When the four (14)C-preparations of (IRS)-trans-, (IR)-trans- , (IRS)-cis, and (IR)-cis-permethrin labeled in the alcohol and acid moieties were administered orally to male rats at 1.6-4.8 mg/kg, the compounds were rapidly metabolized and the (14)C from the acid and alcohol moeity was almost completely eliminated from the body within a few days. ... The major metabolic reactions of both permethrin isomers /(trans and cis)/ were oxidation at the trans and cis portions of the gem-dimethyl group of the acid moiety and at the 2'- and 4'-positions of the alcohol moiety, ester cleavage, and the conjugation of the resulting carboxylic acids, alcohols, and phenols with glucuronic acid, glycine, and sulfuric acid. The cis isomer is more stable than the tans isomer, and the cis isomer yielded four fecal ester metabolites which resulted from hydroxylation at the 2'- and 4'-positions of the phenoxy group, at the trans- methyl group, and at both of the two latter sites. The ester-cleaved metabolites were extensively excreted into the urine, whereas the metablites retaining ester linkage were found only in the feces. There were no significant differences in metabolism between the (IRS)-isomers and (IR)-isomers.
When White Leghorn hens were treated orally three consecutive days with one of four (14)C-trans- and cis-permethrin isomers labelled in the alcohol or acid at 10 mg/kg body weight, they showed no signs of poisoning. More than 87% of the radiocarbon from the four labelled perparations was found in the excreta 9 days after the initial dose, 0.7-4.7% of the dose was exhaled as (14)CO2, and 0.12-0.47% and 0.06-0.66% of the radiocarbon was recovered in egg yolk and fat (subcutaneous and visceral fat), respectively. Both the cis isomers labelled in the alcohol and acid moieties showed recoveries 3 to >10 times higher in the fat and egg yolk than those shown by the corresponding trans isomers. The excreta (0-72 hr) contained 1.7 times more cis-permethrin than trans-permethrin. Hydroxylated ester metabolites of trans-permethrin were not excreted, but four monohydroxy and dihydroxy esters (i.e. trans-OH-permethrin, 4'-OH-permethrin, 4'-OH, trans-OH-permethrin and trans-OH-permethrin sulfate) of cis-permethrin were found. Metabolites from the acid moieties of both isomers were the Cl2CA isomers in free, glucuronide, and taurine conjugate forms, trans-OH-Cl2CA, cis-OH-Cl2CA, cis-OH-Cl2CA lactone, and cis-OH-Cl2CA sulfate. trans-OH-Cl2CA was obtained from the cis isomer to larger extents than from the trans isomer, whereas the amounts of cis-OH-Cl2-CA were larger with the trans isomer than with the cis isomer. The metabolites from the alcohol moiety included PBalc, PBacid, their 4'-hydroxy-derivatives and the corresponding sulfate the glucuronide of PBalc, and a variety of unidentified conjugates of 4'-OH-PBalc and 4'-OH-PBacid. The taurine conjugate of PBacid was not detected. The metabolites produced in largest amounts were the unidentified conjugates of 4'-OH-PBalc (6-13% of the dose) and 4'-OH-PBacid (2-11%). The yolk of eggs 5 and 6 days after initial dosing contained 4.4 times cis-perethrin than trans-permethrin in unchanged form and the same ester metabolites of cis-permethrin as those found in the excreta. Other metabolites in the yolk were generally the same as those in the excreta. Overall, cis-permethrin appeared at higher levels than trans-permethrin in the egg yolk, fatty tissues, and excreta. Radiocarbon from cis-permethrin preparations also persisted longer in the blood than that from trans-permethrin preparations. It probably resulted from more rapid ester cleavage of the trans isomer than the cis isomer, based on the relative amounts of hydrolysis products form the two isomers in hen excreta.
Two human volunteers, who consumed about 2 and 4 mg of permethrin (25:75), respectively, excreted 18-37% and 32-39% of the administered dose, detected as the metabolite Cl2CA, after acid hydrolysis of their urine collected over 24 hr.
The permethrin metabolites in goats were formed through cleavage of the ester linkage, hydroxylation at the cis- or trans-methyl of the geminal dimethyl group, and hydroxylation at the 4'-position of the phenoxybenzyl moiety. Some of these metabolic products were further oxidized and/or conjugated with glycine, glutamic acid and glucuronic acid. The major compounds found in feces after dosing with cis-permethrin were unmetabolized parent compound 4'-OH-permethrin, trans-OH-permethrin, PBalc, cis-OH-cis-Cl2CA-lactone and eight unidentified ester metabolites. The feces of goats treated with the trans isomer contained large amounts of the parent compound (41-79% of the fecal (14)C and of PBalc (8-25%) and cis-OH-trans-Cl2CA-lactone. Also, three unidentified ester metabolites were found (8-23%). On the other hand, major urinary metabolites from the alcohol moiety of both isomers were PBacid-glycine (7-9% of the urinary (14)C) and r'-OH-PBacid-glycine (4-12%). PBalc, PBacid, 4'-OH-PBalc, 4'-OH-PBacid, PBacid-glutamic acid and 4'-OH-PBacid-glutamic acid were also identified as minor metabolites. The urine of goats treated with both isomers contained as major components, Cl2CA in the free form (2-4% of the urinary (14)C) and as a glucuronide (27-71%). Cl2CA-glucuronide was obtained to a larger extent with the trans isomer than with the cis isomer. Other major metabolites of the cis isomer were cis-OH-Cl2CA (33) (9-11%) and cis-OH-cis-Cl2CA-lactone (11-16%). trans-OH-Cl2CA was detected as a minor metabolite of both isomers. The milk of goats contained the parent compounds, PBacid-glycine, and 4'-OH-PBacide-glycine. On administration of the cis isomer, a large amount of the parent compund was excreted in the milk than in the case of the trans isomer. Comparatively, when the trans isomer was administered, PBacid-glycine was detected in the milk to a larger extent than with the cis isomer. Most of the radioactivity in the fat was attributed to the parent compound or ester metabolites such as trans-OH-permethrin and trans-OH-permethrin conjugate.
Pyrethroids exert their effect by prolonging the open phase of the sodium channel gates when a nerve cell is excited. They appear to bind to the membrane lipid phase in the immediate vicinity of the sodium channel, thus modifying the channel kinetics. This blocks the closing of the sodium gates in the nerves, and thus prolongs the return of the membrane potential to its resting state. The repetitive (sensory, motor) neuronal discharge and a prolonged negative afterpotential produces effects quite similar to those produced by DDT, leading to hyperactivity of the nervous system which can result in paralysis and/or death. Other mechanisms of action of pyrethroids include antagonism of gamma-aminobutyric acid (GABA)-mediated inhibition, modulation of nicotinic cholinergic transmission, enhancement of noradrenaline release, and actions on calcium ions. (T18, L857)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
美国环保局将permethrin归类为“可能对人类有致癌性”，这一分类是基于在小鼠中可复现的两种良性肿瘤类型（肺和肝脏），在长艾文大鼠中致癌性的不明确证据，以及支持的结构-活性关系（SAR）信息。为了进行风险评估，使用了低剂量外推模型（Q1*）。Q1*值为9.6 x 10-3 (mg/kg/天)-1，来源于雌性小鼠肺部（腺瘤和/或癌瘤）肿瘤。
The /Environmental Protection/ Agency classified permethrin as "Likely to be Carcinogenic to Humans" by the oral route. This classification was based on two reproducible benign tumor types (lung and liver) in the mouse, equivocal evidence of carcinogenicity in Long-Evans rats, and supporting structural activity relationships (SAR) information. For the purpose of risk characterization, a low dose extrapolation model (Q1*) was used. The Q1* is 9.6 x 10-3 (mg/kg/day)-1 and was derived from the female mouse lung (adenoma and/or carcinoma) tumors
Lactating cows (three/group) fed permethrin at dose levels of 0, 0.2, 1.0, 10, 50 mg/kg diet for 28 days showed no mortality, and growth and milk production were normal. Permethrin residues were observed in the milk within 3 days at the two highest dietary levels; levels appeared to reach a plateau rapidly and not to increase with time. Analysis of individual cis and trans isomers showed that the ratio of permethrin isomers in milk appeared to change during the course of the study with the cis isomer predominating. Permethrin residues were not found in the tissues of animals that received doses of 1 mg/kg or less. At dose levels of 10 or 50 mg/kg, residues were detected in the tissues, predominantly in the fat. Low levels were also present in the muscle and kidney at the highest dose level. Permethrin did not appear to accumulate in the fat but to reach a plateau rapidly.
(14)C-cis-Permethrin was applied to the clipped skin of mice at a level of 1 mg/kg body weight in 0.1 mL of acetone. The mice were restrained until the solvent had evaporated and then placed in mouse metabolism cages. They were sacrificed at 1, 5, 15, 50, 480, and 2880 min after treatment and examined for absorption, distribution, and excretion of the insecticide. About 40% of the applied permethrin had moved from the site of application within 5 min and appeared to move rapidly to other parts of the body.
When ten consecutive oral doses of (14)C-trans- or (14)C-cis- permethrin (labelled in the acid or alcohol moieties) at 0.2-0.3 mg/kg bw/day were given to lactating goats, they excreted 72-79% and 25-36% of the trans and cis isomer doses, respectively, in urine & 12-15%, respectively, in the feces. The amounts of the radiocarbon appearing in the milk were <0.7% with any one of the four (14)C-labelled preparations. Concerning the tissue residues 24 hr after the last dose, detectable levels of radiocarbon were found in most tissue, but none was >0.04 mg/kg for the trans isomer or 0.25 mg/kg for the cis isomer.
