Environmental Health PerspectivesVol. 21, pp. 285-292, 1977

Metabolism and Toxicology ofPyrethroids with DihalovinylSubstituentsby Luis 0. Ruzo* and John E. Casida*

Replacement of the photolabile and biodegradable isobutenyl substituent of pyrethroids with a di-halovinyl group often leads to improved insecticidal potency and enhanced photostability. This type ofstructural modification does not greatiy alter the ease of detoxification in mammals since other sites in themolecule undergo metabolic attack. The available toxicological information on dihalovinyl pyrethroidsindicates that they are suitable replacements for other insecticides with less favorable persistence andtoxicological characteristics.

Pest control to maintain and improve crop yieldsand human health standards requires the use of ef-fective and biodegradable insecticides with minimalhazard for man, domestic animals and wildlife.Strong reliance was placed in the past on chlori-nated hydrocarbon insecticides, such as DDT andthe cyclodienes, compounds whose use is now re-stricted because of unfavorable persistence and tox-icological properties. The current replacements forchlorinated hydrocarbons are organophosphoruscompounds and methylcarbamates that are lesspersistent but many of which have a high acute tox-icity for man and higher animals. There is a criticalneed for alternative insecticides with many of thebenefits but not the disadvantages of the chlori-nated hydrocarbons. It appears likely that some ofthe newer pyrethroids will meet this need.

Discovery and Structure-ActivityRelationships

Pyrethroids, one of the oldest classes of insec-ticides, have been modified in recent years to bringthem to the forefront as insect control agents for

*Laboratory of Pesticide Chemistry and Toxicology, Depart-ment of Entomological Sciences, University of California, Ber-keley, California 94720.

agriculture and public health. Pyrethrum flowersand their extracts were used for more than a cen-tury prior to identification of the six insecticidalcomponents, the most active of which is pyrethrin I(I) (1). Twenty-five years of structure-activitystudies resulted in a series of useful syntheticpyrethroids, starting with allethrin and later includ-ing resmethrin and phenothrin and a variety of otherchrysanthemates important in household, veteri-nary and stored products insect control (2-6). The1 R isomers are much more active than the IS isom-ers, while the optimal configuration at the3-position varies between different series of com-pounds.

x

x33:

x3~m

pyrethrin I (IR, S,aS): X a Me2C-CH-;Y a-CH2CH-CHCH-C142

allethrin (IRS,3RS,aRS): X a Me2C-CH-;Y -CH2CH-CH2

"dichloroollethrin' (IRS,3RS,aRS):X - C12C-CH-; Y a-CH2CH-CH2

resmethrin (IRS, 3RS) X a Me2C-CH-"holoresmethrins"(various isomers):

X z C12C-CH- or other halogenanalogs

phenothrin (IRS, 3RS) X - Me2C-CH-; Y *-Hpermethrin (IRS, 3RS) X a C12C-CH-; Y a-HNRDC 149 (IRS, 3RS,aRS): X a C12C-CH-; Y a-CNdecomethrin (IR,3R,aS): X' Br2C-CH-; Ya-CN

(1)

December 1977 285

Chrysanthemates with a variety of alcoholmoieties proved inefficient in crop protection, inpart because they lacked sufficient stability in lightand air. Attempts to stabilize them by adding an-tioxidants or by formulation to minimize decompo-sition proved inadequate. It became apparent thatimproved pyrethroids must combine increased po-tency with enhanced photostability.The isobutenyl substituent of chrysanthemates is

important in conferring high insecticidal activity butit also limits their metabolic and photochemical sta-bility [Eq. (1)]. Insects rapidly oxidize thetrans-methyl group of this substituent to the corre-sponding alcohol, aldehyde, and carboxylic acidwith loss of insecticidal activity (7, 8). This oxida-tion is inhibited and the insecticidal activity in-creased on addition of a mixed-function oxidase(mfo) inhibitor such as piperonyl butoxide (PB).The isobutenyl group also undergoes rapid photo-oxidation, forming the epoxide and various hy-droxy, keto, and carboxylic acid derivatives (9-11).Pyrethroids of greater insecticidal activity and per-sistence therefore require replacement of theisobutenyl group by more stable substituents whichmaintain adequate fit at the irnsect nerve receptorsite.

XL)~0 mfo or X 5nzR ha 02 g hp,

thy,02

AO%R+ 0 r

°2 OSRorX2

or 02

+X+ O

Hd

larly active compounds are NRDC 149 and de-camethrin. The aS configuration at the benzyl car-bon provides much greater potency than its aRisomer (16). Decamethrin, the lR-ester with a3R-dibromovinyl substituent and an aS-cyanogroup, is the most potent insecticide known of anytype (16).The dihalovinyl pyrethroids are more expensive

than most other insecticides. Fortunately, thesepyrethroids are effective at very low doses (10-100gr/ha depending on the compound and the pest) andthey are sufficiently stable that one or only a fewapplications per season may suffice. The potency ofthese pyrethroids has other beneficial aspects inthat the very low dose required minimizes crop res-idues and the environmental burden in agriculturalareas. Further, there are higher crop yields in somecases due to reduced phytotoxicity relative to otherinsecticides.

Synthesis3-(2,2-Dihalovinyl)-2,2-dimethylcyclopropane-

carboxylic acids, the acid moieties of dihalovinylpyrethroids, can be prepared by several routes in-volving a variety of starting materials and yieldingproducts with different cis/trans isomer ratios orstereochemical purities. A few examples are givenbelow, using the dichlorovinyl acid for illustration.The ethyl ester of the dichlorovinyl acid was first

prepared by the carbene reaction of ethyl diazoace-tate and 1,1-dichloro-4-methyl-1,3-pentadiene [Eq.(2)] (12).

Cl>> +Cl

(2)

N2CH"..OEt cu dichlorovinyl acid,

ethyl esterc/s /frcns = 1:1

(3)On replacement of the isobutenyl group with a

dichlorovinyl substituent, the highly insecticidal al-lethrin is converted to "dichloroallethrin" (I) with a3-fold increase in potency for killing houseflies anda 3-fold decrease in knockdown activity (12). Thissame type of structural modification was foundmany years later to increase the potency and stabil-ity of other chrysanthemate insecticides (3-6,13-21) (Table 1). The dihalovinyl-containing estersof 3-phenoxybenzyl alcohol (e.g., permethrin), al-though less potent than the corresponding esters of5-benzyl-3-furylmethyl alcohol (i.e., the halores-methrins), are preferred for two reasons: they aremore stable in light and air since they lack thephotolabile furan group; they are less toxic tomammals (6, 9, 13-15, 17, 18). Incorporation of ana-cyano group further increases the potency of thephenoxybenzyl esters (3-6, 16, 18, 22, 23). Particu-

Many methods are currently being evaluated forcommercial synthesis of the dichlorodiene (12, 24,25). This route to the dichlorovinyl ester requiresspecial precautions in the safe handling of ethyldiazoacetate.The dichlorovinyl acid or its esters can also be

prepared by radical addition of carbon tetrachlorideto appropriate unsaturated esters (26) or ketones(27) [Eqs. (3) and (4)].

\ V dichlorovinyl acid,=Et H-lCC4 Ct oOEt ethyl ester

-A OE - CCi'-.Ot-- cis/frans-3:70

CI3C NoON 2. NoCIC dichloroninyl acid

I.NeC dichlorovinyl acid2NOCN~ cis/tlAns r 9l

(4)

Environmental Health Perspectives286

E~zo

n

adE-b.

to.,*E ',U

u 4

r40s

*C

(A j

0

C0)

co

0C)

Ld0u

+

LLa+

0

00 r-

cr 000 TZ:

V= v v z

8 mA

N

A

oO% enA

e" (1 o ON _ "" o0 - - -

--

o 'I W 00 V 00

<, " _ _

r- r"V

r- V" VV

A A A

A A A

A A A

) 0o ~b Wo,, o o O.,

V) RW1oM V o

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A00 A0A0

A A A

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so W x - IC WI) -r _- _%WI _}WI,IM I I I I I

I1 I1 I1

-' U.UL U U.u LL

_

_ ',_C)o

~-7.. =

E-u-o;

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-

11

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D0 , XX *-D-.e E t

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z

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0.

--

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December 1977

.-C

, Cu

0-

0

.CCu

C-p)*) IbS

Cu .0

-.C

.0YCu-

_

Z.

287

Synthesis via the ester generally gives more transthan cis isomer, whereas the ketone intermediateyields either trans-rich or cis-rich mixtures, depend-ing on the order of treatment with base and oxidant.

In some cases it is advantageous to use a specificstereoisomer (lR,3S or 1R,3R) of the acid in pre-paring the pyrethroid. The cis- and trans-isomers astheir ethyl esters are readily separated by spinningband distillation and the IR and IS epimers of thecis- or trans-acid are easily resolved with appro-priate optically active amines (17). The 1S isomer ofthe dichlorovinyl acid chloride can be thermallyepimerized to its 1 R isomer (28).The lR,3S isomer of chrysanthemic acid is ob-

tained in a somewhat analogous manner (29) in theproduction of commercial chrysanthemate insec-ticides. Insecticidally inactive 1S acids can then beepimerized to the IR acids, via their esters orchlorides (29), so [lR,3S]- and [IR,3R]-chrysan-themic acids are potentially available in largeamounts. This is important because the chrysan-themates can be converted to the correspondingdichlorovinyl derivatives having the samestereochemistry as the starting material. Thus,ozonolysis of the chrysanthemate ester gives thecaronaldehyde ester (29) which by a Wittig reaction(13, 18-20) or base addition of chloroform (27) givesthe dichlorovinyl ester [Eq. (5)].

)Et + C -

140XEt

C13C

dichlorovinyl acid,ethyl ester

(retention of stereo-chemical configuration)

1. Ac20/. Zn

(30-32) and later with dihalovinyl-cyclo-propanecarboxylates (11, 33, 34) exposed in varioussolvents to ultraviolet irradiation. It also occurswith dihalovinyl pyrethroids exposed to sunlight asthin films on various surfaces (11) and on plantfoliage (35), where it is a relatively slow process sothat the applied isomer dominates the residue pic-ture. This cis/trans isomerization in solution isgreatly enhanced by triplet sensitizers such as ben-zophenone and isobutyrophenone (31, 33, 34). Inaddition to isomerization, the 1,3-diradical inter-mediate can either disproportionate to yield the3,3-dimethylacrylate (30, 32, 34) or cyclize afterradical rearrangement to give the lactone (30, 32).

\ OR

0

hp

X

X)IR,3SI

h,

X AVR

IS,3R

=nxz/gfOR

IR,3R

>1)-OR

IS,3S

Me //Me R

X= Me,Cl,Br

(6)

Reductive photodehalogenation occurs withpermethrin and particularly decamethrin in solu-tions exposed to ultraviolet irradiation (11, 33, 34)but the dehalogenation products are not detected insignificant amounts with either compound upon

(5) sunlight irradiation (11, 34).

Each of these synthetic methods and others stillunder investigation yield their own complement ofimpurities, often in trace amounts, which must beconsidered in toxicological evaluations.

hv

BrBrR + OH

(7)

PhotochemistryChrysanthemates and the analogous dihalovinyl

compounds undergo photoisomerization via a dirad-ical intermediate so that an individual isomer yieldsa 1RS,3RS mixture (11) with the anticipatedchanges in biological activity [Eqs. (6)]. Thisisomerization was first noted with chrysanthemates

In addition to these photochemical reactions ofthe acid moiety, pyrethroids in general undergomodifications in the alcohol moiety and extensiveester cleavage on irradiation in solution or as thinfilms (9-11, 33, 34). Photodecomposition generallyreduces the toxicity of pyrethroids (9, 10, 34) exceptin mouse assays on the resmethrin photoproducts(9).

Environmental Health Perspectives

0

0

CHC OH

x

x R

XXx

mMe

MetabolismPyrethroids with dihalovinyl substituents are

metabolized in the animal and plant systems ex-amined by reactions that involve no modification ofthe dihalovinyl group. Other portions of themolecule and particularly the ester linkage and al-cohol moiety are more susceptible to attack. Theacid moiety of permethrin is metabolized in rats,cows, adults cockroaches, adult houseflies, cab-bage looper larvae, and bean and cotton plants asshown in Eqs. (8) (28, 35-38). The cis isomer isgenerally cleaved more slowly than the trans isomerand a greater extent of oxidation of the geminal-dimethyl group is obtained with cis-permethrin.

glucoside

I HO<i

C'

I \,IOR l, OR

gltuicaidcoi

I lI HO

glcine conj.gluoseineconj.glycine conj.serine conj.

glucoside

+ OR°iI -OH

C / ---OCi

+C __,,C tOH"

CI

glucosideglucuronide

The 2-cis-hydroxymethyl acids and esters eitherundergo lactonization in vivo or the lactone isformed as an artifact during analysis. The type ofconjugate formed is dependent on the particular or-ganism involved. The preferred methyl group for invivo hydroxylation of trans- and cis-permethrin var-ies somewhat with the isomer and species underinvestigation (28, 35-37). The acid moiety from de-camethrin metabolism is excreted by rats as the freeacid and its glucuronide and glycine conjugates, andlittle or no metabolites are detected which may ariseby hydroxylation of the geminal-dimethyl sub-stituent (39).Microsomal enzyme systems from mouse and rat

liver have been used to examine the effect of thedihalovinyl group on metabolism of pyrethroids(40-45). Quantitative data on mouse microsomal es-terases, oxidases, and esterases plus oxidases aregiven in Table 1 (41, 42). The cis isomers are notcleaved at a significant rate by esterases, but theyare oxidized at nearly the same rates as the corre-sponding trans-esters. Esterase cleavage is en-hanced by chloro and fluoro substituents and re-tarded by bromo substituents. Oxidation rates arealtered very little on replacing the methyl groups bychlorines but they are possibly lowered by bromo

Table 2. In vivo metabolism of isomer mixtures.

Mammals InsectsCabbage

Rat Cow Cockroach Housefly_ Looper

c > t>> c t t t

t> c t t> c t> c t

substituents and are definitely reduced by fluorosubstituents. Thus, replacement of the isobutenylsubstituent, which is easily oxidized, by a di-halovinyl group does not greatly alter the overallrate of pyrethroid metabolism, presumably becauseother substituents are also available for oxidation,i.e., the 2' -, 6- and especially the 4'-positions of thephenoxybenzyl moiety. In the absence of theisobutenyl group, oxidation in the acid moiety isdiverted to the geminal-dimethyl group at C-2 in thecyclopropane ring, with very interesting stereo-specificity [Eq. (9)] (43). The IR,3S isomer is hydroxy-lated by rat and mouse mfo systems only at the 2-cis-methyl while the 1S,3R isomer is oxidized ex-clusively at the 2-trans-methyl group. In the I R,3Risomer, rat microsomes preferentially hydroxylatethe 2-trans-methyl group while mouse microsomesdo so at the 2-cis-methyl position. [1S,3S]-Permethrin is mostly hydroxylated at the methyl cisto the carboxyl by rat and trans by mouse micro-somes. The preferred methyl group for hy-droxylation varies not only with the isomer but alsowith the species from which the microsomal prep-arations are obtained.

rat rataoe mocse Clrat rmouse mt rat

C+~~CI9 C>*,4 C OR

IR,35 IS,3R IR,3R IS,3S (9)

ToxicologyThe toxicology of pyrethroids with dihalovinyl

substituents is similar to that of the pyrethrins andother pyrethroids. Permethrin has been studied ingreater detail (45, 46) than other dihalovinyl pyre-throids, but unpublished studies by severallaboratories on NRDC 149 and decamethrin indi-cate that they have many of the same characteris-tics.

December 1977

I

"'Zoci

289

N- N-N-N

0

~c 0)C4) ~-.,40COC

(A= C

0 4 0z >. z

4) 4)4) 4 0>.1 >- >1 >-.z

0 0z z

1.

en "L.C-

-n

~Ll~t ;~m 1-1 en "I< 8s8 rZ

0 I I10 0 0_ _ _ _ _ _ _ _ _ sNcd

0

Q-

31.

64

IQ

efn'I

00V-)

.4 .

00

< «_ _ _

6 6-

00

:zo

.- --Z

z Zs ::s

* - w *- (A*-L : Z =

,z Iz oF.

.

Lw Ci c )'

4-c

e

=

L., -CO

c o c.+.

m

4)

~CC

C O

. r.0

E

1W

H-C~

000-1-COu

03

4)

0

4)

M.-.

C,X°C e.° 7 v

C13 ° 3 *

L'l 75D"0 uS z

"b0

vC0

CO_

C/) 4)

_ "0

en "0 c_ 4) C

XQX~~~~~44) -

T *Q *D -

Y0

05C D)"0

U 0 4) _

"0 QX,E

toX Y E X, Y o '-e-a_

^9z ¢ a.c C.

Environmental Health Perspectives

'U

2i0'U

0

rA

iU

3.C

4.-

0 r.* C

"0> r=

Ue

.- elrA- u

awco

(A

0~._

V)

"0

0

4)

[IRS,3RS]-Permethrin has an acute oral LD50 of490 mg/kg for male and female mice and >5000mg/kg for male and female rats (45). Variouslaboratories and even the same laboratory (46)report the rat oral LD50 values of [lRS,3RS]-permethrin from - 450 to >5000 mg/kg,without explanation as to the possible reasons forthe discrepancies. The individual isomers of perme-thrin have mouse oral LD50 values as follows:lR,3S-3150 mg/kg; 1R,3R- -96 mg/kg; 1S,3R andIS,3S- >5000 mg/kg (45). The toxicity of isomermixtures approximates that expected if there is nopotentiating effect of one isomer component withanother. The symptoms of permethrin poisoning inmice and rats include hypersensitivity, tremor andmotor ataxia, sometimes with fibrillation and saliva-tion. The subcutaneous and dermal toxicities arevery low as compared with the oral toxicity. Per-methrin does not cause eye or skin irritation or skinsensitizing effects. In six-month feeding studieswith rats, the dietary no-effect level is 1500 ppm. Ata higher level (3000 ppm) there is slight hypertrophyof hepatoparenchymal cells. The acute and sub-acute inhalation toxicity to rats and mice indicates awide margin of safety between the no-effect con-centration of permethrin and the levels likely to beused as aerosols in insect control.

Mutagenicity tests in a variety of systems give noindication that permethrin poses a problem in thisrespect (Table 3). The studies with bacteria includestrains sensitive to base-pair substitution andframeshift mutagens, and with increased permeabil-ity to large molecules and DNA-repair deficientmechanisms. The bacterial tests were made withand without exogenous metabolic activation (mouseand rat liver homogenate) and also in a host(mouse)-mediated assay. Tests on mammals weremade with cultured mouse lymphomal cells withand without metabolic activation and by the dom-inant lethal system in male mice. The doses testedvaried from low to high levels. These findings are ofparticular interest because of the relatively highcorrelation between mutagenicity and oncogenicityand because permethrin bears a partial structuralsimilarity to two chemical carcinogens, vinylchloride (47) and 1,1-dichloro-2,2-bis (p-chlo-rophenyl) ethylene (48). It appears that the dichlo-rovinyl group as a portion of the permethrin mole-cule does not confer mutagenic activity under thetest conditions used. Permethrin is not teratogenicin mice when administered orally from days 7 to 12of gestation at doses of 15, 50, and 100 mg/kg (45).

Decamethrin has an acute oral LD50 of 67-139mg/kg for male and female rats and 19-34 mg/kg formale and female mice, the range in values resultingfrom the use of different carrier solvents for ad-ministration (49).

Prior to extensive use of permethrin and relateddihalovinyl-containing pyrethroids in pest control,further carcinogenicity and multigeneration repro-duction tests must be completed.The toxicity of some pyrethroids administered in-

traperitoneally to mice is increased by the mfo in-hibitor PB and an esterase inhibitor (S, S, S-tributylphosphorotrithioate or DEF, a cotton defoliant)(Table 1). [IRS,trans]-Permethrin, on the otherhand, appears to be so efficiently metabolized byboth oxidases and esterases that its toxicity is notsynergized by these compounds. If synergists are tobe used with dihalovinyl-containing pyrethroids,they must be selected with care and thoroughlytested to ascertain that no unique hazards are as-sociated with such combinations.

Pyrethroids in general seem to have low toxicityto birds but very high toxicity to fish (45). Theymust be used under conditions that fish are not ex-posed directly or indirectly to avoid severe en-vironmental consequences.

Portions of this research were supported by grants from theNational Institute of Environmental Health Sciences (Grant No.5 PO1 ES00049), FMC Corporation (Middleport, N.Y.), andWellcome Foundation Ltd. (London, England).

REFERENCES

1. Casida, J. E., Ed. Pyrethrum. The Natural Insecticide.Academic Press, New York, 1973.

2. Elliott, M. The relationship between the structure and theactivity of pyrethroids. Bull. World Health Org. 44: 315(1971).

3. Elliott, M., et al. Insecticidally active conformations ofpyrethroids. In: Mechanisms of Pesticide Action (ACSSymposium Series, No. 2), American Chemical Society,Washington, D. C., 1974, pp. 80-91.

4. Elliott, M. Future use of natural and synthetic pyrethroids.In: The Future for Insecticides. Needs and Prospects. R. L.Metcalf and J. J. McKelvey, Jr., Eds., Wiley, New York,1976, pp. 163-193.

5. Elliott, M. Properties and applications of pyrethroids. Envi-ron. Health Perspect. 14: 3 (1976).

6. Elliott, M. Synthetic pyrethroids. In: Synthetic Pyrethroids(ACS Symposium Series, No. 42), American Chemical So-ciety, Washington, D. C., 1977, pp. 1-28.

7. Yamamoto, 1., and Casida, J. E. O-Demethyl pyrethrin IIanalogs from oxidation of pyrethrin I, allethrin, dimethrin,and phthalthrin by a house fly enzyme system. J. Econ.Entomol. 59: 1542 (1966).

8. Yamamoto, I., Kimmel, E. C., and Casida, J. E. Oxidativemetabolism of pyrethroids in houseflies. J. Agr. FoodChem. 17: 1227 (1969).

9. Ueda, K., Gaughan, L. C., and Casida, J. E. Photodecom-position of resmethrin and related pyrethroids. J. Agr. FoodChem. 22: 212 (1974).

10. Chen, Y.-L., and Casida, J. E. Photodecomposition ofpyrethrin 1, allethrin, phthalthrin, and dimethrin. Modifica-tions in the acid moiety. J. Agr. Food Chem. 17: 208 (1969).

11. Holmstead, R. L., Casida, J. E., and Ruzo, L. 0. Photo-chemical reactions of pyrethroid insecticides. In: SyntheticPyrethroids (ACS Symposium Series, No. 42), American

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Chemical Society, Washington, D. C., 1977, pp. 137-146.12. Farkas, J., Kourim, P., and Sorm, F. Relation between

chemical structure and insecticidal activity in pyrethroidcompounds. 1. An analogue of chrysanthemic acid contain-ing chlorine in the side chain. Coll. Czech. Chem. Commun.24: 2230 (1959).

13. Elliott, M., et al. Potent pyrethroid insecticides from mod-ified cyclopropane acids. Nature 244: 456 (1973).

14. Elliott, M., et al. A photostable pyrethroid. Nature 246: 169(1973).

15. Elliott, M., et al. NRDC 143, a more stable pyrethroid.Proc. 7th Brit. Ins. Fung. Conf., Brighton, 1973,pp. 721-728.

16. Elliott, M., et al. Synthetic insecticide with a new order ofactivity. Nature 248: 710 (1974).

17. Burt, P. E., et al. The pyrethrins and related compounds.XIX. Geometrical and optical isomers of 2, 2-di-methyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acidand insecticidal esters with 5-benzyl-3-furymethyl and3-phenoxybenzyl alcohols. Pestic. Sci. 5: 791 (1974).

18. Elliott, M., et al. Insecticidal activity of the pyrethrins andrelated compounds. VII. Insecticidal dihalovinyl analoguesof cis and trans chrysanthemates Pestic. Sci. 6: 537 (1975).

19. Brown, D. G., Bodenstein, 0. F., and Norton, S. J. Newpotent pyrethroid, bromethrin. J. Agr. Food Chem. 21: 767(1973).

20. Brown, D. G., Bodenstein, 0. F., and Norton, S. J.Halopyrethroids. II. A difluoropyrethroid. J. Agr. FoodChem. 23: 115 (1975).

21. Norton, S. J., Bodenstein, 0. F., and Brown, D. G.Halopyrethroids: structure-activity relations. Botyu-Kagaku 41: 1 (1976).

22. Ohno, N., et al. 2-Arylalkanoates, a new group of syntheticpyrethroid esters not containing cyclopropanecarboxylates.Pestic. Sci. 7: 241 (1976).

23. Matsuo, T., -et al. 3-Phenoxy-a-cyano-benzyl esters, themost potent synthetic pyrethroids. Agr. Biol. Chem. 40: 247(1976).

24. Glenn, M. S., and Scharpf, W. G. Synthetic route to theacid portion of permethrin. In: Synthetic Pyrethroids (ACSSymposium Series, No. 42), American Chemical Society,Washington, D. C., 1977, pp. 116-118.

25. Alvarez, M., and Fishman, M. Novel routes to 1,1-dichlo-ro-4-methyl-1,4-pentadiene and 1,1-dichloro-4-methyl-1,3-pentadiene. In: Synthetic Pyrethroids (ACS SymposiumSeries, No. 42), American Chemical Society, Washington,D. C., 1977, pp. 119-127.

26. Kondo, K., Matsui, K., and Negishi, A. New synthesis ofthe acid moiety of pyrethroids. In: Synthetic Pyrethroids(ACS Symposium Series, No. 42), American Chemical So-ciety, Washington, D. C., 1977, pp. 128-136.

27. Itaya, N., et al. Recent progress in syntheses of the new andmost potent pyrethroids. In: Synthetic Pyrethroids (ACSSymposium Series, No. 42), American Chemical Society,Washington, D. C., 1977, pp. 45-54.

28. Elliott, M., et al. Radiosynthesis and metabolism in rats ofthe I R isomers of the insecticide permethrin. J. Agr. FoodChem. 24: 270 (1976).

29. Elliott, M., and Janes, N. F. Chemistry of the natural pyre-thrins. In: Pyrethrum. The Natural Insecticide. J. E.Casida, Ed., Academic Press, New York, 1973, pp. 55-100.

30. Sasaki, T., Eguchi, S., and Ohno, M. Studies on chrysan-themic acid. IV. Photochemical behavior of chrysanthemicacid and its derivatives. J. Org. Chem. 35: 790 (1970).

31. Ueda, K., and Matsui, M. Studies on chrysanthemicacid-XXI. Photochemical isomerization of chrysanthemic

acid and its derivatives. Tetrahedron 27: 2771 (1971).32. Bullivant, M. J., and Pattenden, G. Photochemical decom-

position of chrysanthemic acid and its alkyl esters. Pyre-thrum Post 11:72(1971).

33. Ruzo, L. O., Holmstead, R. L., and Casida, J. E. Solutionphotochemistry of the potent pyrethroid insecticidea-cyano-3-phenoxybenzyl cis-2 ,2-dimethyl-3-(2,2-dibro-movinyl) cyclopropanecarboxylate. Tetrahedron Letters 35:3045 (1976).

34. Ruzo, L. O., Holmstead, R. L., and Casida, J. E. Pyre-throid photochemistry: decamethrin. J. Agr. Food Chem.,in press.

35. Gaughan, L. C., Unai, T., and Casida, J. E. Permethrinmetabolism in rats and cows and in bean and cotton plants.In: Synthetic Pyrethroids (ACS Symposium Series, No. 42),American Chemical Society, Washington, D. C., 1977,pp. 186-193.

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