UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES DATE: 07/ 11/ 2003 TXR No. 0052016 MEMORANDUM DATE: 07/ 11/ 2003 SUBJECT: ID No. 109702. Cypermethrin: Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document DP Barcode: D289429 Case#: 819433 Submission #: S632879 PC Code: 109702 FROM: Pamela M. Hurley, Toxicologist Reregistration Branch 3 Health Effects Division ( 7509C)

TO: William Donovan, Risk Assessor Reregistration Branch 3 Health Effects Division ( 7509C)

THRU: Catherine Eiden Branch Senior Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

Conclusions:

The existing toxicity database for cypermethrin supports reregistration. With the exception of the developmental neurotoxicity study, the toxicology database for cypermethrin is complete and there are no data gaps. The scientific quality is relatively high and the toxicity profile of cypermethrin can be characterized for all effects, including potential developmental, reproductive and neurotoxic effects. The data provided no indication of increased susceptibility of rats or rabbits to in utero and/ or postnatal exposure.

Action Requested:

The Health Effects Division ( HED) has been requested to prepare the disciplinary toxicology chapter for the Reregistration Eligibility Decision on cypermethrin. Results/ Discussion: 2 In mammals, cypermethrin generally affects the neuromuscular system. The neuromuscular effects ( tremors, gait abnormalies and decreases in activity) are observed across species ( dog and rat) and via both the oral and inhalation routes of administration. As with other pyrethroids, the neuromuscular effects do not appear to increase in severity with increasing duration of exposure. They appear to be more of a transient acute effect as opposed to an effect which appears after a long term accumulated dose. Cypermethrin has been classified as a Category C, possible human carcinogen, based on an increased incidence of lung adenomas and adenomas plus carcinomas combined in female mice ( Cancer Peer Review Committee, 1988). The evidence was not considered strong enough to warrant a quantitative estimation of human risk. Structure activity comparisons with the pyrethroid class of insecticides indicate that lung tumors in mice were induced with 3 other pyrethroids. Cypermethrin is not a developmental/ reproductive toxicant. No developmental toxicity is observed in any of the developmental toxicity studies and in the reproduction studies. Offspring toxicity was observed at the same treatment level which resulted in parental systemic toxicity. There did not appear to be any increases in severity of toxicity for the pups. With the available toxicity database at this time, there is no evidence that cypermethrin induces any endocrine disruption.

Based on the weight of evidence presented, the Hazard Identification Assessment Review Committee ( HIARC) is requiring a developmental neurotoxicity ( DNT) study. This study is to be conducted with z cypermethrin ( see below). A 10X database uncertainty factor ( UF DB ) is needed to account for the lack of the DNT since the available data provide no basis to support reduction or removal of the default 10X factor.

The toxicological endpoints for use in human risk assessment for cypermethrin were selected from the most sensitive species from the combined databases for both cypermethrin and zcypermethrin z Cypermethrin is an enriched isomer of cypermethrin. Cypermethrin is a combination of 8 isomers and z Cypermethrin is generally a combination of 4 of the same 8 isomers, with the two most insecticidally active isomers present at a concentration of 24% each. The following endpoints were selected for estimation of risk: acute dietary ( general population): a NOAEL of 10 mg/ kg from the acute neurotoxicity study in the rat ( zcypermethrin aPAD = 0.01 mg/ kg); chronic dietary: a NOAEL of 6 mg/ kg/ day from the chronic feeding study in the dog ( cPAD = 0.006 mg/ kg/ day); short term incidental oral exposure: a NOAEL of 10 mg/ kg/ day from the acute neurotoxicity study in the rat ( zcypermethrin residential MOE = 1000); intermediate term incidental oral exposure: a NOAEL of 5 mg/ kg/ day from the subchronic neurotoxicity study in the rat ( z cypermethrin, residential MOE = 1000); short and intermediate term dermal exposure: no hazard was identified to support a quantitation of risk; long term dermal exposure: a NOAEL of 6 mg/ kg/ day from the chronic feeding study in the dog ( occupational MOE = 100 and residential MOE = 1000) with an estimated dermal absorption factor of 2.5%; and inhalation exposure ( any time period): a NOAEL of 0.01 mg/ L ( 2.7 mg/ kg/ day) from the 21 day inhalation study in the rat ( short and intermediate term occupational MOE = 100 and long term occupational MOE = 300; short and residential MOE ( all durations) = 1000). The extra 3x for long term 3 occupational exposure was selected because inhalation appears to be the most sensitive endpoint and using the existing oral studies with a route to route extrapolation would result in a less protective endpoint. 4 CYPERMETHRIN PC Code: 109702 and 129064 Toxicology Disciplinary Chapter for the Reregistration Eligibility Decision Document Date completed: July 10, 2003 Health Effects Division Office of Pesticide Programs U. S. Environmental Protection Agency Arlington, VA 22202 Pamela M. Hurley, Toxicologist , Date Reregistration Branch 3 ( 7509C)

TABLE OF CONTENTS 1.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.0 REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.0 DATA GAP( S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.0 HAZARD ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1 Acute Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.2 Subchronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.3 Prenatal Developmental Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4.4 Reproductive Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.5 Chronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 4.6 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 4.7 Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.8 Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.9 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5.0 TOXICITY ENDPOINT SELECTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.1 See Section 8.2 for Endpoint selection table. . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 5.2 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 5.3 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6.0 FQPA CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6.1 Special Sensitivity to Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 6.2 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . . 26 7.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 8.0 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 8.1 Toxicity Profile Summary Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 8.1.1 Acute Toxicity Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 8.1.2 Subchronic, Chronic and Other Toxicity Table . . . . . . . . . . . . . . . . . . . . 38 8.2 Summary of Toxicological Dose and Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . 44 CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 6 1.0 HAZARD CHARACTERIZATION With the exception of the developmental neurotoxicity study, the toxicology database for cypermethrin is complete and there are no data gaps. The scientific quality is relatively high and the toxicity profile of cypermethrin can be characterized for all effects, including potential developmental, reproductive and neurotoxic effects. The data provided no indication of increased susceptibility of rats or rabbits to in utero and/ or postnatal exposure.

The toxicological endpoints for use in human risk assessment for cypermethrin were selected from the most sensitive species from the combined databases for both cypermethrin and zcypermethrin z Cypermethrin is an enriched isomer of cypermethrin. Cypermethrin is a combination of 8 isomers with percentage compositions ranging from 11 14%. z Cypermethrin is a combination of the same 8 isomers with the 4 insecticidally less active ones at a concentration of 1% each. The remaining 4 isomers, two of which are regarded as being the most insecticidally active, are present at a concentration of 24% each. Summaries of the pertinent studies from the z cypermethrin toxicology database are included in this document.

Acute toxicity studies conducted with cypermethrin indicate that it is moderately acutely toxic via the oral route ( Category II); however, it is not very toxic via the dermal and inhalation routes ( Categories III and IV). It is mildly irritating to the eyes and skin and is a dermal sensitizer.

The database on cypermethrin indicates one major target for this chemical: the neuromuscular system. The liver also appears to be affected ( dermal study in rabbits: focal necrosis, abraded animals only) and mice ( may only be an adaptive response)). The neuromuscular effects ( tremors, gait abnormalies and decreases in activity) occur mainly in oral studies in the dog and the rat, but similar effects were also observed in an inhalation study. These effects do not occur in the dermal studies in either rats ( z cypermethrin) or rabbits ( cypermethrin: nonabraded animals; abraded animals did exhibit decreases in activity). The weight of the evidence indicates that the dog appears to be the most sensitive species for neuromuscular effects. In general, neither sex is more sensitive; however, in both the rat 90 day neurotoxicity study ( z cypermethrin) and the 1 year feeding study in the dog ( cypermethrin), the male appears to be more sensitive to these effects. As with other pyrethroids, the tremors do not appear to increase in severity with increasing duration of exposure. They appear to be more of a transient acute effect as opposed to an effect which appears after an accumulated dose. The effect is not consistently observed. Therefore, it is difficult to assess dose response and any differences between the capsule/ gavage/ dietary routes of administration.

A dermal absorption value of 2.5% may be estimated by comparing the maternal LOAEL of 25 mg/ kg/ day from the developmental study in the rat ( z cypermethrin) and the NOAEL ( highest dose tested) of 1000 mg/ kg/ day from the 21 day dermal study in the rat ( z cypermethrin). Since there was no common endpoint because no effects were observed in the 21 day dermal study in the rat, this is considered to be a worst case estimate. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 7 In the prenatal developmental toxicity studies in rats and rabbits with both cypermethrin and zcypermethrin ( rat only), there was no evidence of developmental toxicity at the highest dose tested. Maternal toxicity was observed in these studies in the form of decreased body weight gain and food consumption and/ or clinical signs of neurotoxicity such as gait abnormalities. In the multi generation reproduction studies in rats conducted with both of the cypermethrins, offspring toxicity was observed either at the same treatment level which resulted in parental systemic toxicity or at higher dose levels than the dose levels which induced parental toxicity. There did not appear to be any increases in severity of toxicity for the pups.

Cypermethrin has been classified as a Category C, possible human carcinogen, based on an increased incidence of lung adenomas and adenomas plus carcinomas combined in female mice ( Cancer Peer Review Committee, 1988). The evidence was not considered strong enough to warrant a quantitative estimation of human risk. Cypermethrin has not been classified under the more current, Proposed Guidelines for Carcinogen Risk Assessment ( April 10, 1996). Structureactivity comparisons with the pyrethroid class of insecticides indicate that lung tumors in mice were induced with 3 other pyrethroids. Cypermethrin was negative in all mutagenicity studies available to the Agency.

Cypermethrin is a known neurotoxicant. It is a member of the pyrethroid class of insecticides, which are known to induce transient clinical signs of neurotoxicity in mammals, but do not generally induce neuropathologic lesions. The acute neurotoxicity studies conducted with cypermethrin indicated gait abnormalities, splayed hindlimbs, decreased motor activity, salivation, lacrimation, arousal, urination and/ or soiled fur. Other parameters affected included abnormal motor movement, forelimb or hindlimb grip strength, righting reflex, touch response and tail pinch response. The acute neurotoxicity study conducted with z cypermethrin indicated similar clinical signs plus tremors, convulsions and vocalization. The subchronic neurotoxicity study with both cypermethrin and z cypermethrin indicated the same types of signs and symptoms plus decreased body weight gain. Similar clinical signs of neurotoxicity were observed in the other guideline oral and inhalation toxicity studies in the rat and dog for both cypermethrin and z cypermethrin.

The neuromuscular effects ( i. e. gait abnormalities, tremors, reduced motor activity, changes in FOB parameters and convulsions) occur across species, sexes and routes of administration. These clinical signs appear to be more of a transient acute effect as opposed to an effect which appears after an accumulated dose.

The liver effects are seen in the mouse oncogenicity study and the rabbit dermal study ( abraded animals only). The effects in rabbits would be significant, except that the Agency does not generally use data from abraded animals in a dermal toxicity study. The effects in the mouse may be due to induction of microsomal enzymes in the liver and are likely more of a physiological response as opposed to a toxicological effect. In the presence of a xenobiotic, certain metabolic pathways are stimulated in the liver to increase the ability of the animal to purge itself of the xenobiotic. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 8 Cypermethrin is a type II pyrethroid ( i. e. it has a cyano group at the " carbon position of the alcohol moiety and it is more effective when the ambient temperature is raised). Ware states, " pyrethroids initially stimulate nerve cells to produce repetitive discharges and eventually cause paralysis. Such effects are caused by their action on the sodium channel, a tiny hole through which sodium ions are permitted to enter the axon to cause excitation. These effects are produced in insect nerve cord, which contains ganglia and synapses, as well as in giant nerve fiber axons. The stimulating effect of pyrethroids is much more pronounced than that of DDT. The exact sites of action of pyrethroids at synapses are not known. It is probable that the toxic action of pyrethroids is primarily due to its blocking action on the nerve axon since this action shows a negative temperature coefficient. But because the cockroach ganglion is affected by pyrethroid concentrations many fold less than are required to block conduction in giant fibers, it also seems likely that pyrethroids act on some aspect of synaptic function. The fast knockdown of flying insects could be the result of rapid muscular paralysis, suggesting that the ganglia of the insect central nervous system are affected."

2.0 REQUIREMENTS The requirements ( CFR 158.340) for Food/ Feed use for cypermethrin are in Table 1. Use of the new guideline numbers does not imply that the new ( 1998) guideline protocols were used. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 9 Table 1.

Test Technical Required Satisfied 870.1100 Acute Oral Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.1200 Acute Dermal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.1300 Acute Inhalation Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 870.2400 Primary Eye Irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.2500 Primary Dermal Irritation . . . . . . . . . . . . . . . . . . . . . . . . . 870.2600 Dermal Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 Oral Subchronic ( Rodent) . . . . . . . . . . . . . . . . . . . . . . . . . 870.3150 Oral Subchronic ( Non Rodent) . . . . . . . . . . . . . . . . . . . . . 870.3200 21 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.3250 90 Day Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . No number 21 Day Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes no no yes yes yes N/ A yes 870.3700a Developmental Toxicity ( Rodent) . . . . . . . . . . . . . . . . . . . 870.3700b Developmental Toxicity( Non rodent) . . . . . . . . . . . . . . . 870.3800 Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes 870.4100a Chronic Toxicity ( Rodent) . . . . . . . . . . . . . . . . . . . . . . . . 870.4100b Chronic Toxicity ( Non rodent) . . . . . . . . . . . . . . . . . . . . . 870.4200a Oncogenicity ( Rat) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.4200b Oncogenicity ( Mouse) . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.4300 Chronic/ Oncogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes yes yes yes yes yes yes 870.5100 Mutagenicity  Gene Mutation  bacterial . . . . . . . . . . . . . 870.5300 Mutagenicity  Gene Mutation  mammalian . . . . . . . . . . 870.5375 Mutagenicity  Structural Chromosomal Aberrations . . . . 870.5385 Mutagenicity  Structural Chromosomal Aberrations . . . . 870.5550 Mutagenicity  Other Genotoxic Effects . . . . . . . . . . . . . . yes1 yes1 yes1 yes1 yes1 yes yes yes yes yes 870.6100a Acute Delayed Neurotox. ( Hen) . . . . . . . . . . . . . . . . . . . . 870.6100b 90 Day Neurotoxicity Hen) . . . . . . . . . . . . . . . . . . . . . . . 870.6200a Acute Neurotox. Screening Battery ( Rat) . . . . . . . . . . . . . 870.6200b 90 Day Neuro. Screening Battery ( Rat) . . . . . . . . . . . . . . . 870.6300 Develop. Neuro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . no no yes yes yes2 N/ A N/ A yes yes no 870.7485 General Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870.7600 Dermal Penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . yes yes yes yes 870.7200 Companion Animal Safety . . . . . . . . . . . . . . . . . . . . . . . . yes yes Special Studies for Ocular Effects Acute Oral ( Rat) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subchronic Oral ( Rat) . . . . . . . . . . . . . . . . . . . . . . . . . . . Six month Oral ( Dog) . . . . . . . . . . . . . . . . . . . . . . . . . . . no no no N/ A N/ A N/ A 1Mutagenicity requirements are under the new guideline requirements. In vitro structural chromosomal aberration study conducted with z cypermethrin. 2Required by Hazard Identification Assessment Review Committee ( HIARC) on 9/ 19/ 2000 and is to be conducted with zcypermethrin CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 10 3.0 DATA GAP( S)

The toxicology data base for cypermethrin is not complete, but it is adequate to support reregistration at this time. A requirement for a developmental neurotoxicity study was recommended by HIARC on 9/ 19/ 00.

4.0 HAZARD ASSESSMENT The hazard assessment includes toxicology studies conducted with cypermethrin and selected studies conducted with z cypermethrin..

4.1 Acute Toxicity Adequacy of data base for acute toxicity: The data base for acute toxicity is complete. Acute toxicity studies conducted with cypermethrin indicate that it is Category II via the oral route; however, it is not very toxic via the dermal and inhalation routes ( Categories III and IV). It is mildly irritating to the eyes and skin and is a dermal sensitizer.

The acute toxicity data on cypermethrin are summarized below in Table 2. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 11 Table 2. Acute Toxicity Data on Cypermethrin Guideline No. Study Type MRIDs # Results Toxicity Category 870.1000 Acute Oral  rat 00056800 LD 50 ( M): 247 mg/ kg ( F): 309 mg/ kg females Deaths: $ 150 mg/ kg, usually in first day. Clinical signs of neurotoxicity, gait abnormalities; some persisting to 14 days. II 870.1100 Acute Dermal Rats Rabbits 00056800 00056800 LD 50 > 4920 mg/ kg/ day. Clinical signs of neurotoxicity.

Abraded skin: LD 50 > 2460 mg/ kg. Lacrimation, discharge from the eye and " nervous and shaking". III III 870.1200 Acute Inhalation  rat 42395702 LC 50 : % ( not calculated but higher than &) LC 50 : & 2.5 ( 1.6 3.4) mg/ L. Clinical signs of neurotoxicity. IV 870.2400 Primary Eye Irritation  rabbit 00056800 Slight redness of conjunctivae, chemosis & discharge. Persisted to day 7. III 870.2500 Primary Skin Irritation rabbit 00056800 Slight to mild erythema on intact & abraded skin. Regressed by 48 hours. Primary Irritation Index: 0.71 IV CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter Guideline No. Study Type MRIDs # Results Toxicity Category 12 870.2600 Dermal Sensitization 00056800 40377701 Not a sensitizer in Buehler assay. Moderate sensitizer in Magnusson Kligman Maximization method. N/ A 4.2 Subchronic Toxicity Adequacy of data base for subchronic toxicity: The data base for subchronic toxicity is incomplete, however, acceptable chronic oral studies are available to fulfill the data requirements for a subchronic oral study in the rat. In addition, a subchronic feeding study is available with zcypermethrin No additional studies are required at this time. The main toxicological effects are neuromuscular effects and decreases in body weight and body weight gain in both rats and dogs.. No effects are observed when z cypermethrin is administered to rats via the dermal route. No effects are observed when cypermethrin is administered to nonabraded rabbits at dose levels up to 200 mg/ kg/ day via the dermal route either. When cypermethrin is administered via inhalation, clinical signs of neurotoxicity and decreases in body weight are observed.

870.3100 90 Day Oral Toxicity  Rat In a subchronic toxicity study ( MRID 00056802 and 92027034) cypermethrin ( 92% purity) was administered to four groups of 20 SPF Alderley Park strain rats/ sex at dose levels of 0, 75, 150 or 1500 ppm ( corresponding to 0, 3.75, 7.5 or 75 mg/ kg/ day) for 90 days. Groups of 4/ sex/ dose were allowed 28 days for recovery. The male rats dosed with 7.5 mg/ kg/ day had increases ( 260%) in hepatic aminopyrine demethylase. This was increased to 539% in the 75 mg/ kg/ day dose group. Females ( 466%) were increased in the 75 mg/ kg/ day dose group only. Recovery was evident after 28 days. Body weight was decreased in the 75 mg/ kg/ day dose groups for both males ( i. e. 17% at week 9) and females ( i. e. 8% at week 9). The LOAEL is 1500 ppm ( 75 mg/ kg/ day) based on decreases in body weight. The NOAEL is 150 ppm ( 7.5 mg/ kg/ day). The increase in hepatic aminopyrine demethylase is considered a physiological rather than toxicological response but its presence is indicated. This subchronic toxicity study is classified as supplementary ( due to insufficient tables) and does not satisfy the guideline requirement for a subchronic oral study ( 82 1) in rats. The study does not require upgrading because an acceptable chronic feeding study with rats is available.

z Cypermethrin ( 88.2% a. i.) was tested in a 90 day feeding study in groups of 10 male and 10 female Fisher 344 ( CDF) rats at the following dose levels: 0, 10, 50, 150, 250, 500 or 900 ppm ( 0, 0.6, 2.7, 8.4, 13.8, 28.2 or 55.7 mg/ kg/ day for males and 0, 0.6, 3.3, 9.6, 16.3, 32.2 or 65.2 mg/ kg/ day for females) ( MRID 41776101). At 500 ppm, females had significantly decreased glucose levels. Clinical chemistries were not obtained for females at 900 ppm due to high mortality. This was attributed to decreased food consumption. At 500 and 900 ppm, both sexes CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 13 had significantly decreased body weights ( 12 and 38%, respectively in males, 9 and 35%, respectively in females), body weight gains ( 15 and 63%, respectively in males and 21% in females at 500 ppm) and food consumption when compared to controls. At 900 ppm, 70 and 100 percent of the males and females, respectively died. The deaths were attributed to " inanition". Food efficiency was also significantly decreased ( 48% in males and 65% in females). These animals exhibited abdominal genital staining, ataxia, clonic convulsions, chromodacryorrhea, chromorhinorrhea, decreased feces, decreased locomotion, dehydration, hypersensitivity to touch and sound, splayed hindlimbs and unthriftiness. Females also exhibited abdominal recumbency and walking on toes. Males had significant decreases in erythrocyte and leukocyte counts when compared to controls. Hemoglobin and hematocrit were also decreased in males as well as increases in BUN. The NOAEL is 250 ppm ( 13.9 mg/ kg/ day) and the LOAEL is 500 ppm ( 28.2 mg/ kg/ day) based on decreases in body weight and body weight gains and food consumption at 28.2 mg/ kg/ day and above and deaths; clinical signs of neurotoxicity; decreases in erythrocyte and leukocyte counts, hemoglobin and hematocrit and increases in BUN at 55.7 mg/ kg/ day. The study is acceptable.

870.3150 90 Day Oral Toxicity  Dog There are two available subchronic dog studies with cypermethrin; only one study is acceptable.

In a subchronic toxicity study ( MRID 44527002), cypermethrin ( 95.7% a. i.) was administered to beagle dogs ( 4/ sex/ group) at concentrations of 0, 300, 600, 800, or 1100 ppm in the diet ( achieved doses 0/ 0, 10.4/ 12.2, 20.7/ 25.4, 24.6/ 34.3, and 37.0/ 45.2 mg/ kg/ day [ M/ F], respectively) for 3 months. No deaths occurred during the study. In the 1100 ppm group, two males and one female exhibited slight tremor activity beginning on day 49 ( female), 60, or 71 through study termination, and one male and one female exhibited moderate tremor activity either on two occasions ( male) or during the week 8, 9, and 12 detailed physical examinations ( female). Males and females displayed decreases in body weights throughout the study, reduced body weight gains and gained little or no weight during the study. No treatment related differences in food consumption, hematological, clinical chemistry, or urinalysis parameters, ophthalmoscopic abnormalities, organ weight, or gross or microscopic pathology were observed. No neoplastic tissue was observed. The LOAEL is 1100 ppm ( equivalent to 37.0/ 45.2 mg/ kg/ day [ M/ F]), based on tremor activity in both sexes and decreased body weight and body weight gains in the males and females. The NOAEL is 800 ppm ( equivalent to 24.6/ 34.3 mg/ kg/ day [ M/ F]). This study is classified acceptable ( § 82 1b) and satisfies the guideline requirements for a subchronic toxicity study in the dog.

In a subchronic toxicity study ( MRID 00112929, 42068502) cypermethrin ( 98% purity) was administered to four groups of 4 beagle dogs/ sex at dose levels of 0, 5, 50, 500 or 1500 ppm ( corresponding to 0.. 125, 1.25, 12.5 and 37.5 mg/ kg/ day) for 13 weeks. Responses to treatment were noted at 37.5 mg/ kg/ day in both sexes and consisted of whole body tremors, exaggerated gait, ataxia, incoordination, hyperaesthesia, licking and chewing of paws as well as diarrhea and anorexia and decreased body weight. The LOAEL is 1500 ppm ( 37.5 mg/ kg/ day, based on clinical signs indicating neurotoxicity. The NOAEL is 500 ppm ( 12.5 mg/ kg/ day). This subchronic CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 14 toxicity study is classified as unacceptable guideline and does not satisfy the guideline requirement for a subchronic oral study ( 82 1b) in dogs. The limiting factors include no data tables for clinical signs to determine their onset and duration, there is no discussion of the body weight effect at 1500 ppm and the copy available is unreadable in most places.

870.3200 21/ 28 Day Dermal Toxicity   Rat or Rabbit In a 21 day dermal toxicity study, cypermethrin ( 91.5% purity) was applied to the skin of 10 New Zealand White rabbits/ sex/ dose at doses of 0 ( polyethylene glycol, PEG 300), 2, 20 or 200 mg/ kg/ day for approximately 6 hours/ day, 5 days/ week, for a total of 15 applications during a 21 day period ( MRID 00090035, 92027036). The skin of five/ sex/ dose was abraded weekly. There were no apparent effects on mortality, food consumption, hematology parameters, clinical chemistry parameters or macroscopic pathology. At 200 mg/ kg/ day, increased incidences in subdued behavior, flacidity and possibly fecal incontinence were observed when compared to the control or lower dose groups. With the exception of fecal incontinence, the increased incidence of clinical signs were observed in the abraded animals. A decrease in body weight was observed in abraded females ( 0.35 kg versus  0.05 kg in the control group, p < 0.01) and possibly the abraded males ( not statistically significant, loss of 0.26 kg compared to loss of 0.04 kg in the control group). There was an increased incidence of microscopic liver focal necrosis in the abraded females ( 1/ 5 in controls versus 4/ 5 for abraded and 1/ 5 in controls versus 2/ 5 for nonabraded and possibly abraded males ( 1/ 5 in controls versus 3/ 5 for abraded and 1/ 5 in controls versus 0/ 5 for non abraded). Testicular weights were also decreased ( absolute 19% less ( p< 0.05), relative 15% less ( statistics not calculated). Individual animal data indicate that most of the animals with decreased testicular weights were in the abraded group. Increased incidences and severity of skin changes were noted ( erythema, edema, desquamation, flaking/ sloughing, redness, scabbing, cracking and wrinking), particularly in females. Microscopically, there was an increased incidence of dermal leucocyte infiltration in males. Combining abraded and nonabraded there were 0/ 10 in the control group and 3/ 10, 3/ 10 and 5/ 10 in the 2, 20 and 200 mg/ kg/ day, respectively. For females, there were 3/ 10 in the control group and no more than 4/ 10 in any treated group. There were no parameters which seemed to clearly distinguish the abraded from the non abraded animals. At lower doses, the number of animals involved and the severity of the findings in the skin was considerably reduced and were not considered to be sufficient to be related to treatment. The combined abraded & nonabraded animal systemic LOAEL was 200 mg/ kg/ day based on female body weight loss ( abraded only), a decrease in testicular weights ( absolute and possibly relative, attributed to abraded group) and liver pathology in females and possibly males ( focal necrosis, abraded only). The combined abraded & nonabraded animal systemic NOAEL was 20 mg/ kg/ day. The non abraded animal systemic LOAEL was greater than 200 mg/ kg/ day and the non abraded animal systemic NOAEL was 200 mg/ kg/ day, the highest dose tested. The dermal LOAEL was 200 mg/ kg/ day based on male and female clinical signs ( erythema, edema and other skin lesions) as well as dermal leucocyte infiltration in both sexes. The dermal NOAEL was 20 mg/ kg/ day. This study is classified as acceptable ( 82 2b; 870.3200) and satisfies the guideline for a repeated dose dermal toxicity study in rabbits. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 15 In a repeated dose dermal toxicity study ( MRID 45010401), z cypermethrin ( 86% a. i., Lot/ Batch #: FMC T# 1517) was applied to the clipped intact skin of 10 Sprague Dawley rats/ sex/ dose at nominal doses of 0 ( untreated control), 100, 500, or 1000 mg/ kg/ day ( limit dose) for 6 hours/ day, 7 days/ week, for a total of 21 applications during a 21 day period. On day 21, all surviving rats underwent Functional Observational Battery ( FOB) and motor activity testing. All animals survived to the end of the study and no treatment related clinical signs were observed. No treatment related differences in body weights, organ weights, food consumption, FOB, motor activity, ophthalmology, hematology, clinical chemistry, or pathology ( gross or microscopic) between the treatment and control groups were observed. At the site of application, erythema and/ or eschar, desquamation, and ulcerations were observed in both males and females. After pathological evaluation, it was concluded that these findings were due to clipping and/ or scratching by the animals. The systemic LOAEL was not established. The systemic NOAEL is 1000 mg/ kg/ day ( limit dose). The dermal LOAEL was not established. The dermal NOAEL is 1000 mg/ kg/ day ( limit dose). This study is classified acceptable ( § 82 2a) and does satisfy the guideline requirement for a repeated dose dermal toxicity study. Although a LOAEL was not observed, the test substance was tested up to the limit dose.

870.34xx 21/ 28 Day Inhalation Toxicity   Rat In a 21 day subchronic inhalation toxicity study ( MRID 43507101) cypermethrin ( 87.1% purity, 1: 1 cis: trans) was ad ministered to 5/ sex rats ( Alpk: Apfsd, Wistar Derived)/ sex/ dose group by nose only exposure at concentrations of 0, 0.01, 0.05 or 0.25 mg/ L for six hours per day, 5 days per week for a total of 15 exposures. Additional satellite groups of 5/ sex were included for recovery assessment and analysis of cypermethrin in the brain. The MMAD was determined to be 2.63 to 2.86 uM. At 0.05 mg/ L/ day there was slight but consistently statistically significant (< 5% body, p < 0.05) body weight loss also reflected as a 16% decrease in body weight gain. All males and 4 females had occasional salivation. At 0.25 mg/ L clinical signs were evident from day 10 on ( particularly including decreased activity, salivation, lachrymation, tail erection, head and/ or paw flicking and tip toe gait and others, see results). Changes in RBC parameters were slight and equivocal. Cypermethrin was not detected in the brain at day 10 or 22. The LOAEL is 0.05 mg/ L based mainly on body weight decrease. The NOAEL is 0.01 mg/ L. Classification: This study is classified as acceptable. Histopathology was assessed for only 5 rats/ sex and 10 rats/ sex should have been assessed. Future studies should assess 10/ sex/ group.

4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is considered complete. No additional studies are required at this time. Maternal toxicity in rats was evident and included clinical signs of toxicity ( especially neurotoxicity); stained abdominal and perineal fur; decreased body weights, body weight gains, and food consumption; and soft or liquid feces. Maternal toxicity in rabbits included decreased body weight gain, clinical signs of toxicity, red or pink material in the pan and decreased feces. No developmental effects were observed in either rats or rabbits. Developmental NOAELs were greater than the maternal NOAELs. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 16 870.3700a Prenatal Developmental Toxicity Study  Rat In a developmental toxicity study ( MRID 00056804, 42068505, 92027039 or 92027061), cypermethrin ( 98.2% purity) in corn oil was administered by gavage to four groups of 25 mated CD strain Charles River rats at dose levels of 0, 17.5, 35 or 70 mg/ kg/ day on days 6 15 of gestation. The rats were sacrificed at day 21 of gestation. Dose levels of 35 ( 12%) and 70 ( 28%) mg/ kg/ day resulted in decreased body weight gain. The dams dosed with 70 mg/ kg/ day displayed neurological signs such as splayed limbs, spasms, and hypersensitivity to noise and convulsions. The maternal LOAEL is 35 mg/ kg/ day, based on decreased body weight gain. The maternal NOAEL is 17.5 mg/ kg/ day. There were no effects on either skeletal or visceral structures reported. The developmental LOAEL is > 70 mg/ kg/ day. The developmental NOAEL is > 70 mg/ kg/ day. This developmental toxicity study in the rat is classified as ACCEPTABLE and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700, 83 a).

z Cypermethrin ( 89.6% a. i.) was tested in a developmental toxicity study in Charles River Crl: CD ( SD) BR rats at the following dose levels: 0, 5, 12,5, 25, or 35 mg/ kg/ day ( MRID 41776102). Groups of 25 females were administered the test chemical by gavage on gestation days 6 through 15 in a volume of 5 ml/ kg bodyweight. At 25 mg/ kg/ day and above, ataxia and urine stained abdominal fur was observed as well as reduced body weight gains and food consumption. Fecal stained perineal fur was also observed at 25 mg/ kg/ day. At 35 mg/ kg/ day, hypersensitivity, emaciated appearance, excessive salivation and soft or liquid feces were observed. One rat had tremors, red exudate on the snout, front limbs and abdomen, chromorhinorrhea, clonic convulsions, swollen snout and a nasal lesion. No developmental toxicity was observed at any dose level. The maternal NOAEL is 12.5 mg/ kg and the maternal LOAEL is 25 mg/ kg based on decreases in bodyweight and bodyweight gain and food consumption and clinical signs of toxicity, particularly neurotoxicity. The developmental NOAEL is 35 mg/ kg/ day ( HDT). The LOAEL was not established. The study is classified as acceptable.

870.3700b Prenatal Developmental Toxicity Study  Rabbit There are two developmental rabbit studies conducted with cypermethrin. One study was not tested at a sufficiently high dose level.

In a developmental toxicity study ( MRID 00056805), cypermethrin ( 98.5% purity) in corn oil was administered to banded Dutch rabbits by gelatin capsule at dose levels of 0 ( empty capsule), 0 ( capsule plus corn oil), 3, 10 or 30 mg/ kg/ day on days 6 to 18 inclusive of gestation. There were no effects on the does of any kind reported. The maternal LOAEL is > 30 mg/ kg/ day. The maternal NOAEL is > 30 mg/ kg/ day. There were no treatment related effects on either the skeletal or visceral structures reported. The developmental LOAEL is > 30 mg/ kg/ day. The developmental NOAEL is > 30 mg/ kg/ day. The developmental toxicity study in the rabbit is classified as unacceptable and does not satisfy the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; § 83 3b in the rabbit. The study is not considered upgradeable because the dose levels selected are too low. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 17 In a developmental toxicity study ( MRID No.: 43776302) cypermethrin ( 94 96% pure, cis/ trans ration approximately 1: 1) was administered to 20 New Zealand White rabbits per dose group by gavage at dose levels of 0, 100, 450 or 700 mg/ kg/ day from days 7 through 19 of gestation. The does were sacrificed on day 29 of gestation. Cypermethrin was administered as a 50% w/ v solution in corn oil at varying volumes and corn oil was administered to the control group. Body weight gain was decreased during dosing at 450 ( 25%) and 700 ( 30%) mg/ kg/ day and this was followed by compensatory increases. Exacerbation of some clinical signs such as anorexia, abdominogenital staining and decreased feces and red or pink material in the pan also resulted in the 700 mg/ kg/ day dose group and in a few does in the 450 mg/ kg/ day group. The maternal LOAEL is 450 mg/ kg/ day, based on body weight gain. The maternal NOAEL is 100 mg/ kg/ day. There were no indications of developmental toxicity. The NOAEL and LOAEL for developmental toxicity is > 700 mg/ kg/ day. classification: This developmental toxicity study in the rabbit is classified acceptable and satisfies the guideline requirement for a developmental toxicity study ( OPPTS 870.3700; § 83 3( b).

4.4 Reproductive Toxicity Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete. No additional studies are required at this time. Two reproduction studies are available with cypermethrin. In these studies, decreased body weight gain was observed in both the parents and pups. The offspring NOAELs were equivalent to the parental NOAELs. In a two generation reproduction study conducted with z cypermethrin in rats, decreased body weight gains, mortality and clinical signs of neurotoxicity were observed in the parents. In the pups, decreased body weight gain and mortality were also observed. The offspring NOAEL was also equivalent to the parental NOAEL.

870.3800 Reproduction and Fertility Effects  Rat In a 3 generation reproduction study ( MRID 00112912, 42068504, 92027040) cypermethrin ( 90.6 to 93.1%) was administered to four groups of 15 male and 30 female Wistar derived SPF strain rats at dose levels of 0, 50, 150 or 1000/ 750 ppm ( reduced to 750 ppm after 12 weeks because of severe neurological symptoms). These dose levels correspond to 2.5, 7.5 or 50/ 37.5 mg/ kg/ day. Three successive generations were produced, each consisting of 2 separate breedings to produce six sets of litters. At 150 ppm ( 7.5 mg/ kg/ day), parental weight gain was decreased in males ( i. e. about 7% for F 2 at week 5) and females ( i. e. about 4.5% for F o at week 8 and about 10% for F 2 week 8). At 1000/ 750 ppm ( 50/ 37.5 mg/ kg/ day) parental body weight gain was typically 10% decreased for both males and females and there was decreased mean litter weight gain during lactation ( i. e. 12% to 21% for F 1 B and 12 to 17% for F 1 B females for days 10 to 28). At 1000 ppm ( 50 mg/ kg/ day) there were obvious clinical signs of neurotoxicity ( i. e. ataxia etc). The parental/ offspring LOAEL is 750 ppm ( 50/ 37.5 mg/ kg/ day) based on consistent decreased body weight gain in both sexes in the parents and decreased mean litter weight gain during lactation. The parental/ offspring NOAEL is 150 ppm ( 7.5 mg/ kg/ day; the decreases in mean body weight and body weight gain at 150 ppm are not considered to be toxicologically significant). The reproductive study in the rat is classified ACCEPTABLE and CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 18 satisfies the guideline requirement for a 3 generation reproductive study ( OPPTS 870.3800, § 83 4) in the rat.

In a 3 generation ( 2 litters/ generation) reproduction study ( MRID 00090040) cypermethrin ( 98% purity) was administered to four groups of 30/ sex Wistar SPF strain rats/ sex/ dose group in their diets at dose levels of 0, 10, 100 or 500 ppm ( 0, 0.5, 5 or 25 mg/ kg/ day). The first parental group produced two litters ( F1A and F1B), the F1B litter was culled to produce the F2A and F2B litters and the F2B litter was culled to produce the F3A and F3B litters. At 25 mg/ kg/ day there was decreased parental weight gain ( i. e. about 3% for males and 7% for females for the F1 generation) and pup weight at day 21 of lactation for one or both litters of one or both sexes ( about 4% but p< 0.01). The parental LOAEL is 25 mg/ kg/ day based on decreased body weight gain. The NOAEL is 5 mg/ kg/ day. The offspring LOAEL is 25 mg/ kg/ day based on a decrease in pup body weight gain on lactation day 21 for one or both sexes of one or both litters of each generation. The offspring NOAEL is 5 mg/ kg/ day. Regarding the lactation day 21 pup body weights/ gains, there was a small but statistically significant decrease ( p< 0.01) in body weight at 100 ( 3%) and 500 ( 4%) ppm. The small decrement at 100 ppm is not considered of sufficient magnitude to be included in the LOAEL as the pups in the 100 ppm dose group matured to be the parental groups and there was no statistical difference regarding the parental body weights. This reproductive study in the rat is classified as SUPPLEMENTARY and does not satisfy the guideline requirement for a 3 generation reproductive study ( OPPTS 870.3800, 83 4) in the rat. The study is in summary form only and is not supported by the individual animal data.

z Cypermethrin ( 89.6% a. i.) was tested in a 2 generation reproduction study in groups of 30 male and 30 female Charles River Crl: CD ( SD) BR rats at the following dose levels: 0, 7.5, 25, 100, 375 or 750 ppm ( 0, 0.5, 1.8, 7, 27 or 45 mg/ kg/ day; MRID 41968204). At 27 mg/ kg/ day, decreased parental weight ( particularly during lactation), increased relative brain weight, clinical signs of toxicity ( particularly neurotoxicity) and decreased pup weight gain during lactation were observed. At 45 mg/ kg/ day, pup and parental deaths and more severe clinical signs of toxicity were observed. The parental and offspring NOAELs are 7 mg/ kg/ day and LOAELs are 27 mg/ kg/ day based on decreased parental and pup weight, particularly during lactation, clinical signs of toxicity and death at 45 mg/ kg/ day. This study is classified as Acceptable.

4.5 Chronic Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is considered complete. No additional studies are required at this time. The main effects from chronic exposure are decreases in body weight gain in rats and clinical signs of neurotoxicity and gastrointestinal effects in dogs.

870.4100a ( 870.4300) Chronic Toxicity   Rat In a chronic toxicity/ carcinogenicity study ( MRID 00112910, 92027041) cypermethrin ( 88 93% purity, 55% cis and 45% trans) was administered to 5 groups of 52/ sex Wistar derived Alderley Park SPF strain rats at dose levels of control 1, control 2, 20, 150 or 1500 ppm ( corresponding to CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 19 0, 0, 1, 7.5 or 75 mg/ kg/ day) for 2 years. Satellite groups of 12/ sex were sacrificed after one year of dosing. Definite signs of toxicity were evident at 75 mg/ kg/ day and these consisted of body weight gain decrease throughout the study ( i. e. about 10% for males and 13% for females at week 13), slight effects on several hematological parameters ( both red and white cells), slight effects on clinical chemistry parameters ( decreased cholesterol and triglycerides and glucose and increased urea. Decreases in urine volume, pH and an increase in specific gravity were noted. Liver weight was increased in females. The LOAEL is 1500 ppm ( 75 mg/ kg/ day) based on decrease in body weight gain. The NOAEL is 150 ppm ( 7.5 mg/ kg/ day). Cypermethrin was not considered to be oncogenic in this study. A possible association with increased testicular interstitial tumors was not considered definite. This chronic toxicity/ carcinogenicity study is classified as acceptable and satisfies the guideline requirement for a chronic oral feeding/ carcinogenicity study ( 83 5) in rats.

870.4100b Chronic Toxicity  Dog In a chronic toxicity study ( MRID 44536801), cypermethrin ( 95.7% a. i.) in corn oil was administered to beagle dogs ( 4/ sex/ dose) in the diet at dose levels of 0, 100, 200, 600, or 1100 ppm ( achieved doses 0/ 0, 2.9/ 3.3, 6.0/ 5.7, 20.4/ 18.1, or 33.9/ 38.1 mg/ kg/ day [ M/ F], respectively) for 12 months.

One 600 ppm male died and two 1100 ppm males were sacrificed moribund during the study interval. At 600 ppm, one male exhibited tremors, irregular gait, and excessive salivation on two occasions each prior to death ( day 133). A second male exhibited irregular gait and tremors during weeks 39 or 44 ( 1 or 2 incidents). Females had reduced body weights ( 91 16%, not statistically significant [ NS]) beginning at week 9 and reduced body weight gains throughout the study ( week 52: 0, 100, 200, 600 and 1100 ppm = 2.0, 1.8, 2.6, 0.7 and  0.2 kg). In the 1100 ppm group, two males were sacrificed moribund on day 276 or 324. Males exhibited the following clinical signs: tremors in four males during weeks 16 51 ( 47/ 276, 54/ 324, 6/ 368, or 53/ 367 incidents); irregular gait in four males during weeks 11 52 ( 47/ 276, 90/ 324, 2/ 368, or 94/ 367 incidents); excessive salivation in one male during week 8 ( 1/ 368 incidents); prostration in one male during week 27 ( 3/ 368 incidents); uncoordination, characterized by difficulty in supporting own weight, in one male during weeks 37 40 ( 6/ 276 incidents); decreased activity in one male during week 39 ( 1/ 276 incidents); and clonic convulsions in one male during week 32 ( 1/ 324 incidents). Two females exhibited the following clinical signs: tremors during weeks 33 54 ( 63/ 368 or 132/ 372 incidents); irregular gait during weeks 33 54 ( 93/ 368 or 140/ 372 incidents); unthrifty coat during weeks 23 52 ( incidents could not be deduced from data provided); and moderate alopecia during weeks 15 52 ( incidents could not be deduced from data provided). One female also exhibited excessive salivation during week 27 ( 1/ 372 incidents). Females had progressively reduced mean body weights throughout the study ( 92 24%, p# 0.05 during weeks 43 47), with maximum decreases beginning at week 31 ( 917 24%) and reduced mean body weight gains throughout the study ( week 52 body weight gains in kg for 0, 100, 200, 600 and 1100 ppm = 2.0, 1.8, 2.6, 0.7 and  0.2). When compared to concurrent controls, no treatment related changes were noted regarding food consumption, ophthalmoscopic abnormalities, hematological, clinical chemistry, or urinalysis parameters, organ weights, or gross CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 20 or microscopic pathological findings. No neoplastic tissue was observed in dogs from any test group. The LOAEL is 600 ppm ( equivalent to 20.4/ 18.1 mg/ kg/ day [ M/ F]), based on mortality and abnormal clinical signs in males, and decreased body weights and body weight gains in females. The NOAEL is 200 ppm ( equivalent to 6.0/ 5.7 mg/ kg/ day [ M/ F]). This study is classified acceptable ( § 83 1b; 870.4100) and satisfies the guideline requirements for a chronic toxicity study in dogs.

In a chronic toxicity study ( MRID 00112909, 42068503, 92027037) cypermethrin ( 90.6%) dissolved in corn oil was administered to 4 groups of 6/ sex beagle dogs in gelatin capsules at dose levels of 0, 1, 5 or 15 mg/ kg/ day for 52 weeks. The males ( 4.75 fold) and females ( 10 fold) dosed with 5 mg/ kg/ day had increased incidence of passage of liquid stools starting in the first week of dosing and the incidence of this condition greatly increased to 31 fold at the 15 mg/ kg/ day dose level compared to controls. At 15 mg/ kg/ day, body tremors, gait abnormalities, uncoordination, disorientation and hyper sensitivity to noise were evident in the first week in addition to body weight decrease. The LOAEL is 5 mg/ kg/ day based on gastrointestinal effects. The NOAEL is 1 mg/ kg/ day. This chronic toxicity study is classified acceptable and satisfies the guideline requirement for a chronic oral study ( 82 1) in the dog.

4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The data base for carcinogenicity is considered complete. No additional studies are required at this time. No evidence of carcinogenicity was observed in rats. In mice, cypermethrin produced a statistically significant increase in lung adenomas, and in adenomas plus carcinomas combined, in female mice at the highest dose level tested. There were also significant positive dose related trends for these tumor combinations in female mice. No significant increases in carcinomas were observed.

870.4200a Carcinogenicity Study  rat This study ( MRID No. 00112910) is presented in the Chronic Toxicity Section ( see 870.4100a) above.

870.4200b Carcinogenicity ( feeding)  Mouse In a carcinogenicity study ( MRID 00112911 and 92027038) cypermethrin ( 53 54% cis and 46 47% trans) was administered to groups of 70/ sex Swiss derived Alderley Park strain SPF mice at dose levels of control 1, control 2, 100, 400 and 1600 ppm ( corresponding to 0, 0, 14, 57 or 229 mg/ kg/ day) for 97 weeks for males and 101 weeks for females. Liver weight was increased at 57 mg/ kg/ day ( 20% absolute weight) and above in males and for females at the high dose only ( 15% for relative weight) at the interim sacrifice but not at the terminal. Other systemic effects were noted at 229 mg/ kg/ day included reduction in RBC parameters ( hemoglobin, hematocrit and RBC count in males, mean cell volume and hemoglobin) and platelet counts ( for males at interim but not terminal sacrifice) and neutrophils and body weight gain ( i. e. about 9% at week 6 for males and 12% for females at week 11). The LOAEL is 400 ppm ( 57 mg/ kg/ day) based on liver CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 21 weight. The NOAEL is 100 ppm ( 14 mg/ kg/ day). This study was determined to be positive for induction of benign alveologenic neoplasms. Adequacy of dosing for carcinogenicity is based upon typically 9% decreases in males and 12% in females in the first months of the study. This carcinogenicity study is classified acceptable and satisfies the guideline requirement for a carcinogenicity study ( 83 2) in mice.

4.7 Mutagenicity Adequacy of data base for Mutagenicity: The data base for Mutagenicity is considered adequate based on 1991 mutagenicity guidelines. Data requirements are satisfied by these submissions and no further studies are required. There was no evidence of mutagenic activity in any of the assays conducted with cypermethrin.

Gene Mutation Doses: 4, 20, 100, 500 or 2500 ug/ plate. No evidence of bacterial mutations in S. typhimurium strains TA 1535, TA 1537, TA 1538, TA 98 or TA 100 with and without metabolic activation ( S 9) at dose levels of 4, 20, 100, 500 or 2500 ug/ plate. Strains of yeast ( s. cerevisiae) also assessed and negative. ( MRIDs 00090037, 92027042, and 92027062; 00090036 and 00126834)

Cytogenetics There was no evidence of increased chromosome aberrations in chinese hamster bone marrow cells following gavage dosing with 0, 20 or 40 mg/ kg. ( MRID 00090038, 92027043, 92027063)

There was no evidence of dominant lethal activity in CD 1 strain mice at dose levels of control, 2.5, 5, 7.5 or 10 mg/ kg/ day for five consecutive days. An initial observation of a possible effect in a preliminary experiment with animals dosed at 2.5 or 5 mg/ kg for 5 days was not repeated at higher doses. ( MRID 00090039)

Unscheduled DNA Synthesis No evidence of induction of unscheduled DNA synthesis in vivo at dose levels of 100 and 200 mg/ kg by gavage in corn oil) in Alpk: APfSD strain rats ( males only) assessed 4 and 12 hours post dosing. The 200 mg/ kg dose was considered near the MTD and displayed toxic behavioral reactions. ( MRID 41599801)

4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: The data base for neurotoxicity is considered incomplete. A developmental neurotoxicity study is required. Gait abnormalities were observed in acute neurotoxicity studies conducted with cypermethrin. In an acute study with zcypermethrin evidence of neurotoxicity was also noted as clinical signs and treatment related changes in the FOB. In the subchronic mammalian neurotoxicity study conducted with CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 22 cypermethrin, gait abnormalites, increased landing foot splay, splayed hindlimbs and decreased body weight gains were observed. In a subchronic mammalian neurotoxicity study conducted with z cypermethrin, decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption were observed.

870.6200 Acute Neurotoxicity Screening Battery In an acute neurotoxicity screen, cypermethrin ( 95.5/ 95.7% purity, 1: 1 cis: trans) was administered once by gavage in corn oil to four groups of 12 hour fasted Sprague Dawley rats ( 10/ sex/ group) at doses of 0 ( corn oil only), 30, 100 or 200 mg/ kg. The rats were assessed at pretest, four hours after treatment and on days 7 and 14 for FOB and motor activity. After day 14, 5/ sex/ dose were prepared for neurohistopathology. ( MRID 43152001). At 100 mg/ kg, on days 0, 1 or 2 only, ataxia ( 2 males and 2 females) and related conditions ( staggered or impaired gait, decreased activity, splayed hindlimbs and limp condition) and decreased motor activity ( 49%, p< 0.001 for males and 33%, p< 0.01 for females) resulted. In addition, some females had salivation, lacrimation and/ or soiled fur. At 200 mg/ kg, one male and two females died on day 0; the majority of the following clinical signs were noted on day 0 in one or more of 7/ 10 males and 9/ 10 females: ataxia, staggered gait, abdominogenital staining, oral discharge and decreased locomotion. Neurohistopathologically, no treatment related lesions in any of the various structures were reported. Acceptable positive control data were provided by the sponsor. The LOAEL is 100 mg/ kg based primarily on ataxia and related conditions ( staggered or impaired gait, decreased activity, splayed hindlimbs and limp conditions in addition to decreased motor activity in males and females on days 0, 1 or 2). The NOAEL is 30 mg/ kg. This study is ACCEPTABLE and satisfies the requirement for an acute neurotoxicity screen ( 81 8, 870.6200) in rats.

Four groups of 8/ sex Charles River Long Evans rats were administered by gavage cypermethrin ( 97% a. i., 1: 1 ratios of cis and trans isomers) at single doses of 0 ( corn oil), 20, 60 or 120 ( FOB experiment)/ 100 ( motor activity) mg/ kg. Separate sets of animals were treated for the FOB and motor assessments. FOB was examined 1.5 and 3 hours post dosing. Motor activity was examined 3 hours post dosing. Both FOB and motor activity were also examined pretest as well as after 24 and 48 hours post dosing. During the FOB assessments, one male and 6 of 12 ( 8 original and 4 replacements) female rats dosed with 120 mg/ kg died. The dose was then reduced to 100 mg/ kg for the motor assessments and, at this level, two males and one female died ( symptoms prior to death not described). Transient weight losses of 7.5 and 9% for males and females were observed 24 hours postdosing in the highest dose ( persisted to 48 hours). No body weight effects at lower doses. There were gait and muscle effects as well as choreoathetosis. Motor activity was decreased for all doses groups for males ( estimated 45%, 66% and 85% for the 20, 60 and 100 mg/ kg groups, respectively). Gait abnormalities were noted in all dose groups ( males only at 20 mg/ kg) at 1.5 hours post dosing with the 60 and 100 mg/ kg rats showing progressively higher median scores. The high dose males and females showed gait abnormalities at 24 and possibly 48 hours. Effects were reported for males and females regarding the following parameters at 60 and 100 mg/ kg: salivation, urination, arousal, abnormal motor movement, forelimb or hindlimb grip strength, landing foot splay, righting reflex, touch response and tail CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 23 pinch response. [ Details of these effects were not included in the DER.] Regarding body temperature, the 20 mg/ kg males had statistically significant increased temperature at 1.5 hours ( 38.5 to slightly over 39 ° C; male and female 100 mg/ kg as well as male 60 mg/ kg had temperature decreased to below 37 ° C at 1.5 hours for females and 3 hours for males; and females were still decreased after 24 and 48 hours. No histopathology or perfusion data were included. The LOAEL for neurotoxicity was 20 mg/ kg based on decreased motor activity and gait abnormalities. The NOAEL was < 20 mg/ kg. This single dose neurotoxicity study is classified as SUPPLEMENTARY. It was in the form of a literature reprint and was not designed to meet a specific guideline protocol. [ Most of the data were presented in a semi quantitative manner and no individual animal data were presented to verify the observations.]

In an acute neurotoxicity screening battery study ( MRID 44962201), male and female Long Evans rats ( 10 animals/ sex/ group) were dosed once orally by gavage with undiluted zcypermethrin ( 84.4% a. i.) at levels of 0 ( water only), 10, 50 or 250 mg/ kg. The functional observational battery ( FOB) and motor activity were evaluated prior to treatment and on study days 0, 7 and 14 post dosing. At study termination, 5 animals/ sex/ dose were perfused in situ, and animals from the control and 250 mg/ kg dose groups were subjected to neuropathological examinations.

No treatment related findings were observed in the 10 mg/ kg group. Body weights, body weight gains, motor activity, gross pathology and neuropathology were unaffected by the test substance. At 50 mg/ kg, noted clinical observations included the following ( data presented as total occurrences/ number of animals): ( i) abdominogenital staining ( 1/ 1, both sexes); ( ii) oral discharge ( 1/ 1, males); ( iii) splayed hindlimbs ( 1/ 1, males); ( iv) staggered gait ( 2/ 2, males); and ( v) tremors ( 1/ 1, males). On day 0 during the homecage portion of the FOB, treatment related observations included the following: ( i) abnormal mobile posture ( 1/ 10, females); ( ii) splayed hindlimbs ( 1/ 10, females); ( iii) soiled fur ( males 2/ 10, females 1/ 10); and ( iv) unable to walk ( 1/ 10, females). All groups were comparable during the pretest evaluation and on test days 7 and 14. On day 0 during the open field portion of the FOB, treatment related observations noted in the females included the following: ( i) abnormal mobile posture ( 1/ 10); ( ii) unusual immobile posture ( 1/ 10); ( iii) severely impaired gait ( 1/ 10); ( iv) splayed hindlimbs ( 1/ 10); ( v) lands on back ( 1/ 10); ( vi) whole body tremors ( 1/ 10); and ( vii) convulsions ( 1/ 10). All female groups were comparable during the pretest evaluation and on test days 7 and 14. None of these findings were observed in the controls. At 250 mg/ kg, one female died on the day following test substance administration ( no cause of death determined). Clinical observations included the following ( data presented as total occurrences/ number of animals): ( i) abdominal gripping ( 1/ 1, females): ( ii) abdominogenital staining ( males 6/ 4, females 4/ 3); ( iii) ataxia ( 1/ 1, females); ( iv) decreased locomotion ( males 2/ 2, females 1/ 1); ( v) lacrimation ( 1/ 1, females); ( vi) loss of muscle control ( 1/ 1, females); ( vii) oral discharge ( males 3/ 3, females 2/ 1); ( viii) splayed hindlimbs ( males 2/ 2, females 3/ 2); ( ix) staggered gait ( 4/ 4, males); ( x) tremors ( 2/ 2, both sexes); ( xi) tonic clonic convulsions ( 2/ 2, females); and ( xii) vocalization ( 1/ 1, both sexes). These findings were not observed in concurrent controls. The only statistically significant ( p< 0.05) finding noted during the home cage portion of the FOB on day 0 was soiled fur in the males ( 4/ 10); this finding was not observed in any control animal. Other treatment related observations included the following: ( i) staggered gait ( 2/ 10, CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 24 males); ( ii) abnormal mobile posture ( males 1/ 10, females 3/ 10); ( iii) splayed hindlimbs ( males 1/ 10, females 2/ 10); ( iv) soiled fur ( 2/ 10, females); and ( v) inability to walk ( 1/ 10, females). Treatment related effects noted on day 0 during the open field portion of the FOB included the following: ( i) abnormal mobile posture ( males 1/ 10, females 3/ 10); ( ii) unusual immobile posture ( 1/ 10, females only); ( iii) staggered gait ( males 2/ 10, females 1/ 10); ( iv) splayed hindlimbs ( males 1/ 10, females  2/ 10); ( v) slightly impaired gait ( 1/ 10, both sexes); ( vi) moderately impaired gait ( 1/ 10, males only); ( vii) severely impaired gait ( 1/ 10, females only); ( viii) dragging hindlimbs ( 1/ 10, females only); ( ix) incoordinated landing ( 1/ 10, both sexes); ( x) lands on back ( 1/ 10, females only); ( xi) whole body tremors ( 3/ 10, females only); ( vii) convulsions ( 1/ 10, females only); and ( xiii) decreased activity ( 1/ 10, both sexes). None of these findings were observed in the controls. Acceptable positive control data were provided by the sponsor.

The acute neurotoxicity LOAEL is 50 mg/ kg based on clinical signs of toxicity and FOB findings. The acute neurotoxicity NOAEL for this study is 10 mg/ kg. This submitted study is classified as acceptable/ guideline ( 81 8[ a]; 870.6200) and satisfies the guideline requirements for an acute neurotoxicity screening battery in rats.

870.6200 Subchronic Neurotoxicity Screening Battery Cypermethrin ( 95.7% purity) was administered by dietary admix to four groups of 10/ sex Sprague Dawley strain rats at doses of 0, 500, 1300 or 1700 ppm ( mg/ kg/ day: 0, 31, 77 or 102 for males and 0, 37, 95 or 121 for females) for 90 days in a subchronic neurotoxicity study ( MRID 43152002). Rats were assessed twice daily for clinical signs and mortality; FOB and motor activity were examined pretest as well as at weeks 4, 8 and 13. Neurohistopathology was performed. MRID 43152002. At 1300 ppm, females displayed the following ( number of rats with sign/ total number of rats in the group): ataxia ( 1/ 10), splayed hindlimbs ( 5/ 10), impaired gait ( 4/ 10) and decreased feces ( 4/ 10) as well as decreased body weight gain ( 41%). Males had only decreased body weight gain ( 27%) and increased landing foot splay. At 1700 ppm, males showed ataxia ( 8/ 10) and additional related symptoms; females had decreased motor activity ( 27%). No test article related neurohistopathological lesions were reported. Acceptable positive control data were included. The LOAEL is 1300 ppm ( 77 mg/ kg/ day) based on the following: males = decreased body weight gain and increased landing foot splay; females = ataxia, splayed hindlimbs, impaired gait and decreased feces as well as decreased body weight gain. The NOAEL is 500 ppm ( 31 mg/ kg/ day). This study is ACCEPTABLE and satisfies the guideline ( 82 7, 870.6200) requirements for a subchronic neurotoxicity study in rats.

In this subchronic neurotoxicity screening battery, z cypermethrin, purity of 86.0% ( MRID 44962202), was administered continuously in the diet for 13 weeks to 10 Charles River Long Evans rats/ sex/ group at doses of 0, 75, 400 or 750 ppm ( equivalent to [ M/ F] 0/ 0, 5.0/ 5.9, 26.3/ 31.5, or 47.2/ 55.6 mg/ kg/ day). Five animals/ sex/ group were perfused for neurohistological examination, and the control and high dose animals were examined microscopically. Functional observational battery ( FOB) and motor activity were evaluated during the pretest interval, and following weeks 4, 8, and 13. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 25 No treatment related deaths occurred. Clinical signs, gross pathology and neuropathology were unaffected by the test substance; furthermore, no treatment related findings were noted in the home cage observations of the FOB at any dose. No treatment related findings were observed in the 75 ppm group. In the 400 ppm males, statistically significant decreases in body weights were observed at all intervals except week 3 ( 95 8%), p # 0.05); overall ( weeks 0 13) body weight gains were also decreased relative to concurrent controls in these animals ( 915%, p # 0.05). Decreased food consumption was observed throughout the study, but statistical significance was sporadic ( 96 17%, p # 0.01 or 0.05). During the open field portion of the FOB, increased landing foot splay was observed at week 13 ( 833%, p # 0.01). In addition, mean motor activity was decreased ( p # 0.01 or 0.05) at weeks 8 ( 936%) and 13 ( 951%). At 750 ppm, one female was sacrificed in extremis on day 51 following mechanical injury; this death was considered not to be treatment related. Body weights were decreased throughout the study ( 912 17%, p # 0.01) in the males. In the females, body weights were decreased sporadically for the first 9 weeks of the study, and continually at weeks 10 13 ( 95 10%, p # 0.05 or 0.01). Overall ( weeks 0 13) body weight gains were decreased ( p # 0.01) in both sexes ( 928 31%) as was food consumption ( 98 29%). During the open field portion of the FOB, increased landing foot splay was observed in the males at week 13 ( 841%, p # 0.01). Mean motor activity was decreased ( p # 0.05 or 0.01) in the males at weeks 8 ( 925%) and 13 ( 942%).

The LOAEL for this study is 400 ppm for males ( equivalent to 26.3 mg/ kg/ day), based on decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption; and 750 ppm for females ( equivalent to 55.6 mg/ kg/ day) based on decreased body weights, body weight gains, and food consumption. The NOAEL for this study is 75 ppm for males ( equivalent to 5.0 mg/ kg/ day) and 400 ppm for females ( equivalent to 31.5 mg/ kg/ day). The submitted study is classified as acceptable/ guideline ( § 82 7[ a]; 870.6200) and satisfies the guideline requirements for a subchronic neurotoxicity screening battery in rats.

4.9 Metabolism Adequacy of data base for metabolism: The data base for metabolism is considered to be complete. No additional studies are required at this time. Several studies with both rats, dogs, humans and mice are available to support the requirement for metabolism in mammals. Some of these studies assess individual cis and trans radiolabelled isomers and other studies assess the metabolism of cypermethrin with the label in either the cyclopropyl of the phenoxybenzyl ring. Cypermethrin is readily absorbed from the gastrointestinal tract and extensively metabolized. It mostly excreted in the urine that contains several characterized metabolites derived from conjugation of the hydrolysis products of the parent compound following cleavage of the esteratic linkage site.

870.7485 Metabolism  Rat First Study. First group. Six/ sex rats Wistar strain rats were dosed with a single dose 0.61 mg/ animal of labelled cis cypermethrin isomers in 0.5 ml of corn oil. The rats were individually CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 26 housed in metabolism cages and their urine and fecal matter collected daily until sacrifice. Two rats of each sex were sacrificed after 24 and 72 hours and after eight days. Samples of the blood and selected tissues were assessed for radioactivity content. Second group. Three/ sex rats were dosed with 0.615 mg/ animal of labelled trans cypermethrin in 0.8 ml of corn oil. In addition to the urine and fecal collections, expired air was also collected from one male and one female. MRID No. 41551102. Total recovery was from 97.2 to 100.5%. About 70% of cis and 80% of trans cypermethrin was excreted in 24 hours. Essentially all was excreted in 8 days. Most of the label was excreted in the urine (> 53%) with less in the feces and (< 20%) for the trans ( males and females) and cis ( males only) groups and < 1% in the air for all groups. A sex difference with respect to excretion in the urine from the cis isomer was noted for females since about equal amounts ( 35%) were found in both the urine and feces. Several urinary and fecal metabolites were tentatively characterized.

Second Study. One group of three/ sex Wistar strain rats was dosed with a single oral dose ( approximately 1.3 mg/ kg) of 14C cyclopropyl labelled cypermethrin in corn oil ( 0.8 ml). The rats were then placed in glass metabolism cages and their urine and feces were collected. Special metabolism cages for trapping any radioactivity expired through their respiratory system were used for one male and female rat. The rats were sacrificed after three days and their blood and selected tissues were assessed for radioactivity. MRID No. 41551103. 85.5% for males and 97.2% for females of 14C was excreted in 72 hours. The urine ( 55.8% for males and 69.4% for females) was the major route of excretion with the feces containing the balance. The air contained only 0.1% or less. Tissue retention was highest in the skin ( 1.2%) and liver ( 0.74% for males but only 0.18% for females) and fat ( 0.57 to 0.66%).

Third Study. In a series of nine different studies, labelled cypermethrin ( 1 mg/ kg or less) in corn oil or separated cis or trans cypermethrin isomers were given by gavage to single or groups of two or three Wistar strain rats. Their urine and in some cases fecal matter were collected at various intervals such as 18 hours to 3 days. In another set of experiments, labelled cypermethrin was administered to rats that were fitted with bile duct cannalulas and their bile collected for 4 5 hours while the rat was under anesthesia. MRID No. 41551104. cis and trans 14C cyclopropyl labelled cypermethrin was demonstrated to form glucuronide conjugations of cis and trans acids and hydroxyacids. Only 1.6% or less of the total dose is excreted in the bile. Most of the cypermethrin in the feces was unmetabolized. The glucuronide conjugates in the urine were found to be unstable and subject to hydrolysis.

In addition to the above studies, other data on the metabolism of cypermethrin in rats can be found in MRID Nos.: 00056806, 00056807, 00056809, 00056810 and 00056812 and in 00089002, 00089003 and 00089004 that supports the observations reported above. Also other studies demonstrate the metabolism and pharmacokinetics in mice is similar to that of the rat ( MRID Nos.: 00089007, 00089008 and 00089009) and dogs ( 00089010, 00089011, 00089012 and 00089013).

870.7485 Metabolism  Human CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 27 This dermal metabolism study in the human was designed to determine the quantitative urinary excretion of three cypermethrin metabolites following dermal application to six male human subjects ( MRID 43261603). The metabolites analyzed were dichlorovinyldimethylcyclopropanecarboxylic acid ( DCVA), 3 phenoxybenzoic acid ( 3PBA) and 3( 4' hydroxy) phenoxybenzoic acid ( 4OH3PBA).

Mean total DCVA excretion was 0.33% of the administered dose. However, considering that DCVA is further metabolized this value would under estimate dermal absorption. The sum of 3PBA and 4OH3PBA excretion ranged from 0.85 to 1.77% ( mean 1.23%). Because cypermethrin is hydrolized to yield equimolar quantities of DCVA and 3PBA these values are not additive.

870.7600 Dermal Absorption  Rat There is no series 85 2 dermal penetration/ absorption study available. Dermal absorption was estimated by comparing the developmental rat study with the 21 day dermal study in the rat, both with z cypermethrin ( see Section 5.2 below).

5.0 TOXICITY ENDPOINT SELECTION On November 16 and December 19, 2000 ( HED Doc. No. 014445), the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reviewed the recommendations of the toxicology reviewer for both cypermethrin and zcypermethrin with regard to the acute and chronic Reference Doses ( RfDs) and the toxicological endpoint selection for use as appropriate in occupational/ residential exposure risk assessments. This was a re evaluation of previous HIARC ( 2000 and 1997) and RfD ( 1996) Committee decisions. The December 19 meeting was a re evaluation of the dermal absorption value determined on November 16. The potential for increased susceptibility of infants and children from exposure to either cypermethrin and/ or z cypermethrin was previously evaluated on September 19, 2000 as required by the Food Quality Protection Act ( FQPA) of 1996. On January 22, 2003 the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reassessed FQPA requirements in response to questions posed by the Natural Resources Defense Council ( NRDC). HIARC also reviewed the previous recommendation for a developmental neurotoxicity study in rats and subsequent need for a data base factor to account for this data gap. No new data have been reviewed and no changes were made to the toxicology endpoints previously selected for cypermethrin and z cypermethrin.

5.1 See Section 8.2 for Endpoint selection table.

5.2 Dermal Absorption Dermal Absorption Factor: 2.5% CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 28 A dermal absorption value was estimated by comparing the developmental rat study with the 21 day dermal study in the rat, both conducted with z cypermethrin. Using a comparison of the maternal LOAEL of 25 mg/ kg/ day from the developmental study in the rat and the NOAEL ( highest dose tested) of 1000 mg/ kg/ day from the 21 day dermal study in the rat, dermal absorption would be estimated to be less than 2.5%. Since there was no common endpoint because no effects were observed in the 21 day dermal study in the rat, this is considered to be a worst case estimate ( i. e. the dose level of 1000 mg/ kg/ day was considered to be the LOAEL).

The dermal absorption factor is required for the long term dermal risk assessment since an endpoint from an oral study was selected for this exposure period.

5.3 Classification of Carcinogenic Potential 5.3.1 The HIARC Concluded Carcinogenicity studies in rats ( MRID 00112910, 09202741) and mice ( MRID 00112911, 092027038) were acceptable. Cypermethrin produced a statistically significant increase in lung adenomas, and in adenomas plus carcinomas combined, in female mice at the highest dose level tested. There were also significant positive dose related trends for these tumor combinations in female mice. No significant increases in carcinomas were observed. No evidence of carcinogenicity was observed in rats.

5.3.2 Classification of Carcinogenic Potential The HED Cancer Peer Review Committee classified cypermethrin as a category C oncogen ( possible human carcinogen). The evidence ( common tumor, one species ( mice), one sex ( female), no increase in the proportion of malignant tumors or decrease in the time to tumor occurrence, and lack of mutagenic activity) was not considered strong enough to warrant a quantitative estimation of human risk ( Cancer Peer Review Committee, 1988).

5.3.3 Quantification of Carcinogenic Potential The quantification of cancer risk will not be conducted ( see Section 5.3.2).

6.0 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children The FQPA Safety Factor Committee evaluated the available hazard and exposure data for cypermethrin and z cypermethrin on October 23, 2000 and made the recommendation for the FQPA safety factor to be used in human health risk assessments ( as required by Food CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 29 Quality Protection Act of August 3, 1996). The committee concluded that the FQPA safety factor could be removed ( 1x) in assessing the risk posed by these chemicals. The data demonstrated no indication of increased susceptibility of rats or rabbits to in utero and/ or postnatal exposure to either cypermethrin or z cypermethrin.

On January 22, 2003 the Health Effects Division ( HED) Hazard Identification Assessment Review Committee ( HIARC) reassessed FQPA requirements in response to questions posed by the Natural Resources Defense Council ( NRDC). HIARC also reviewed the previous recommendation for a developmental neurotoxicity study in rats and subsequent need for a data base factor to account for this data gap. No new data had been reviewed and no changes were made to the toxicology endpoints previously selected for cypermethrin and zeta cypermethrin. The HIARC reaffirmed that the special FQPA safety factor should be 1X since there are no residual uncertainties for pre and/ or post natal toxicity.

6.2 Recommendation for a Developmental Neurotoxicity Study The HIARC concluded that there is a concern for developmental neurotoxicity resulting from exposure to cypermethrin and/ or zeta cypermethrin.

On November 16 and December 19, 2000, HIARC recommended that a developmental neurotoxicity study in rats be conducted with zeta cypermethrin based on the following considerations:

C The cypermethrins induce clinical signs of neurotoxicity in at least two species ( rats and dogs).

C There was suggestive evidence of neuropathology ( electron microscope) in a subchronic feeding study in rats conducted with cypermethrin. This study was conducted in 1980. Electron microscopy is not the usual method of examination of tissues.

C In the acute neurotoxicity study conducted with z cypermethrin, there were symptoms related to loss of muscle control, gait abnormalities, decreased motor activity, convulsions, tremors, abdominal gripping and vocalization. In the acute neurotoxicity study conducted with cypermethrin, ataxia and related conditions ( staggered or impaired gait, decreased activity, splayed hindlimbs and limp condition) and decreased motor activity were observed.

C In the subchronic neurotoxicity study conducted with z cypermethrin, there was increased landing foot splay and decreases in mean motor activity. In the subchronic neurotoxicity study with cypermethrin, ataxia, splayed hindlimbs, impaired gait, increased landing foot splay, and decreased motor activity were observed.

C The cypermethrins are members of the synthetic pyrethroid class of insecticides, which are known to induce transient tremors in mammals.

Evidence to the contrary included: CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 30 C There was no indication of increased sensitivity of rats or rabbits to in utero and/ or postnatal exposure to either z cypermethrin or cypermethrin.

C There is no indication of light microscopy neuropathology with at least 15 other pyrethroids in standard toxicity studies. Mammalian neurotoxicity testing with this group of chemicals has only recently been initiated.

C No neuropathology has been observed in either the acute or subchronic mammalian neurotoxicity studies.

C No malformations of the central nervous system were observed in the developmental and reproduction studies.

On January 22, 2003, based on the weight of evidence presented, the HIARC reaffirmed the previous conclusion that a developmental neurotoxicity ( DNT) study conducted with zeta cypermethrin in rats is required. HIARC determined that a 10X database uncertainty factor ( UF DB ) is needed to account for the lack of the DNT since the available data provide no basis to support reduction or removal of the default 10X factor. The following points were considered in this determination: ° It is assumed that the DNT study will be conducted at dose levels similar to those used in the rat reproduction study with zeta cypermethrin ( 0.5, 1.8, 7, 27, 45 mg/ kg/ day) wherein the offspring NOAEL / LOAEL was 7 / 27 mg/ kg/ day, respectively. ° It is possible that the results of the DNT study could impact the current selected regulatory doses since the NOAELs used for risk assessment endpoints ( e. g., 10 mg/ kg/ day for acute and 6 mg/ kg/ day for chronic) are approximately the same order of magnitude as the offspring NOAEL in the rat reproduction study conducted with zeta cypermethrin ( 7 mg/ kg/ day).

Therefore, a UF DB of 10X will be applied to account for the lack of the DNT study with zeta cypermethrin. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 31 7.0 REFERENCES No MRID Katherine L. McDaniel and Virginia C. Moser, " Utility of a Neurobehavioral Screening Battery for Differentiating the Effects of Two Pyrethroids, Permethrin and Cypermethrin", Neurotoxicology and Teratology 15: 71 83 ( 1993).

00056800 Henderson, C.; Oliver, G. A.; Smith, I. K.; et al. ( 1980) Cypermethrin ( PP383): Acute Toxicity and Local Irritation: Report No. CTL/ P/ 537. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Imperial Chemical Industries, Ltd., United Kingdom, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 B)

00056802 Glaister et. al. ( 1980) PP383: 90 Day Feeding Study in Rats: Study No.: CTL/ P/ 327. Unpublished Study Prepared by ICI Central Toxicology Laboratory.

00056804 Tesh, J. M.; Tesh, S. A.; Davies, W. ( 1978) WL 43467: Effects upon the Progress and Outcome of Pregnancy in the Rat: LSR Report No. 78/ SHL2/ 364. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Life Science Research, England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 F)

00056805 Dix, K. M.; Van der Pauw, C. L.; Whitaker, J.; et al. ( 1978) Toxicity of WL 43467: Teratological Studies in Rabbits Given WL 43467Orally: Group Research Report TLGR. 0010.78. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 G)

00056806 Crawford, M. J.; Croucher, A.; Hutson, D. H.; et al. ( 1980) The Metabolism of WL 43467 in Mammals ( 1). The Fate of a Single Oral Dose of ¢ ¬ 14æC Benzyl| WL 43481 (~ Cis~ WL 43467) in the Rat: Group Research Report TLGR. 0046.76. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 H)

00056807 Crawford, M. J.; Croucher, A.; Stevenson, D. E.; et al. ( 1980) The Metabolism of WL 43467 in Mammals. The Fate of a Single Oral Dose of ¢ ¬ 14æC| WL 42641 (~ trans~ WL 43467) in the Rat: Group Research Report TLGR. 0077.76. ( Unpublished study received Dec 29 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 I) CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 32 00056808 Crawford, M. J.; Hutson, D. H.; Bryant, P.; et al. ( 1980) The Metabolic Fate of the~ cis~ and~ trans~ Isomers of WL 43467 ( Cypermethrin). Metabolism and Elimination of ¬ 14æC Aryl Labelled '~ cis~ and~ trans~ isomers in rats: Group Research Report TLGP. 0131.77. ( Unpublished study received Dec 19, 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 J)

00056809 Crawford, M. J.; Croucher, A.; Stevenson, D. E.; et al. ( 1980) The Metabolism of WL 43467 in Mammals. The Fate of a Single Oral Dose of ¢ ¬ 14æCCyclopropyl WL 43467 in the Rat: Group Research Report TLGR. 0004.77. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 K)

00056810 Crawford, M. J.; Hutson, D. H.; Croucher, A.; et al. ( 1980) The Metabolic Fate of the~ cis~ and~ trans~ Isomers of Cypermethrin in the Rat. Metabolites Derived from the ¬ 14æC Labelled Cyclopropyl Ring: Group Research Report TLGR. 0183.78. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 L)

00056811 Crawford, M. J.; Hutson, D. H.; Moss, P. A.; et al. ( 1980) The Elimination of Residues from the Fat of Rats following the Oral Administration of ¢ ¬ 14æCBenzyl WL 43481 (~ cis~ WL 43467): Group Research Report TLGR. 0078.78. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 M)

00056812 Crayford, J. V.; Fish, A.; Hutson, D. H. ( 1980) A Study of the Metabolism of 3 phenoxybenzoic acid and Its Glucoside Conjugate in Rats: Group Research Report TLGR. 0186.78. ( Unpublished study received Dec 29, 1980 under 10182 EX 19; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 099855 N)

00089002 Logan, C. J.; Hutson, D. H. ( 1980) Cypermethrin: Excretion and Retention of Cypermethrin and Its Metabolites in Rats following a Single Oral Dose ( 1~ ca~ 1200 mg/ kg): TLER. 80.083; UR 0126. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 A) CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 33 00089003 Hall, B. E.; Vickers, J. A.; Hopkins, R. ( 1981) ( ¼ 14: C) Cypermethrin: A Study To Determine the Bioaccumulation of Radioactivity in the Rat Following Repeated Oral Administration: Report No. 2487 72/ 201; CTL/ C/ 1059. Final rept. ( Unpublished study received Dec30, 1981 under 10182 64; prepared by Hazleton Laboratories Europe, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 B)

00089004 Jones, B. K.; Rhodes, C. ( 1981) Cypermethrin: Bioaccumulation Study in the Rat: Report No. CTL/ P/ 599. Final rept. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by ImperialChemical Industries, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 C)

00089007 Hutson, D. H.; Fish, A. ( 1978) The Elimination of Radioactivity by Mice following Oral Dosing with ¼ 14: C 1~ cis~ 1 and ¼ 14: C 1~ trans~ 1 WL 43467 ( Cypermethrin): TLRG. 0079.78. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 H)

00089008 Crawford, M. J.; Hutson, D. H.; Moss, P. A.; et al. ( 1978) The Elimination of Residues from the Fat of Mice following the Oral Administration of ó ¼ 14: C Benzyl| WL 43481 ( 1~ cis~ 1 WL 43467): TLGR. 0080.78. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 I)

00089009 Hutson, D. H.; Casida, J. E.; Fish, A. ( 1978) The Metabolites of 1~ cis~ 1 and1~ trans~ 1 cypermethrin ( WL 43467) in Mice: TLGR. 0102.78. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England and Univ. of California Berkeley, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 J)

00089010 Crawford, M. J.; Crayford, J. V.; Croucher, A.; et al. ( 1979) The Metabolism of Cypermethrin ( WL 43467) in Mammals: The Fate of Single Oral Doses of~ cis~ and~ trans~ ó ¼ 14: C Benzyl| cypermethrin in the Dog: TLGR. 0011.79. ( Unpublished study received Dec 30, 1981under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 L)

00089011 Crawford, M. J.; Croucher, A.; Cheeseman, M. E.; et al. ( 1979) The Metabolic Fate of the1~ cis~ 1 and1~ trans~ 1 Isomers of WL 43467 ( cypermethrin) and of 3 Phenoxybenzoic Acid in Dogs: TLGR. 79.012. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 M) CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 34 00089012 Crawford, M. J.; Cheeseman, M. E.; Crayford, J. V.; et al. ( 1979) The Metabolism of Cypermethrin ( WL 43467) in Mammals: The Fate of a Single Oral Dose of ó ¼ 14: C Cyclopropyl| cypermethrin in the Dog: TLGR. 79.029. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 N)

00089013 Crawford, M. J.; Croucher, A.; Fish, A.; et al. ( 1979) The Metabolism of Cypermethrin ( WL 43467) in Mammals: Metabolites Derived from a Single Oral Dose of ó ¼ 14: C Cyclopropyl| cypermethrin in the Dog: TLGR. 79.096. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070565 O)

00090035 Henderson, C.; Parkinson, G. R.; Smith, I. K. ( 1981) Cypermethrin Technical: Subacute Dermal Toxicity Study in Rabbits: Report No. CTL/ P/ 588. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Imperial Chemical Industries, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070564 C)

00090036 Brooks, T. M.; Dean, B. J.; Gonzalez, L. P.; et al. ( 1980) Toxicity Studies with Agricultural Chemicals: Mutagenicity Studies with Ripcord in Microorganisms~ in vitro~ and in the Host mediated Assay: Group Research Report TLGR. 80.059. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070564 D)

00090037 Trueman, R. W.; Longstaff, E. ( 1981) An Examination of Cypermethrin for Potential Mutagenicity Using the~ Salmonella~ 1/ Microsome Reverse Mutation Assay: Report No. CTL/ P/ 595. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Imperial Chemical Industries, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070564 E)

00090038 Dean, B. J.; Thorpe, E.; Stevenson, D. E. ( 1980) Toxicity Studies with WL 43467: Chromosome Studies on Bone Marrow Cells of Chinese Hamsters after Two Daily Oral Doses of WL 43467: Group Research Report TLGR. 0136.77. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070564 F)

00090039 Dean, B. J.; Van der Pauw, C. L.; Butterworth, S. T. G.; et al. ( 1980) Toxicity Studies with WL 43467: Dominant Lethal Assay in Male Mice after Single Oral Doses of WL 43467: Group Research Report TLGR. 0042.77. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Toxicology Laboratory, England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070564 G) CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 35 00090040 Hend, R. W.; Hendy, R.; Fleming, D. J. ( 1972?) Toxicity Studies on the Insecticide WL 43467: A Three Generation Reproduction Study in Rats: Group Research Report TLGR. 0188.78. ( Unpublished study received Dec 30, 1981 under 10182 64; prepared by Shell Research, Ltd., England, submitted by ICI Americas, Inc., Wilmington, Del.; CDL: 070564 H)

00112909 Ishmael, J.; Kalinowski, A.; Banham, P.; et al. ( 1982) Cypermethrin: One Year Oral Dosing Study in Dogs: Report No. CTL/ P/ 703. ( Unpublished study received Sep 1, 1982 under 2F2623; prepared by Imperial Chemical Industries PLC, Eng., submitted by ICI Americas, Inc., Wilmington, DE; CDL: 071069 B)

00112910 Milburn, G.; Forbes, D.; Banham, P.; et al. ( 1982) Cypermethrin: 2 Year Feeding Study in Rats: Report No. CTL/ P/ 669. ( Unpublished study received Sep 1, 1982 under 2F2623; prepared by Imperial Chemical Industries PLC, Eng., submitted by ICI Americas, Inc., Wilmington, DE; CDL: 071070 A; 071071)

00112911 Lindsay, S.; Banham, P.; Chart, I.; et al. ( 1982) Cypermethrin: Lifetime Feeding Study in Mice: Report No. CTL/ P/ 687. ( Unpub lished study received Sep 1, 1982 under 2F2623; prepared by Imperial Chemical Industries PLC, Eng., submitted by ICI Americas, Inc., Wilmington, DE; CDL: 071072 A; 071073)

00112912 Milburn, G.; Banham, P.; Birtley, R.; et al. ( 1982) Cypermethrin: Three Generation Reproduction Study in the Rat: Report No. CTL/ P/ 683. ( Unpublished study received Sep 1, 1982 under 2F2623; prepared by Imperial Chemical Industries PLC, Eng., submitted by ICI Americas, Inc., Wilmington, DE; CDL: 071074 A; 071075)

00112929 Buckwell, A.; Butterworth, S.; Stevenson, D. ( 1977) Toxicity Stud ies on the Pyrethroid Insecticide WL 43467: A 13 week Feeding Study in Dogs: TLGR. 0127.77, Experiment No. 1112. ( Unpublished study received Apr 15, 1981 under 10182 EX 19; prepared by Shell Research, Ltd., Eng., submitted by ICI Americas, Inc., Wilming ton, DE; CDL: 071077 A)

00164942 Barnham, J. ( 1986) Cypermethrin 90 Day Dog Study: Dietary Analysis: TLGR. 0127.77. Unpublished study prepared by Shell Inter national Chemical Co. Limited. 5 p.

40377701 Barber, J. ( 1984) Cypermethrin 70% Technical Material: Acute Oral Toxicity, Acute Dermal Toxicity, Skin and Eye Irritation and Skin Sensitization Studies: Laboratory Project ID CTL/ P/ 866. Unpublished study prepared by ICI Central Toxicology Laboratory. 107 p. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 36 41551101 McGregor, D.; Riach, C. ( 1982) Cypermethrin: Assessment of Mutagenic Potential in the Mouse Lymphoma Assay: Lab Project Number: TL/ C/ 1201. Unpublished study prepared by Inversek Research International. 32 p.

41551102 Crawford, M.; Huston, D. ( 1977) Cypermethrin: The Metabolic Fate of the Cis and Trans Isomers of WL 43467 ( Cypermethrin): Metabolism and Elimination of óCarbon 14| Aryl Labelled Cis and Trans Isomers in Rats: Lab Project Number: CTL/ C/ 1146. Unpublished study prepared by Shell Research Ltd. 25 p.

41551103 Crawford, M. ( 1977) Cypermethrin: The Metabolism of WL 43467 in Animals: The Fate of a Single Oral Dose of ó14 Cyclopropyl| WL 43467 in the Rat: Lab Project Number: CTL/ C/ 1147. Unpublished study prepared by Shell Research Ltd. 14 p.

41551104 Crawford, M.; Hudson, D. ( 1978) Cypermethrin: The Metabolic Fate of Cis and Trans Isomers of Cypermethrin in the Rat:: Lab Project Number: CTL/ C/ 1154. Unpublished study prepared by Shell Research Ltd. 30 p.

41599801 Kennelly, J. ( 1990) Cypermethrin: Assessment for the Induction of Unscheduled DNA Systhesis in Rat Hepatocytes in vivo: Lab Project Number: CTL/ P/ 3080; SR0449. Unpublished study prepared by ICI Central Toxicology Laboratory. 44 p.

41776101 McCarty, J. ( 1990) FMC 56701 Technical: Ninety Day Feeding Study in Rats: Lab Project Number: A89 2880. Unpublished study prepared by FMC Corp. 511 p.

41776102 Hoberman. A. ( 1990) Developmental Toxicity ( Enbryo Fetal Toxicity and Teratogenic Potential) Study of FMC 56701 Technical Administered Orally via Gavage to Crl: CD ( SD) BR Presumed Pregnant Rats: Lab Project Number: 106 006: FMC A89 2958. Unpublished study prepared by Angus Research Laboratories, Inc. 210 p.

41968204 Hoberman, A. ( 1991) Multigeneration Study with FMC 56701 Technical Administered Orally via Diet to Crl: CD ( SD) BR Rats: Lab Project Number: A89 2959: 106 007. Unpublished study prepared by Argus Research Laboratories, Inc. 1211 p.

42068502 Berry, D. ( 1991) Addendum to Phase 3 Summary of MRID No. 112929 and 164942, Toxicity Studies on the Pyrethroid Insecticide Cypermethrin ( WL43467): A 13 Week Feeding Study in Dogs: Lab Project Number: TLGR. 0127.77. Unpublished study prepared by Shell Toxicology Laboratory. 6 p. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 37 42068503 Berry, D. ( 1991) Addendum to Phase 3 Summary of MRID No. 112909, Cypermethrin: One Oral Dosing in Dogs: Lab Project Number: CTL/ P/ 703. Unpublished study prepared by ICI Central Toxicology Lab. 5 p.

42068504 Berry, D. ( 1991) Addendum to Phase 3 Summary of MRID No. 112912, Cypermethrin: Three Generation Reproduction Study in the Rat: Lab Project Number: CTL/ P/ 683. Unpublished study prepared by ICI Central Toxicology Lab. 6 p.

42068505 Berry, D. ( 1991) Addendum to Phase 3 Summary of MRID No. 56804, Cypermethrin ( WL43467): Effect Upon the Progress and Outcome of Pregnancy in the Rat: Lab Project Number: CTL/ C/ 1054. Unpublished study prepared by Life Science Research. 4 p.

42395702 Mount, E. ( 1992) Cypermethrin Technical: Acute Inhalation Toxicity Study in Rats: Lab Project Number: A91 3534. Unpublished study prepared by FMC Corp. 53 p.

43152001 Freeman, C. ( 1994) Cypermethrin Technical: Acute Neurotoxicity Screen in Rats: Lab Project Number: A92/ 3542. Unpublished study prepared by FMC Corp. 571 p.

43152002 Freeman, C. ( 1993) Cypermethrin Technical: Subchronic Neurotoxicity Screen in Rats: Lab Project Number: A92/ 3543. Unpublished study prepared by FMC Corp. 608 p.

43261603 Woollen, B. H..; Marsh, J. R.; Thomley, K. F. ( 1992) Cypermethrin: Pharmacokinetics in Man Following a Single Dermal Dose: Lab Project Number: CTL/ R/ 1077. Unpublished study prepared by Zeneca Central Toxicology Laboratory.

43507101 Parr Dobrzanski, R. ( 1994) Cypermethrin: 21 Day Sub acute Inhalation Toxicity Study in the Rat: Lab Project Number: CTL/ P/ 4534: MR0165. Unpublished study prepared by Zeneca Central Toxicology Lab. 401 p.

43776301 Freeman, C. ( 1994) Cypermethrin Technical: Pilot OralTeratology Study in Rabbits: Lab Project Number: A93 3823: ATM 0179: GQA 82 1. Unpublished study prepared by FMC Corp. 150 p.

43776302 Freeman, C. ( 1994) Cypermethrin Technical: Oral Teratology Study in Rabbits: Lab Project Number: 93 4063: A93 3822: 93 8242. Unpublished study prepared by FMC Corp. 335 p. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 38 44527002 Daly, I. ( 1994) A Subchronic ( 3 month) Oral Toxicity Study of FMC 30980 Technical in the Dog Via Dietary Administration: Final Report: Lab Project Number: 92 3114: A92 3706: 92 8122. Unpublished study prepared by Pharmaco LSR Inc. 480 p.

44536801 Daly, I. ( 1995) A Chronic ( 12 Month) Oral Toxicity Study of FMC 30980 Technical in the Dog via Dietary Administration: Final Report: Lab Project Number: 92 3115: A93 3821: 92 8123. Unpublished study prepared by Pharmaco LSR, Inc. 876 p.

44962201 Watt, B. ( 1998) FMC 56701 Technical: Acute Neurotoxicity Screen in Rats: Lab Project Number: A97 4642: P97 0141: P 3261. Unpublished study prepared by FMC Corporation. 336 p.

44962202 Freeman, C. ( 1999) Zeta cypermethrin Technical: Subchronic Neurotoxicity Screen in Rats: Lab Project Number: A98 4874: P98 0166: 194TST98403. Unpublished study prepared by FMC Corporation. 377 p.

45010401 Freeman, C. ( 1999) Zeta cypermethrin Technical 21 Day Repeated Dose Dermal Study in Rats: Lab Project Number: A98 4885: 194TST98403: 240. Unpublished study prepared by FMC Corp. 297 p.

92027034 Barber, J. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00056802. Cypermethrin ( PP383): 90 Day Feeding Study in Rats: CTL Report No.: CTL/ P/ 327; CTL Study No.: PR0044.: 10 p.

92027036 McCall, J. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00090035. Cypermethrin Technical: Subacute Dermal Toxicity Study in Rabbits: CTL Report No.: P/ 588; CTL Study No.: LB0019. Prepared by ICI Central Toxicology Laboratory. 8 p.

92027037 Guttmann, E. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00112909. Cypermethrin: One Year Oral Dosing Study in Dogs: CTL Report No.: CTL/ P/ 703; CTL Study No.: PD0398.: 8 p.

92027038 Barber, J. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00112911 and Related MRIDs 00133338, 00163497. Cypermethrin: Lifetime Feeding Study in Mice: CTL Report Nos.: CTL/ P/ 687, CTL/ P/ 687A, CTL/ P/ 1614; CTL Study No.: PM0366.: 8 p.

92027039 Guttmann, E. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00056804. Cypermethrin ( WL43467): Effects Upon the Progress and Outcome of Pregnancy in the Rat: Life Science Report No.: 78/ SHL2/ 364; CTL Report No.: CTL/ C/ 1054.: 7 p. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 39 92027040 Guttmann, E. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00112912. Cypermethrin: Three Generation Reproduction Study in the Rat: CTL Report No.: CTL/ P/ 683; CTL Study No.: RR0143.: 9 p.

92027041 Barber, J. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00112910. Cypermethrin: 2 Year Feeding Study in Rats: CTL Report No.: CTL/ P/ 669; CTL Study No,: PR0352.: 9 p.

92027042 Callander, R. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00090037. An Examination of Cypermethrin for Potential Mutagenicity Using the Salmonella/ Microsome Reverse Mutation Assay: CTL Report No.: CTL/ P/ 595; CTL Study Nos.: YV0017, YV0026, YV0199. Prepared by ICI Central Toxicology Laboratory. 7 p.

92027043 Mackay, J. ( 1990) ICI Americas Inc. Phase 3 Summary of MRID 00090038. Toxicity Studies with WL 43467: Chromosome Studies on Bone Marrow Cells of Chinese Hamsters after Two Daily Oral Doses of WL 43467: Report No.: TLGR. 0136.77; Study No.: 1110; CTL Report No.: CTl/ C/ 1052. Prepared by Shell Research Ltd. 6 p.

92027061 Tesh, J.; Tesh, S.; Davies, W. ( 1990) ICI Americas Inc. Phase 3 Reformat of MRID 00056804. Cypermethrin ( WL43467): Effects upon the Progress and Outcome of Pregnancy in the Rat: Life Science Research Report No. 78/ SHL2/ 364; CTL Report No.: CTL/ C/ 1054. Prepared by Life Science Research Ltd. 40 p.

92027062 Trueman, R, ( 1990) ICI Americas Inc. Phase 3 Reformat of MRID 00090037. An Examination of Cypermethrin for Potential Mutagenicity Using the Salmonella/ Microsome Reverse Mutation Assay: CTL Report No.: CTL/ P/ 595; CTL Study Nos.: YV0017, YV0199, YV0026. Prepared by ICI Central Toxicology Laboratory. 40 p.

92027063 Dean, B. ( 1990) ICI Americas Inc. Phase 3 Reformat of MRID 00090038. Toxicity Studies with WL 43467: Chromosome Studies on Bone Marrow Cells of Chinese Hamsters After Two Daily Oral Doses of WL 43467: Shell Report No.: TLGR. 0136.77; Shell Study No.: 1110; CTL Report No.: CTL/ C/ 1052. Prepared by Shell Toxicology Laboratory, Shell Research Centre. 23 p. 8.0 APPENDICES Tables for Use in Risk Assessment CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 41 8.1 Toxicity Profile Summary Tables 8.1.1 Acute Toxicity Table  See Section 4.1 8.1.2 Subchronic, Chronic and Other Toxicity Table*

Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Resultsa 870.3100 90 Day oral toxicity  rat MRID 00056802 & 92027034 ( 1980)/ Unacceptable ppm = 0, 75, 150 or 1500 mg/ kg/ day = 0, 3.75, 7.5 or 75 NOAEL = 7.5 mg/ kg/ day LOAEL = 75 mg/ kg/ day based on decreased body weight in both sexes.

870.3100 90 Day oral toxicity  rat: zcypermethrin MRID 41776101 ( 1990)/ Acceptable ppm = 0, 10, 50, 150, 250, 500 or 900 mg/ kg/ day = M: 0, 0.6, 2.7, 8.4, 13.8, 28.2 or 55.7; F: 0, 0.6, 3.3, 9.6, 16.3, 32.2 or 65.2 NOAEL = M = 13.8 ( M), 16.3 ( F) mg/ kg/ day LOAEL = 28.2 mg/ kg/ day ( M) based on decreased body wt, body wt gain and food consumption; at 55.7 mg/ kg/ day, mortality as well as decreased RBC, WBC, HGB & HCT plus increase in BUN. 32.2 mg/ kg/ day ( F) based on decreased body wt, body wt gain and food consumption as well as interference with estrous cycle and decreased glucose; mortality at 65.2 mg/ kg/ day.

870.3150 90 Day oral toxicity in dogs ( feeding) MRID 44527002 ( 1994)/ Acceptable ppm = 0, 300, 600, 800 or 1100 mg/ kg/ day = M: 0, 10.4, 20.7, 24.6 or 37.0 F: 0, 12.2, 25.4, 34.3 or 45.2 NOAEL = 24.6 ( M), 34.3 ( F) mg/ kg/ day LOAEL = 37.0 ( M), 45.2 ( F) mg/ kg/ day based on tremors as well as decreased body wt and body wt gains in both sexes.

870.3150 90 Day oral toxicity in dogs ( feeding) MRID 00112929 ( 1977)/ Unacceptable ppm = 0, 5, 50, 500 or 1500 mg/ kg/ day = 0, 0.125, 1.25, 12.5 or 37.5 NOAEL = 12.5 mg/ kg/ day LOAEL = 37.5 mg/ kg/ day based on clinical signs ( whole body tremors, exaggerated gait, ataxia, incoordination, hyperaesthesia, licking & chewing of paws; diarrhea, anorexia) & decreased body wt CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Resultsa 42 870.3200 21 Day dermal toxicity  rat: zcypermethrin MRID 45010401 ( 1999)/ Acceptable mg/ kg/ day = 0, 100, 500 or 1000 NOAEL = systemic: 1000 mg/ kg/ day. Dermal: < 100 mg/ kg/ day LOAEL = systemic: > 1000 mg/ kg/ day ( LIMIT DOSE). Dermal: 100 mg/ kg/ day, based on erythema &/ or eschar 1/ 10 M & 6/ 10 F; desquamation 0/ 10 M & 2/ 10 F ( no effects in any M or F controls).

870.3200 21 Day dermal toxicity  rabbit MRID 00090035 ( 1981)/ Acceptable mg/ kg/ day = 0, 2, 20, 200 NOAEL = Systemic nonabraded animals: 200 mg/ kg/ day ( HDT) Dermal: 20 mg/ kg/ day LOAEL = Systemic nonabraded animals: > 200 mg/ kg/ day ( HDT). Dermal: 200 mg/ kg/ day based on signs of dermal irritation.

870.3465 21 Day inhalation toxicity MRID 43507101 ( 1994)/ Acceptable mg/ L = 0, 0.01, 0.05 or 0.25 ( nose only) NOAEL = 0.01 mg/ L LOAEL = 0.05 mg/ L based on decreases in body weight.

870.3700a Prenatal developmental in rats MRID 00056804, 92027039 & 92027601 ( 1978)/ Acceptable mg/ kg/ day = 0, 17.5, 35 or 70 Maternal NOAEL = 17.5 mg/ kg/ day LOAEL = 35 mg/ kg/ day based on decreased body wt gain; at 70mg/ kg/ day, splayed limbs, spasms & hypersensitivity to noise & convulsions. Developmental NOAEL = 70 mg/ kg/ day ( HDT). LOAEL = > 70 mg/ kg/ day .

870.3700a Prenatal developmental in rats  zcypermethrin MRID 41776102 ( 1990)/ Acceptable mg/ kg/ day = 0, 5, 12.5, 25 or 35 Maternal NOAEL = 12.5 mg/ kg/ day LOAEL = 25 mg/ kg/ day, based on ataxia, urinestained abdominal fur, fecal stained perineal fur, decreased food consumption & decreased body wt gain. Developmental NOAEL $ 35 mg/ kg/ day LOAEL = > 35 mg/ kg/ day 870.3700b Prenatal developmental in rabbits MRID 43776301 & 43776302 ( 1994)/ Acceptable mg/ kg/ day = 0, 100, 450 or 700 Maternal NOAEL = 100 mg/ kg/ day LOAEL = 450 mg/ kg/ day based on decreased body wt gain; anorexia, abdomino genital staining, decreased feces & red or pink material in the pan ( few does). At 700, anorexia, abdomino genital staining, decreased feces & red or pink material in the pan were observed. Developmental NOAEL = 700 mg/ kgday LOAEL = > 700 mg/ kg/ day ( highest dose tested) CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Resultsa 43 870.3700b Prenatal developmental in rabbits MRID 00056805 ( 1978)/ Unacceptable [ dosed by capsule] mg/ kg/ day = 0 ( empty), 0 ( corn oil), 3, 10 or 30 Maternal NOAEL = 30 mg/ kg/ day LOAEL > 30 mg/ kg/ day ( HDT) Developmental NOAEL = 30 mg/ kg/ day LOAEL = > 30 mg/ kg/ day ( highest dose tested)

870.3800 Reproduction and fertility effects MRID 00112912, 42068504 & 92027040 ( 1982)/ Acceptable ppm = 0, 50, 150 or 1000/ 750 ( to 750 after wk 12 due to severe neurological signs) mg/ kg/ day = 0, 2.5, 7.5 or 50/ 37.5 [ 2 litters/ generation] Parental/ Offspring NOAEL = 7.5 mg/ kg/ day LOAEL = 50/ 37.5 mg/ kg/ day based on decreased body wt gain in both sexes and decreased mean litter weight gain during lactation.

870.3800 Reproduction and fertility effects MRID 00090040 ( 1979)/ Unacceptable ppm = 0, 10, 100 or 500 mg/ kg/ day = 0, 0.5, 5 or 25 [ 2 litters/ generation] Parental/ Systemic NOAEL = 5 mg/ kg/ day LOAEL = 25: based on decreased body wt gain. Offspring NOAEL = 5 mg/ kg/ day LOAEL = 25: based on decreased body wt gain ( lactation day 21).

870.3800 Reproduction and fertility effects  zcypermethrin MRID 41968204 ( 1991)/ Acceptable ppm = 0, 7.5, 25, 100, 375 or 750 mg/ kg/ day = 0, 0.5, 1.8, 7, 27 or 45 [ 1 litter/ generation] Parental/ Systemic NOAEL = 7 mg/ kg/ day LOAEL = 27 mg/ kg/ day based on decreased body wt gain ( most noticeable during lactation) and increased relative brain wts M & F; at 45 mg/ kg/ day, some neurotoxic clinical signs in a few animals ( some mortality) . Offspring NOAEL = 7 mg/ kg/ day LOAEL = 27 mg/ kg/ day, based on decreased body wt gain during lactation; at 45 mg/ kg/ day, pup mortality.

870.4100a Chronic toxicity rats MRID 00112910 & 9202741 ( 1982)/ Acceptable ppm = 0 # 1, 0 # 2, 20, 150 or 1500 mg/ kg/ day = 0, 0, 1, 7.5 or 75 NOAEL = 7.5 mg/ kg/ day LOAEL = 75 mg/ kg/ day based on decreases in body wt gain ( both sexes) CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Resultsa 44 870.4100b Chronic toxicity dogs ( capsule) MRID 00112909, 42068503 & 92027037 ( 1982)/ Acceptable mg/ kg/ day = 0, 1, 5 or 15 NOAEL = 1 mg/ kg/ day LOAEL = 5 mg/ kg/ day based on gastrointestinal effects ( liquid stool); at 15 mg/ kg/ day, body tremors, gait abnormalities, uncoordination, disorientation & hypersensitivity to noise plus decrease in body weight.

870.4100b Chronic toxicity dogs ( feeding) MRID 44536801 ( 1995)/ Acceptable ppm = 0, 100, 200, 600 or 1100 mg/ kg/ day = M: 0, 2.9, 6.0, 20.4, 33.9 F: 0, 3.3, 5.7, 18.1, 38.1 NOAEL = 6 mg/ kg/ day ( M), 5.7 mg/ kg/ day ( F) LOAEL = 20.4 mg/ kg/ day ( M) based on abnormal clinical signs ( tremors, excessive salivation, irregular gait); at 33.9 mg/ kg/ day, mortality. 18.1 mg/ kg/ day ( F) based on decreased body wt & wt gains.

870.4200 Carcinogenicity rats MRID 00112910 & 9202741 ( 1982)/ Acceptable ppm = 0 # 1, 0 # 2, 20, 150 or 1500 mg/ kg/ day = 0, 0, 1, 7.5 or 75 NOAEL = 7.5 mg/ kg/ day LOAEL = 75 mg/ kg/ day based on decreases in body wt gain ( both sexes). No evidence of carcinogenicity 870.4300 Carcinogenicity mice MRID 00112911 & 92027038 ( 1982)/ Acceptable ppm = 0 # 1, 0 # 2, 100, 400 or 1600 mg/ kg/ day = 0, 0, 14, 57 or 229 [ M = 97 weeks; F = 101 weeks] NOAEL = 14 mg/ kg/ day LOAEL = 57 mg/ kg/ day ( M) based on increased absolute ( 20%) liver wts Females, there was a 15% increase in relative liver wts only at 229 mg/ kg/ day. CANCER: positive for induction of benign alveologenic neoplasms.

870.5265 Salmonella typhimurium & S. cerevisiae reverse mutation assay MRIDs 00090037, 92027042, 92027062, 00090036, 00126834 ( 1981)/ Acceptable 4, 20, 100, 500, 2500 µ g/ plate Negative up to doses of 2500 µ g/ plate.

870.5380 in vivo cytogenetics MRIDs 0090038, 92027043 ( 1980)/ Acceptable 0, 20, 40 mg/ kg No evidence of structural chromosomal aberrations in rat bone marrow at 20 or 40 mg/ kg. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Resultsa 45 870.5450 Dominant lethal assay in the rodent MRID 00090039 1980/ Acceptable 0, 2.5, 5, 7.5, 10 mg/ kg/ day for 5 days No evidence of dominant lethal activity in CD 1 strain mice up to 10 mg/ kg/ day for five consecutive days.

870.5550 Unscheduled DNA synthesis in mammalian cells in culture MRID 41599801 ( 1990)/ Acceptable 100, 200 mg/ kg No unscheduled DNA synthesis was observed at any dose level up to 200mg/ kg in corn oil in Alpk: APfSD strain rats ( males) assessed 4 and 12 hours post dosing. 200 mg/ kg dose was considered near the MTD.

870.6200a Acute neurotoxicity screening battery MRID 43152001 ( 1994)/ Acceptable mg/ kg = 0, 30, 100 or 200 NOAEL = 30 mg/ kg/ day LOAEL = 100 mg/ kg based primarily on ataxia and related conditions ( staggered or impaired gait, decreased activity, splayed hindlimbs and limp conditions in addition to decreased motor activity in males and females on days 0, 1 or 2).

870.6200a Acute neurotoxicity screening battery MRID N/ A 1993/ Acceptable mg/ kg = 0, 20, 60, 120 LITERATURE STUDY NOAEL = < 20 mg/ kg/ day LOAEL = 20 mg/ kg based on decreased motor activity and gait abnormalities. ( Conducted at RTP).

870.6200a Acute neurotoxicity screening battery  z cypermethrin MRID 44962201 ( 1998)/ Acceptable mg/ kg/ day = 0, 10, 50 or 250 NOAEL = 10 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on clinical signs ( abdominogenital staining, oral discharge, splayed hindlimbs, staggered gait & tremors); FOB findings ( abnormal mobile posture, splayed hindlimbs, soiled fur & unable to walk); at 250, more severe findings.

870.6200b Subchronic neurotoxicity screening battery MRID 43152002 1993/ Acceptable ppm = 0, 500, 1300 or 1700 mg/ kg/ day = M: 0, 31, 77 or 102; F: 0, 37, 95 or 121 NOAEL = 31 mg/ kg/ day LOAEL = 77 mg/ kg/ day based on the following: males: decreased body weight gain and increased landing foot splay; females: ataxia, splayed hindlimbs, impaired gait and decreased feces as well as decreased body weight gain.

870.6200b Subchronic neurotoxicity screening battery  z cypermethrin MRID 44962202 ( 1999)/ Acceptable ppm = 0, 75, 400 or 750 mg/ kg/ day = M: 0, 5.0, 26.3 or 47.2; F: 0, 5.9, 31.5 or 55.6 NOAEL = 5.0 mg/ kg/ day ( M); 31.5 mg/ kg/ day ( F) LOAEL = 26.3 mg/ kg/ day ( M) based on decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption; 55.6 mg/ kg/ day ( F) based on decreased body weights, body weight gains, and food consumption. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Resultsa 46 870.7485 Metabolism and pharmacokinetics 41551102  04 ( 1977 78)/ Acceptable 0.61 mg/ animal; 1.3mg/ kg; 1 mg/ kg or less Several studies with both rats, dogs and mice are available to support the requirement for metabolism in mammals. Some of these studies assess individual cis and trans radiolabelled isomers and other studies assess the metabolism of cypermethrin with the label in either the cyclopropyl of the phenoxybenzyl ring. In general the following has been demonstrated from these studies: cypermethrin is readily absorbed from the gastrointestinal tract and extensively metabolized. It mostly excreted in the urine that contains several characterized metabolites derived from conjugation of the hydrolysis products of the parent compound following cleavage of the esteratic linkage site.

870.7485 Metabolism and pharmacokinetics 43261603 ( 1992)/ Acceptable 31.03 mg Mean total DCVA excretion was 0.33% of the administered dose. However, considering that DCVA is further metabolized this value would under estimate dermal absorption. The sum of 3PBA and 4OH3PBA excretion ranged from 0.85 to 1.77% ( mean 1.23%). Because cypermethrin is hydrolized to yield equimolar quantities of DCVA and 3PBA these values are not additive.

870.7600 Dermal penetration N/ A No study is available.

aStudies conducted with cypermethrin unless specified otherwise. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter 47 8.2 Summary of Toxicological Dose and Endpoints for Cypermethrin for Use in Human Risk Assessment Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effectsb Acute Dietary general population including infants and children NOAEL = 10 mg a. i./ kg UF = 1000a Acute RfD = 0.01 mg/ kg FQPA SF = 1 aPAD = acute RfD FQPA SF = 0.01 mg/ kg Acute neurotoxicity study in the rat ( z cypermethrin). LOAEL = 50 mg/ kg based on clinical signs of toxicity and FOB findings.

Chronic Dietary all populations NOAEL= 6 mg a. i./ kg/ day UF = 1000a Chronic RfD = 0.006 mg/ kg/ day FQPA SF = 1 cPAD = chronic RfD FQPA SF = 0.006 mg/ kg/ day Chronic feeding study in the dog. LOAEL = 20.4/ 18.1 mg/ kg/ day based on clinical signs of neurotoxicity and mortality in males, and decreased body weights and body weight gains in females.

Short Term Incidental Oral ( 1 to 30 days) NOAEL= 10 mg a. i./ kg/ day Residential LOC for MOE = 1000a Occupational LOC for MOE = N/ A Acute neurotoxicity study in the rat ( z cypermethrin). LOAEL = 50 mg/ kg/ day based on clinical signs of neurotoxicity and changes in the FOB Intermediate Term Incidental Oral ( 1  6 months) NOAEL= 5.0 mg a. i./ kg/ day Residential LOC for MOE = 1000a Occupational LOC for MOE = N/ A Subchronic neurotoxicity study in the rat ( z cypermethrin). LOAEL = 26.3 mg/ kg/ day based on decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption Short and Intermediate Term Dermal ( 1 day to 6 months None Residential LOC for MOE = N/ A Occupational LOC for MOE = N/ A No systemic effects in 21 day dermal study ( z cypermethrin) up to 1000 mg/ kg/ day& no developmental concern. No hazard identified to support quantitation of risk. CYPERMETHRIN/ March/ 2003 RED Toxicology Chapter Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effectsb 48 Long Term Dermal (> 6 months) Oral NOAEL= 6 mg a. i./ kg/ day ( dermal absorption factor = 2.5%) Residential LOC for MOE = 1000a Occupational LOC for MOE = 100 Chronic feeding study in the dog. LOAEL = 20.4/ 18.1 mg/ kg/ day based on clinical signs of neurotoxicity and mortality in males, and decreased body weights and body weight gains in females.

Short and Intermediate Term Inhalation ( 1 day to 6 months) Inhalation NOAEL= 0.01 mg a. i./ L/ day ( 2.7 mg/ kg/ day) Residential LOC for MOE = 1000a Occupational LOC for MOE = 100 21 day inhalation study in the rat. LOAEL = 0.05 mg/ L/ day ( 13.5 mg/ kg/ day) based on decrease in body weight and salivation.

Long Term Inhalation (> 6 months) Inhalation NOAEL= 0.01 mg a. i./ L ( 2.7 mg/ kg/ day) Residential LOC for MOE = 1000a Occupational LOC for MOE = 300 for the lack of alternative study. Route to route estimation would result in less protective endpoint. 21 day inhalation study in the rat. LOAEL = 0.05 mg/ L/ day ( 13.5 mg/ kg/ day) based on decrease in body weight and salivation.

Cancer ( oral, dermal, inhalation) Classification: Category C ( possible human carcinogen). No quantitation required.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c= chronic), RfD = reference dose, MOE = margin of exposure, LOC = level of concern, N/ A = not applicable aAdditional 10x database uncertainty factor for lack of a developmental neurotoxicity study. bStudies conducted with cypermethrin unless specified otherwise.

NOTE: The Special FQPA Safety Factor recommended by the HIARC assumes that the exposure databases ( dietary food, drinking water, and residential) are complete and that the risk assessment for each potential exposure scenario includes all metabolites and/ or degradates of concern and does not underestimate the potential risk for infants and children.