodes (sometimes fatal) were observed in males at 1.5 ppm and in animals of each sex at higher doses. Animals at 1.5 ppm, predominantly females, showed irritability, vocalization, salivation, aggression, hyperactivity, and bruxism. Small decreases were noted in erythrocyte count, haemoglobin concentration, mean cell volume and packed cell volume in either males or females or both, and some alterations in protein level were observed in males. An apparent increase in the severity of progressive senile nephropathy was seen in animals of each sex at this dose. Thyroxine concentrations were decreased in both males and females. Thyroid-stimulating hormone levels were increased, notably in males, at doses of 30 ppm and above and in females at 300 ppm. The levels of tri-iodothyronine were elevated in females at 30 ppm, but only during the reversibility phase. At 300 ppm, fipronil induced follicular-cell adenomas of the thyroid gland in both males and females; males at this dose also had an increased incidence of follicular-cell carcinomas. Some thyroid follicular-cell adenomas were noted in male rats at lower doses, but a comparison with historical control data indicated no clear relationship to treatment. The NOAEL for systemic effects was 0.5 ppm, equal to 0.019 mg/kg bw per day.
Fipronil and its metabolites gave negative results in virtually all tests for genotoxicity. Equivocal results were seen in assays for cytogenicity in mammalian cells in vitro (fipronil) and for polyploidy (not clastogenicity) in human lymphocytes (a mammalian metabolite). The weight of evidence indicates that fipronil and its metabolites are not genotoxic.
The Meeting concluded that the thyroid tumours observed in the two-year study in rats occurred by a non-genotoxic, threshold dose-effect mechanism involving continuous stimulation of the thyroid gland associated with persistently elevated thyroid-stimulating hormone levels. It was noted that the levels of this hormone were clearly elevated only at the two highest doses.
In a two-generation study of reproductive toxicity, rats received diets containing fipronil at 0, 3, 30 or 300 ppm. F0 parental animals were mated twice to produce F1a and F1b litters; F1a parents were mated only once to produce F2 litters. In adult animals at 30 ppm, the thyroid and liver weights were increased and the pituitary gland weights were decreased. An increased incidence of thyroid gland follicular epithelial-cell hypertrophy was seen at this dose in males of the F0 and F1 generations and F1 females. At 300 ppm, convulsions were observed in F1 and F2 litters; decreased litter size, decreased body weights and delays in physical development were also seen. Postnatal survival was decreased among pups in the F2 litters. Absolute and relative ovarian weights were decreased in F0 females. At 300 ppm, a decreased percentage of animals that mated and a reduction in the fertility index of F1 parental animals was also observed. These effects may have been related to the systemic toxicity of fipronil at this dose. The NOAEL for parental systemic toxicity was 3 ppm, equal to 0.25 mg/kg bw per day, and the NOAEL for reproductive toxicity was 30 ppm, equal to 2.5 mg/kg bw per day.
Rats were administered fipronil by gavage at doses of 0, 1, 4, or 20 mg/kg bw per day on days 6-15 of gestation. Developmental toxicity was not observed, but there were some signs of maternal toxicity (decreased body-weight gain and food consumption) at 20 mg/kg bw per day. The NOAEL for maternal toxicity was 4 mg/kg bw per day, and that for developmental toxicity was 20 mg/kg bw per day, the highest dose tested.
Rabbits were administered fipronil by gavage at doses of 0, 0.1, 0.2, 0.5, or 1 mg/kg bw per day on days 6-19 of gestation. Developmental toxicity was not observed, but there were some signs of maternal toxicity (decreased body-weight gain, decreased food consumption, and reduced efficiency of food utilization at all doses. An NOAEL for maternal toxicity was not identified; the NOAEL for developmental toxicity was 1 mg/kg bw per day, the highest dose tested.
Two studies of primary dermal irritation in rabbits were performed. Fipronil was a slight irritant when moistened with corn oil before application but was not irritating when moistened with water before application. Fipronil was a slight irritant in two studies of primary ocular irritation in rabbits. It did not sensitize the skin of guinea-pigs when tested by the Buehler method but was a weak sensitizer in guinea-pigs tested by the Magnusson-Kligman method.
In a study of dermal toxicity, fipronil was applied in 0.5% carboxymethylcellulose to the intact skin of rabbits for 6 h per day on five days per week for three weeks at doses of 0, 0.5, 1, 5, or 10 mg/kg bw per day. No dermal irritation was observed. At 10 mg/kg bw per day, body-weight gains and food consumption were reduced in animals of each sex. Some animals showed hyperactivity. The NOAEL was 5 mg/kg bw per day.
In a study of neurotoxicity, rats were given single doses of 0, 0.5, 5, or 50 mg/kg bw fipronil by gavage. At 5 mg/kg bw, decreased hind-leg splay was observed 7 h after treatment in both males and females. The NOAEL was 0.5 mg/kg bw.
In a 13-week study of neurotoxicity, rats received dietary doses of 0, 0.5, 5, or 150 ppm fipronil. At 150 ppm, body weights, weight gains, and food consumption were reduced early in the study in animals of each sex, possibly owing to problems of palatability. Although the findings in a battery of functional operational tests at this dose were relatively minor when taken separately, they appeared to represent a minimal effect of treatment when taken together. The NOAEL for neurotoxicity and systemic effects was 5 ppm, equal to 0.3 mg/kg bw per day.
In a study of neurotoxicity in female dogs, fipronil was administered in capsules at doses of 0 (one animal) or 20 mg/kg bw per day (four animals) until the appearance of neurotoxic signs in each animal, after which they were allowed to recover for 28 days. Severe neurotoxic signs were seen at 20 mg/kg bw per day during the treatment phase and in some animals only during the recovery phase. Most animals appeared to recover, although one had exaggerated reflex responses and was excitable at the end of the recovery period. A limited histopathological examination showed no change. No firm conclusions could be drawn about the reversibility of the effects, given the limitations of the study design. An NOAEL was not identified.
In a study of developmental neurotoxicity, rats were given fipronil in the diet from gestation day 6 through lactation day 10 at doses of 0, 0.5, 10, or 200 ppm. Maternal toxicity (reduced body weight during the treatment period, reduced body-weight gain during gestation, and reduced food consumption) was observed at 200 ppm. Developmental toxicity (reduced body weights in pups and a slight increase in the time to preputial separation) was noted at 10 ppm. An increase in motor activity in female pups at 10 ppm only on day 17 could not be definitively interpreted as an indication of developmental toxicity. Developmental neurotoxicity was clearly observed postnatally in pups at 200 ppm, with delayed swimming development on day 6, increased motor activity on day 17, abnormal auditory startle response on day 22, and impaired learning and memory on day 24. The NOAEL for maternal toxicity and developmental neurotoxicity was 10 ppm (equal to 0.9 mg/kg bw per day) and that for developmental toxicity was 0.5 ppm (equal to 0.05 mg/kg bw per day).
Mechanistic studies conducted with fipronil in rats suggest that it does not interfere with the incorporation of iodine into thyroxine but rather with the biliary clearance of this hormone. This may trigger an increase in the concentration of thyroid-stimulating hormone by interference with the feedback mechanism.
Mammalian metabolites of fipronil
Several mammalian metabolites of fipronil were tested for acute toxicity. The results indicated that their toxicity is comparable to or substantially less than that of fipronil.
Photodegradation products of fipronil
Numerous studies were performed with fipronil-desulfinyl, one of two photodegradation products of fipronil which can be formed in the presence of sunlight and could potentially be produced in the environment or on treated surfaces. Neither is a mammalian metabolite of fipronil. The available information indicates that, of the two, only fipronil-desulfinyl is highly toxic after either single-dose or long-term exposure, and is therefore of toxicological concern.
When 0.08-7.2 mg of [14C] fipronil-desulfinyl was applied dermally to rats, absorption ranged fron 0.2 to 7% of the applied dose within 24 h.
The absorption, distribution, metabolism, and excretion of [14C] fipronil-desulfinyl were studied in rats. Rats received either a single oral dose of [14C] fipronil-desulfinyl at 1 or 10 mg/kg bw or 14 daily oral doses of unlabelled fipronil-desulfinyl at 1 mg/kg bw per day followed by a single oral labelled dose. In animals of each sex, elimination of the radiolabel was much greater in the faeces (46-70% of the dose) than in the urine with all dosing regimens. Appreciable residues were found in the tissues one week after treatment, the highest concentrations being present in the fat and fatty tissues. The long half-life in blood (183-195 h) and increased fat:plasma ratios of the radiolabel suggest potential bioaccumulation of fipronil-desulfinyl and/or its metabolites. Numerous metabolites or conjugates of fipronil-desulfinyl were present in urine and faeces. Biotransformation of fipronil-desulfinyl involved changes at the functional groups attached to the pyrazole ring. Only unchanged fipronil-desulfinyl was identified in the liver, fat, skin, and residual carcase.
In a 28-day study of toxicity in which fipronil-desulfinyl was administered in the diet to mice at doses of 0, 0.5, 3, 30, or 60 ppm, mortality, neurotoxic signs (increased motor activity, excessive jumping, irritability to touch, compulsive biting, and evidence of convulsions), decreased body-weight gain and food consumption, and an increased incidence of centrilobular hypertrophy of the liver were observed in animals of each sex at doses of 30 ppm and above. The NOAEL was 3 ppm, equal to 0.49 mg/kg bw per day.
Fipronil-desulfinyl was administered in the diet for 90 days to mice at doses of 0, 0.5, 2, or 10 ppm. At 2 and 10 ppm, clinical signs of neurotoxicity (irritability to touch, aggressiveness, and/or increased motor activity) were noted in males. The NOAEL was 0.5 ppm, equal to 0.08 mg/kg bw per day.
Rats received fipronil-desulfinyl by gavage for two weeks at doses of 0, 0.3, 1, 3, or 10 mg/kg bw per day. At 1 mg/kg bw per day, pale livers and reduced leukocyte counts were observed in females. Some rats at 3 mg/kg bw per day died or were killed because of poor condition. The NOAEL was 0.3 mg/kg bw per day.
Fipronil-desulfinyl was administered in the diet for 28 days to rats at doses of 0, 0.5, 3, 30 or 100 ppm. One male at 30 ppm died, and clinical signs of toxicity (piloerection and curling up on handling) and decreased body weights, food consumption, and bilirubin concentration were seen in males and females at this dose. Thymus weights were lower in females. The levels of thyroid-stimulating hormone were measured, but no effects were noted at any dose. All animals at 100 ppm died. The NOAEL was 3 ppm, equal to 0.23 mg/kg bw per day.
In a 90-day study of toxicity in rats, fipronil-desulfinyl was administered in the diet at 0, 0.5, 3, 10, or 30 ppm. At 3 ppm and above, clinical signs of neurotoxicity (aggressiveness, irritability to touch, and excessive vocalization) were observed in males. The levels of tri-iodothyronine and thyroxine were affected at higher doses, but the toxicological significance of these changes is probably negligible in the absence of changes in the level of thyroid-stimulating hormone at any dose. The NOAEL in the study was 0.5 ppm, equal to 0.029 mg/kg bw per day.
Dogs received fipronil-desulfinyl in the diet in a 28-day study at doses of 0, 27, 80, or 270 ppm. The groups at 80 and 270 ppm were terminated early because of mortality. In the group at 27 ppm, one male had a clonic convulsion. Reduced thymus weight and pale livers were also reported at this dose. As effects occurred at the lowest dose, an NOAEL was not identified.
In a 90-day study of toxicity, fipronil-desulfinyl was administered in the diet to dogs at doses of 0, 3.5, 9.5, or 35 ppm. The clinical findings in one female at 35 ppm (increased salivation, prostration, writhing, tremors, absence of rotular reflex, noisy breathing, dyspnoea) were attributed to arteritis and myocardial necrosis on the basis of microscopic findings; however, they may also have been indicative (at least in part) of neurotoxicity, because another female in this group exhibited excessive barking, aggressiveness, irritability, tremors, and increased salivation. On this basis, the Meeting concluded that the NOAEL was 9.5 ppm, equal to 0.29 mg/kg bw per day.
In a study of developmental toxicity in rats, fipronil-desulfinyl was administered by gavage on days 6-15 of gestation at doses of 0, 0.5, 1, or 2.5 mg/kg bw per day. Indications of maternal effects (decreased body-weight gain and hair loss in various areas) were observed at 2.5 mg/kg bw per day. Developmental toxicity (increased incidence of incomplete or reduced ossification of several bones and slightly reduced fetal body weight in animals of each sex) was also observed at this dose. The NOAEL for maternal toxicity and developmental toxicity was 1 mg/kg bw per day.
In a study of neurotoxicity in rats, fipronil-desulfinyl was administered by gavage as a single dose of 0, 0.5, 2, or 12 mg/kg bw. At 12 mg/kg bw, decreased body-weight gains and food consumption were observed during week 1 in animals of each sex. Decreased hind-foot splay, rectal temperature, and locomotor activity were also seen in animals of each sex at this dose. There were indications of a slowed righting reflex in males and decreased grip strength in males and females at the high dose. The NOAEL was 2 mg/kg bw per day.
In summary, the toxicity of fipronil-desulfinyl is qualitatively similar to that of fipronil, but the dose-effect curve for neurotoxic effects appears to be steeper for fipronil-desulfinyl than for fipronil. Also, fipronil-desulfinyl appears to have a much greater tendency than fipronil to bind to sites in the chloride ion channel of the rat brain GABA receptor. This finding appears to be consistent with the greater toxicity, relative to fipronil, of fipronil-desulfinyl in the central nervous system of mammals.
The Meeting established an ADI of 0-0.0002 mg/kg bw for fipronil on the basis of the NOAEL of 0.019 mg/kg bw per day in the two-year study of toxicity and carcinogenicity in rats and incorporating a safety factor of 100.
The Meeting also considered that a separate ADI should be established for fipronil-desulfinyl on the basis that it could be a significant residue and that its toxicity is greater than that of the parent molecule fipronil. A temporary ADI of 0-0.00003 mg/kg bw for fipronil-desulfinyl was established on the basis of the NOAEL of 0.029 mg/kg bw per day in the 90-day study in rats and a safety factor of 1000 in view of the lack of a long-term study by oral administration in rats and a study of neurotoxicity in rats given repeated oral doses.
A toxicological monograph was prepared.
TOXICOLOGICAL EVALUATION
Fipronil
Levels that cause no toxic effect
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Mouse: |
0.5 ppm, equal to 0.055 mg/kg bw per day (78-week study of carcinogenicity and toxicity) |
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Rat: |
5 ppm, equal to 0.33 mg/kg bw per day (13-week study of toxicity) |
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0.5 ppm, equal to 0.019 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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3 ppm, equal to 0.25 mg/kg bw per day (parental systemic toxicity in a study of reproductive toxicity) |
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30 ppm, equal to 2.5 mg/kg bw per day (study of reproductive toxicity) |
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4 mg/kg bw per day (maternal toxicity in a study of developmental toxicity by gavage) |
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20 mg/kg bw per day (developmental toxicity in a study of developmental toxicity by gavage; highest dose tested) |
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0.5 mg/kg bw (single dose, study of neurotoxicity by gavage) |
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5 ppm, equal to 0.3 mg/kg bw per day (repeated doses in the diet, study of neurotoxicity) |
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10 ppm, equal to 0.9 mg/kg bw per day (maternal toxicity and developmental neurotoxicity in a study of developmental neurotoxicity) |
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0.5 ppm, equal to 0.05 mg/kg bw per day (developmental toxicity in a study of developmental neurotoxicity) |
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Rabbit: |
0.1 mg/kg bw per day (LOAEL for maternal toxicity in a study of developmental toxicity by gavage) |
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1 mg/kg bw per day (study of developmental toxicity; highest dose tested by gavage) |
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Dog: |
0.3 mg/kg bw per day (one-year study of toxicity) |
Estimate of acceptable daily intake for humans
0-0.0002 mg/kg bw
Fipronil-desulfinyl (fipronil photodegradation product)
Levels that cause no toxic effect
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Mouse: |
3 ppm, equal to 0.49 mg/kg bw per day (28-day study of toxicity) |
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0.5 ppm, equal to 0.08 mg/kg bw per day (90-day study of toxicity) |
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0.3 mg/kg bw per day (two week study of toxicity by gavage) |
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3 ppm, equal to 0.23 mg/kg bw per day (28-day study of toxicity) |
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0.5 ppm, equal to 0.029 mg/kg bw per day (90-day study of toxicity) |
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1 mg/kg bw per day (maternal and developmental toxicity in a study of developmental toxicity by gavage) |
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2 mg/kg bw per day (single dose, study of neurotoxicity by gavage) |
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Dog: |
9.5 ppm, equal to 0.29 mg/kg bw per day (90-day study of toxicity) |
Estimate of temporary acceptable daily intake for humans
0-0.00003 mg/kg bw
Acute reference dose for fipronil
The Meeting allocated an acute reference dose of 0.003 mg/kg bw for both fipronil and fipronil-desulfinyl on the basis of the NOAEL of 0.3 mg/kg bw per day in a study of neurotoxicity in rats given repeated doses of fipronil, and a safety factor of 100. The study of neurotoxicity in rats given single doses was not considered in allocating the acute reference dose because of concern about the prolonged toxicokinetics of fipronil. This acute reference dose will provide a safety factor of about 700 for the NOAEL in the study of neurotoxicity in rats given single doses of fipronil-desulfinyl.
Studies without which the determination of an ADI is impracticable, to be provided by 2000
1. Short-term study of neurotoxicity in rats with fipronil-desulfinyl in the diet.2. Developmental neurotoxicity study in rats with fipronil-desulfinyl in the diet.
3. The results of an ongoing long-term study with fipronil-desulfinyl in rats.
Studies that would provide information useful for the continued evaluation of fipronil and fipronil-desulfinyl
1. Additional studies to investigate the reversibility of the neurotoxic effects of fipronil and its metabolites (functional, behavioural, learning/memory, cellular, and neurotransmitter/receptor effects).2. Observations in humans exposed to fipronil and fipronil-desulfinyl.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to fipronil and its photodegradation product fipronil-desulfinyl
Fipronil
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Human exposure |
Relevant route, study type, species |
Results, remarks |
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Short-term |
Skin, irritation, rabbit |
Slightly irritating |
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Eye, irritation, rabbit |
Minor irritation |
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Skin, sensitization, guinea-pig |
Not a sensitizer (Buehler) |
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Skin, sensitization, guinea-pig |
Mild sensitizer (Magnusson-Kligman) |
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Oral, toxicity, rat |
LD50 = 92 mg/kg bw |
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Dermal, toxicity, rabbit |
LD50 = 350 mg/kg bw |
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Inhalation, toxicity, rat |
LC50 = 0.36 mg/l |
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Neurotoxicity, rat (single dose by gavage) |
NOAEL = 0.5 mg/kg bw per day: decreased hind-leg splay |
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Medium-term |
Repeated dermal, 3 weeks, toxicity, rabbit |
NOAEL = 5 mg/kg bw per day: reduced body-weight gains and food consumption; hyperactivity in some animals; no dermal irritation observed |
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Repeated oral, reproductive toxicity, rat |
NOAEL = 0.25 mg/kg bw per day for maternal toxicity. |
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NOAEL = 2.5 mg/kg bw per day for reproductive toxicity. |
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Repeated oral, developmental neurotoxicity, rat |
NOAEL = 0.9 mg/kg bw per day for maternal toxicity. |
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NOAEL = 0.05 mg/kg bw per day for developmental toxicity. |
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NOAEL = 0.9 mg/kg bw per day for developmental neurotoxicity. |
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Long-term |
Repeated oral, 2 years (terminated at 89-91 weeks), long-term toxicity and carcinogenicity, rat |
NOAEL = 0.019 mg/kg bw per day: convulsions and neurobehavioural clinical signs of toxicity; effects on the thyroid; thyroid follicular-cell adenomas and carcinomas. |
Fipronil-desulfinyl
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Human exposure |
Relevant route, study type, species |
Results, remarks |
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Short-term (1-7 days) |
Oral, toxicity, rat |
LD50 =15 mg/kg bw |
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Dermal, toxicity, rat |
LD50 > 2000 mg/kg bw |
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Neurotoxicity, rat (single dose by gavage) |
NOAEL = 2 mg/kg bw per day. |
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Medium-term (1-26 weeks) |
Repeated oral (diet), 90 days, toxicity, rat |
NOAEL = 0.029 mg/kg bw per day. |
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Repeated oral (gavage), developmental toxicity, rat |
NOAEL = 1.0 mg/kg bw per day: maternal toxicity. |
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NOAEL = 1.0 mg/kg bw per day: developmental toxicity. |
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Long-term (³ 1 year) |
Repeated oral toxicity |
No data |
