1.1.1. Synonyms, structural and molecular data

Table 1.

Chemical Abstract Services Registry numbers, names and synonyms of permethrin.

1.1.2. Chemical and physical properties

1. Description: Colourless to white, odourless crystalline solid (pure); viscous brown liquid or crystalline solid with a sweet odour (technical) (Swaine & Tandy, 1984; Roussel Bio Corp., undated)
2. Boiling-point: 220°C at 0.05 mm Hg [6.7 × 10⁻³ kPa] (Roussel Bio Corp., undated);
3. Melting-point: 34–39°C (technical), 63–65°C (c/s-isomers), 44–47°C (trans-isomers) (Worthing & Walker, 1987; WHO, 1990)
4. Solubility: Insoluble in water (0.2 mg/l at 30°C); soluble in or miscible with most organic solvents (acetone (450 g/l), chloroform, cyclohexanone, ethanol, ether, hexane (> 1 kg/kg at 25 ° C), methanol (258 g/kg at 25 ° C), dichloromethane, xylene (> 1 kg/kg at 25°C) (Swaine & Tandy, 1984; Worthing & Walker, 1987; The Royal Society of Chemistry, 1989; WHO, 1990; Roussel Bio Corp., undated)
5. Volatility: Vapour pressure, 3.4 × 10⁻⁷ mm Hg [0.45 × 10⁻⁷ kPa] at 25°C (technical) (FMC Corp., 1984); 15 × 10⁻⁹ mm Hg [2.0 × 10⁻⁹ kPa] at 20°C (cis-isomer), 7.5 × 10⁻⁹ mm Hg [1.0 × 10⁻⁹ kPa] at 20°C (trans-isomer) (Swaine & Tandy, 1984)
6. Stability: Stable in neutral and weak acidic media, but hydrolysis can occur under alkaline or strongly acidic conditions (Swaine & Tandy, 1984).
7. Half-time: 10–25 days at 25°C in soil, depending on soil type (Roussel Bio Corp., undated)
8. Octanol/water partition coefficient (P): log P, 6,5 (WHO, 1990)
9. Conversion factor for airborne concentrations¹: mg/m³ = 16.0 × ppm

1.1.3. Trade names, technical products and impurities

Some examples of trade names are: Adion; Ambush; Ambushfog; Anomethrin N; Antiborer 3768; Atroban; BW-21-Z; Cellutec; Chinetrin; Coopex; Corsair; Diffusil H; Dragon; Ecsumin; Ectiban; Efmethrin; Eksmin; Exmin; Imperator; Indothrin; Ipitox; Kafil; Kavil; Kestrel; LE 79-519; MP 79; NIA 33297; Outflank; Perigen; Permanone; Permasect; Permit; Perthrine; Picket; Pounce; PP 557; Pramex; Pynosect; Qamlin; S 3151; SBP 1513; SBP 15131TEC; Spartan; Stockade; Stomoxin; Talcord; Torpedo

Technical-grade permethrin contains from a minimum of 35% to a maximum of 55% (±)-cis isomer and from a minimum of 45% to a maximum of 65% (±)-trans isomer (Roussel Bio Corp., 1987; Anon., 1989). In the common technical-grade products, the cis:trans ratio is either 2:3 (WHO, 1990) or 1:3 (Worthing & Walker, 1987).

Permethrin is available in the USA as a technical-grade product containing 91.0–95.0% w/w of the pure chemical and 5.0–9.0% impurities (Fairfield American Corp., 1989; Roussel Bio Corp., 1989; ICI Americas, 1990).

Several of the minor components have been identified in technical permethrin. These were principally: ethyl (±)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-l-car-boxylate, 3-phenoxytoluene, 4-phenoxybenzyl (±)-cis,trans-3-(2,2-dichlorovinyl)-2,2-di-methylcyclopropane-1-carboxylate, and 6-bromo-3-phenoxybenzyl (±)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate. Other minor components were found to be xylene (see Horiba et al., 1977).

Permethrin is formulated as granules, emulsifiable concentrates, wettable powders, dusts, smokes, ultra-low-volume sprays, fumigants, aerosols, fogging solutions and water-dispersible granules. In one European country, registered permethrin products also include capsule suspensions and lacquer formulations (Meister, 1990). In Europe, permethrin is also registered in combination with piperonyl butoxide (see IARC, 1983,1987), tetramethrin, plifenate and other pyrethrins (Royal Society of Chemistry, 1986).

1.1.4. Analysis

Selected methods for the analysis of permethrin in various matrices are given in Table 2. Permethrin can be determined in pesticide formulations using gas chromatography with flame ionization detection (Association of Official Analytical Chemists, 1986; WHO, 1990).

Table 2.

Methods for the analysis of permethrin.

Several other methods for the determination of permethrin (and its individual isomers) in various matrices, including high-performance liquid chromatography and gas chromatography, have been reviewed (Horiba et al., 1977; Miyamoto et al., 1981; Baker & Bottomley, 1982; Papadopoulou-Mourkidou, 1983; Nehmer & Dimov, 1984; Swaine & Tandy, 1984).

1.2.1. Production

Permethrin was first synthesized in 1973 (Swaine & Tandy, 1984) and first marketed in 1977 (WHO, 1990).

The starting acid is prepared by a variation of the conventional chrysanthemic acid synthesis using ethyldiazoacetate in which 1,1-dichloro-4-methyl-l,3-pentadiene is reacted with ethyldiazoacetate in the presence of a copper catalyst and the resulting ethyl (±)-cis,trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate hydrolysed to the free acid. The cis- and trans-isomers can be separated from one another by selective crystallization from n-hexane in which the cis-isomer is more soluble. The starting acid is then reacted with 3-phenoxybenzyl alcohol to give permethrin (Sittig, 1980).

Permethrin is produced currently in Japan, the United Kingdom and the USA (Meister, 1990).

1.2.2. Use

Permethrin is a synthetic contact pyrethroid insecticide with a high level of activity against a wide range of insects, including Lepidoptera, Hemiptera, Diptera and Coleoptera. It is used mainly in agriculture, where it is fast acting and effective against all growth stages, particularly larvae. About 60% of the permethrin produced is used on cotton plants. Other crops to which permethrin is applied are maize, soya beans, coffee, tobacco, rape seed oil, wheat, barley, alfalfa, vegetables and fruit (WHO, 1990).

Permethrin is also used for control of insects in household and animal facilities and in forest pest control, as a fog in mushroom houses, and as a wood preservative. Other applications are in public health, particularly for insect control in buildings and in aircraft, treatment of mosquito nets and control of human lice (WHO, 1990). It is also used for termite control as a barrier treatment on building foundations (Anon., 1989).

Approximately 600 tonnes of permethrin are used annually worldwide. The major countries or regions that were using permethrin in 1980 were (tonnes): the USA (263), Brazil (38), Mexico (36) and Central America (27) (WHO, 1990). In Finland, about 3.5 tonnes (active ingredient) permethrin were used in 1988 (Agrochemical Producers' Association of Finland, 1989)

1.3.1. Food

Samples (1954) of fruits, vegetables, grains, meats, dairy products and wine were analysed as part of the Canadian national surveillance programme in 1984–89. A total of 29 samples contained permethrin residues; of these 25 of 118 were in lettuce, 2 of 100 in pears and 2 of 97 in tomatoes. The residue levels ranged from 0.01 to 1.67 mg/kg (Government of Canada, 1990).

Cows were fed cis:trans (40:60)-permethrin at rates of 0.2–150 mg/kg diet for 28–31 days. Residues plateaued in milk, with means of < 0.01 µg/g and 0.3 µg/g at dietary levels of 0.2 and 150 mg/kg, respectively. Milk levels declined to < 0.01 µg/g within five days after permethrin administration ceased. Residue levels of < 0.01–0.04 and 2.8–6.2 µg/g fat were found in perirenal fat of cows given dietary levels of 0.2 and 150 mg/kg, respectively (as reported by WHO, 1990). Levels of radioactivity retained in tissues and secreted in milk were appreciably higher in goats treated with cis-permethrin than with trans-permethrin (Hunt & Gilbert, 1977). In goats dosed orally with 40:60 cis:trans permethrin equivalent to 10 mg/kg in the diet for seven days, residues in milk also plateaud at 0.02–0.03 µg permethrin equivalents/g after five days (FAO/WHO, 1982).

In supervised trials in Spain and the USA with citrus fruits, permethrin residues in the edible parts did not exceed 0.01 mg/kg and 0.05 mg/kg, respectively, when applied at the recommended rates. The residues were found almost exclusively in the peel (FAO/WHO, 1982).

1.3.2. Occupational exposure

Four of five workers in Sweden who packed conifer seedlings for 6 h in a tunnel that had been sprayed 1 h earlier with a 2% aqueous solution of permethrin, resulting in atmospheric concentrations of permethrin of 0.011–0.085 mg/m³ in the breathing zone, did not excrete detectable amounts of acid pyrethrin metabolites in the urine. One very short person whose face was close to the plants and who had the highest concentration of permethrin in the breathing zone excreted 0.26 µg/ml permethrin acid metabolites in the urine the following morning; in the afternoon, excretion was below the detection limit of the method. A group of five workers who planted the treated conifer seedlings were exposed to non-detectable to low permethrin levels in the breathing zone (mean, 0.002 mg/m³; range, not detected-0.006 mg/m³) and excreted no detectable amount of permethrin metabolites in the urine (Kolmodin-Hedman et al., 1982).

4.1.1. Humans

Ten scabies patients (five men and five women) had about 25 g (range, 21–32 g) of a 5% permethrin cream applied to the skin of the whole body, with the exception of the head and neck. Dermal absorption of permethrin was calculated from the quantity of conjugated and nonconjugated cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CVA) metabolites of permethrin determined in the urine. In samples of urine collected by seven patients one and two days after application of the permethrin cream, 414 and 439 µg mean total CVA were found, respectively. The mean total CVA in the urine of three patients who collected their urine in the same container for two days was 1435 µg. The urinary concentration of trans-CVA varied during the first 48 h from 0.11 to 1.07 µg/ml and that of the cis-isomer from 0.02 to 0.21 µg/ml. CVA was still detectable in the urine of three patients after a week and in the urine of one patient, reported to be an alcoholic, after two weeks. The absorption of permethrin over the first 48 h after application was estimated from the urinary CVA excretion levels to be 6 mg (range, 3–11 mg), i.e., 0.5% of the dose applied (van der Rhee et al., 1989).

Among approximately 350 people who were individually dusted against body lice with 30–50 g of powders containing 2.5 or 5.0 g/kg permethrin (cis:trans, 25:75), the mean amount of permethrin absorbed during the first 24 h after treatment was estimated to be 14 µg/kg bw among 19 of the subjects using the powder containing 2.5 g/kg permethrin and 39 µg/kg bw among 15 of the subjects using the 5 g/kg powder. No residue was found in samples of urine taken 30 and 60 days after treatment (Nassif et al., 1980).

4.1.2. Experimental systems

Pyrethroids are absorbed through the skin and the respiratory and digestive tracts, although absorption from the gastrointestinal tract appears to be incomplete. Pyrethroids undergo metabolic degradation at numerous sites (Miyamoto, 1976). In mammals, they are generally metabolized through ester hydrolysis, oxidation and conjugation (WHO, 1990).

The metabolism of permethrin has been studied in great detail in various species of mammals using isomers labelled in the alcohol or acid moiety. The metabolic pathways of permethrin in mammals are given in Figure 1 (WHO, 1990). It is metabolized and almost completely eliminated from the body within approximately 12 days in rats, goats and cows following oral administration; trans-permethrin is eliminated more rapidly than is cis-permethrin, and trace tissue residue levels of the cis isomer were higher than those of the trans isomer in these species (Elliot et al., 1976, Gaughan et al., 1977, 1978; Ivie & Hunt, 1980). Absorption through the skin has been demonstrated in mice (Shah et al., 1981), rats (Shah et al., 1987; Sidon et al., 1988) and monkeys (Sidon et al., 1988). Dermal absorption was greater in rats than in monkeys (Sidon et al., 1988). After an intramuscular injection of ¹⁴C-Iabelled permethrin, the urinary half-time values were similar for the cis and trans isomers in rats and monkeys. Radiocarbon from trans-permethrin was excreted mostly in the urine, whereas that from the cis-permethrin was eliminated in both urine and faeces (Sidon et al., 1988).

Fig. 1.

Metabolic pathways of permethrin in mammals^a

4.2.1. Humans

Volunteers received applications to an area of 4 cm² on an ear lobe of 0.05 ml of a field-strength preparation of technical (94–96% active ingredients) or formulated (32–36%) permethrin (0.13 mg/cm²) or of the inert ingredients; 0.05 ml of the vehicle (ethanol as the control for technical permethrin and water as the control for formulated permethrin) was applied to the other lobe. The intensity of paraesthesia induced by permethrin was four-fold stronger than that induced by a similar application of fenvalerate, permethrin being the least active compound for both the technical and formulated preparations. No cutaneous sensation was elicited by the inert ingredients. Paraesthesia appeared after a latent period of about 30 min, peaked between 8 and 12 h and disappeared after about 24 h. Further studies using a range of doses demonstrated that the response was dose-related (Flannigan et al., 1985).

Workers who handled seedlings treated with permethrin (cisitrans, 25:75 wettable powder or cis:trans, 40:60) reported irritation on the skin (63% of subjects) and in the upper respiratory tract (33%) (Kolmodin-Hedman et al., 1982).

A group of 435 patients, most of them children, were treated for pediculosis capitis; approximately half of the group were treated with a single, 10-min application of 25–50 ml of a permethrin (1%) and isopropanol (20%) cream rinse after towel drying of washed hair, and the remainder were treated with a liquid product containing pyrethrins (0.3%), piperonyl butoxide (3%), petroleum distillate (1.2%) and benzyl alcohol (2.4%). Cutaneous side-effects (pruritus, mild transient skin burning, stinging sensations, skin tingling, erythema and scalp rash) were reported by 7% of the patients in the first group and by 16% of those in the second (DiNapoli et al., 1988). Similar results and side-effects were reported by Brandenburg et al. (1986).

One of 28 subjects with pediculosis pubis treated with a 1% permethrin rinse developed mild scrotal erythema and irritation 12 h after application (Kalter et al., 1987).

Of 10 scabies patients treated with one application of 25 g (range, 21–32 g) of a 5% permethrin cream, followed by a thorough washing approximately 8–20 h after treatment, six had limited, mild-to-moderate not pre-existing eczema on the scabies-affected skin at one or more examinations (van der Rhee et al., 1989).

4.2.2. Experimental systems

Synthetic pyrethroids act on axons in the peripheral and central nervous system by interacting with sodium channels in mammals and/or insects. The mechanism of toxicity of synthetic pyrethroids and their classification into two types were reviewed by WHO (1990). Permethrin does not contain an α-cyano-group and is a type I pyrethroid.

Oral LD_50s in aqueous suspension generally ranged from approximately 3000 to > 4000 mg/kg bw, while the use of corn oil as the vehicle generally gave LD₅₀ values of about 500 mg/kg bw (WHO, 1990). cis-Permethrin is considerably more toxic than trans-permethrin when given orally to rats (in WHO, 1990) or intraperitoneally or intravenously to mice (Glickman et al., 1982). After oral administration of 40:60 cis:trans permethrin to rats, signs of poisoning became apparent after 2 h and persisted for up to three days; these included whole-body tremors, sometimes accompanied by salivation. Other signs were hyperactivity, hyperexcitability, urination, defaecation and ataxia (WHO, 1990).

In several subacute and subchronic studies by oral administration of permethrin to mice, rats and dogs, repeated findings were increases in absolute and relative liver weights, proliferation of smooth endoplasmic reticulum and increased activity of microsomal oxidative enzymes. In 90-day studies in rats, increased absolute and relative liver weights were reported to be evident with doses of 100 mg/kg of diet; in dogs, such effects were reported to be apparent with doses of 50 mg/kg bw and upwards for 90 days. In some but not all studies, high doses of permethrin were reported to damage peripheral nerves in rats (WHO, 1990). In rats fed diets of 20, 100 or 500 ppm (mg/kg) permethrin [isomeric composition unspecified] for two years or in rats from the third generation in a three-generation study with dietary exposure to 20 or 100 ppm, however, there was no evidence of morphological damage to nervous tissue when compared to control groups (Dyck et al., 1984).

Long-term studies with rats and mice fed diets containing up to 2500 ppm (mg/kg) permethrin (40:60 cis:trans) indicated effects on the central nervous system, such as tremors and hypersensitivity to noise, in rats only and only during the first two weeks. Liver hypertrophy, increased microsomal enzyme activity and proliferation of smooth endoplasmic reticulum occurred in both species but was less pronounced in mice (Ishmael & Litchfield, 1988).

Permethrin (80:20 cis:trans) (50 mg/kg bw per day orally to rats) increased the levels of cytochrome P450 in liver after four, eight or 12 days of administration and NADPH cytochrome c reductase after eight or 12 days. A mixture containing less of the cis form (40:60 cis:trans) increased the levels of the two enzymes only after eight or 12 days of administration (Carlson & Schoenig, 1980). Treatment of rats with 190 mg/kg bw permethrin (25:75 cis:trans permethrin) intraperitoneally for three days decreased antipyrine half-time, and γ-glutamyl-transpeptidase activity in plasma was significantly increased within 21 and 14 days at doses of 95 and 190 mg/kg bw per day, respectively (Anadon et al., 1988).

4.3.1. Humans

No data were available to the Working Group.

4.3.2. Experimental systems

Following immersion of fertile mallard eggs (30 per dose group) for 30 sec in an aqueous solution of permethrin, the LC₅₀ for embryonic death was > 40 lb/acre at 100 gal/acre (> 45 kg/ha at 935 l/ha; more than 100 times the usual field application rate); no malformation was observed in mallard chicks (Hoffman & Albers, 1984).

Sprague-Dawley rats, weighing 180–200 g, were treated with permethrin in water at concentrations ranging from 500 to 4000 ppm (mg/l) or with drinking-water (control) on days 6–15 of gestation. At concentrations of 2500 ppm or more, the protein and glycogen content of the placenta was reduced (actual weight not given). The resorption index was increased at all doses, but there was no change in the number of live fetuses at day 20 of gestation in any treatment group (Spencer & Berhane, 1982).

4.4.1. Humans

No data were available to the Working Group.

4.4.2. Experimental systems

Several unpublished studies were cited in a recent review (WHO, 1990).

Permethrin did not induce mutation in either bacteria or cultured Chinese hamster V79 cells. It did not induce mutation or aneuploidy in Drosophila melanogaster, nor did it inhibit gap-junctional intercellular communication in V79 cells.

[The Working Group noted that the studies by Páldy (1981) and by Hoellinger et al. (1987) on rodent bone marrow in vivo could not be evaluated because of inadequacies in the experimental design and reporting of the studies.]

Overall evaluation

Permethrin is not classifiable as to its carcinogenicity to humans (Group 3).