Permethrin Metabolism in Rats and Cows and in Bean and Cotton Plants

17 Permethrin Metabolism in Rats and Cows and in Bean and Cotton Plants LORETTA C. GAUGHAN, TADAAKI UNAI, and JOHN E. CASIDA

Downloaded by YORK UNIV on June 2, 2018 | https://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0042.ch017

Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720

The discovery that 3-pbenoxybenzyl 3-(2,2-dichlorovinyl)2,2-dimethylcyclopropaiiecarboxylate (permethrin) combines outstanding insecticidal activity, low mammalian toxicity and adequate s t a b i l i t y in l i g h t and a i r has focused attention on the potential of synthetic pyrethroids in agricultural pest insect control (1,2). Most permethrin preparations are [1RS, trans,cis]-mixtures, the [lR,trans]- and [lR,cis]-isomers being the insecticidal components (3). The importance of understanding permethrin biodegradation prompted the present study on the comparative metabolism of [ l R , t r a n s ] - , [1RS, t r a n s ] - , [ l R , c i s J - and [1RS,cis]-permethrin in rats (4,5) and of [1RS,trans]- and [1RS,cis]-permethrin in cows and in bean and cotton plants. [ C] Permethrin Preparations and Experimental Procedures for Rats and Cows 14

Eight [ C] permethrinpreparations were used with specific activities ranging from 1.7 to 58.2 mCi/mmole (Figure l ) . The [lR]-isomers were prepared as previously reported (4) and the [1RS]-isomers were provided by FMC Corporation (Middleport, N . Y . ) . Rats (male, albino, Sprague-Dawley strain) treated with a 14

1RS,trans (rat, cow, plant)

IRS,c/s (rat, cow, plant)

Figure 1. Eight preparations of Cpermethrin (specific activity, mCi/mmol) 14

186

Elliott; Synthetic Pyrethroids ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

17.

G A U G H A N

single mg/kg

oral were

dose held

sacrificed

o f each 4-

in

theurine

cochromatography compounds

(6)

glucuronides lites


in

in

both

acid

moiety

findings tions of

results,

or with metabo

enzymes

and base

(β-

t o

obtain

identification were

a l lproducts

were

with

chromatofree

chromatographed

systems,

the latter

[-^"C p r e p a r a t i o n s a n d-C*(0)-

t o

in

rats

labels

labels

in

o f the [ \ 0 a c i d

the acid

the [lR]used

in

with

These

t o detect a l l

moieties,

a n d [1RS]-isomers

so the [lRS]-isomers

gave the

prepara

can be used

and a l c o h o l

in

the alco

p r o d u c t i o n , in a n y c a s e .

either

were

standard

metabolites.

preparations

55.9-58.2 mCi/mmole

respec

gave

almost

specific

the studies

with

activities cows a n d

organisms.

treated rumen as

solvent

(methanol tot i c

Individual

f o r t h e - C H ^ - and phenoxy

I n addition,

Cows

1

t o move

2

from

tissues.

with

metabolites

metabolites

f o r t h e C1 C*=

or [^C]alcohol

other

Urinary

and w i t h n o ^ C O p

and

) derivatives

acid

1-4

then

subjected

f3).

or with

o f ester

that

CO

hydrolyzed with

comparing a l l 8

results and

(CH^N

systems

and n e u t r a l

themetabolites

identical of

solvent

indicate

tively.

also

sulfatase)

decomposition

moiety

were

enzymatically

Thef e c a l

studies

feces,

at

and

μ ΐ ) a n d in t h e f e c e s

f o r t i c c©chromatographic

acidic

similar

cages

g e l chromatoplates

derivatization.

acidic

The very hol

aryl

the origin.

minimize

o f urine,

methylated

b y t i c were

products

and without from

on s i l i c a

preparations

metabolism

(40-100

synthesized

glucuronidase,

graphed

in

t o 40-230 mg f e c e s )

o r their

isolated

cleavage

o f the 8 labeled

o r l4-days

equivalent

187

Metabolism

f o r radioanalysis

Metabolites extract

Permethrin

E T A L .

(lactating

with

Jersey,

3 consecutive

o f the 4 labeled

mg/kg

were

held

arrangements

daily

doses

preparations

12- or l4-days

b y FMC

Corporation)

by intubation

into the

o f [1RS]-permethrin

prior

to sacrifice

and

a t analyses

above.

[ ^ C ] P e r m e t h r in M e t a b o l i t e s The

[1RS,trans]-isomer

radiocarbon

than

hol-labeled

preparations

Table

I .

Percent

and

label

Rats

a n d Cows

o f permethrin yields

L1RS,cis]-permethrin with

Urinary

[1RS,cis3Isomer

in

and with

either

Radiocarbon

[^C]Permethrin

position

rats

from

more

either

urinary

acid-

o r cows

or

[1RS, t r a n s J - a n d

Preparations Rats

alco

(Table

Cows

1RS,trans Acid

82

39

Alcohol

79

47

Acid

54

29

Alcohol

52

22

1RS,cis


i ) .

188

SYNTHETIC

The m a j o r i t y and

in

sive

o f themetabolites

the feces

ester

cleavage

trans-permethrin pared

t o

the

cows.

appear

These

or conjugation

than

with

in

theurine

with

rats

indicate

more

exten

results

o f themetabolites

with

c i s - p e r m e t h r in a n d in r a t s

as

com

cows.

The cation

with

PYRETHROIDS

t i c cochromatographic

i s illustrated

acid

moiety

in

technique

Figure

2 with

f o rmetabolite

i d e n t i f i

t h emetabolites

o f [1RS,trans]-permethrin

in

rats

from

a n d cows.

hydroxy esters


L4'-H0,/-H0 /-H0-CI CA \ 2

φ

Per

/-HO 4'-HO

Φ

.

7

©

^-H0-CI CA 2

c l 2 C A

c-HO-ClgCA-

CI^A-glutamate

lactone

CI CA-conjugate 2

|K>CI CA-glucuronide 2

^HO-CI CA-glucuronide 2

t Figure 2. Metabolites from acid moiety of (1RS, trans)-permethrin. Ο represents rat; . , cow; and 3 , rat and cow.

The

solvent

separates resolves the to

system

permethrin,

trans-

the

group

acid moiety

before Most

(t-HO;

2

However,

only

gem-dimethyl additional contrast,

cows group,

give

rats

form

from

rats

on analysis).

a n d cows.

o f ClpCA

atthe

and an

o f the acid moiety.

glucuronides

from

(t-HO-Cl^CA;

hydroxylated

conjugate

at

relative

cyclization

cyclization

b y both

metabolites

unidentified metabolite only

(from

2

ester

then

(V - H O , t - H O ) ,

derivatives

o f c-H0-Cl CA

t h e glutamate

group

derivative

a n di t s h y d r o x y

a r e formed

system

i t s V - H O derivative

c-HO),

o r as an a r t i f a c t

o f themetabolites

development

with monohydroxylation

i t s dihydroxy

(C1 CA)

o f

solvent

o f t h e gem-dimethyl

and the lactone

excretion

direction

i t s derivatives

hydroxylation,

c-HO-Cl^CA),

first

:

and t h e second

or cis-position

the carboxyl

phenoxy

f o r the

t h e conjugates

2 — • (benzene-sat'd formic acid)-ether (I0 3)x2

In

o f t h e HO-Cl^CA

derivatives. Studies preparation to

define

(Figure case,

the sites

3).

with

o f t h e type

indicated

o f [1RS,trans3There

o f metabolic

attack

arek principal

an additional

above

with

each

labeled

and[1RS,cis3-permethrin

site

in

sites

f o r rats

rats

served

a n d cows

o f attack

administered

in

each [1RS,cis3-


17.

GAUGHAN

Permethrin

E T AL.

189

Metabolism

Ester hydrolysis φ : trans » cis Preferred methyl for hydroxylation (£,3) cis {2) in 1RS,trans :

trans (3) in \RS,cis Phenoxy hydroxylation (4,5): 4'inrat and cow 2' in rat, cis only


Figure 3.

permethrin. with

isomers

in

Eight moiety

(Figure tion the

4 ) .

a n d cows

rats

ester

stable

-position

hydroxylated

from group

compound

cis-permethrin derivative

T

than

occurs

Γ1RS,trans]-permethrin

a t theV - p o s i t i o n

the feces

o f theh possible

a t t h e gem-dimethyl

hydroxy

in

transgroup

(h)

The

with

both

( 5 7 "with c i s -

only.

a r eidentified

2-trans-hydroxy

with

U-RS,cis]-permethrin.

and a t the2

metabolites

Three

( 2 )

in

i s hydroxylated

rats in

(j)

rapid

a t t h e gem-dimethyl

a t thecis-position

group

permethrin

( l ) i s more

Oxidation

a t thetrans-position

phenoxy

hol

hydrolysis

cis-permethrin.

selectively and

Ester

Sites of metabolic attack from rat and cow

isomer

i s present

trans

cow Figure 4.

appear

from

esters in in

both

theacid from

or alco

a n d cows monohydroxyla-

cowf e c e s

t h emore

appears with

in

o f rats

b u t only

metabolically-

r a tfeces. trans-

The V

and c i s -

cis

rot, cow

Rat and cow hydroxy ester metabolites


-

190

SYNTHETIC

permethrin

a n d in b o t h

derivative

appears

in

both

rats

a n d cows

administered These

a b i l i t y

in

a n dcows. cows

with

with

differences

ester

o f rats

T h eV - H O , t - H O trans -permethrinand

cis-permethrin.

ci s - p e r m e t h r i n c o n t a i n s

species

extensive

rats

only

Thefeces

the 2'-hydroxy

areattributable

hydrolysis

in

cows

than

to carry outaryl

PYRETHROIDS

in

in

part

rats

o f

rats

derivative. to

less

and the

hydroxylation a t t h e 2*-

position. The are

acid moieties

mostly

excreted

glucuronides. both

species

hydroxy


part

from

[1RS]-trans-

rats

a n d cows

T h eo t h e r except

acids

with

in

that

metabolites in

cows

arenot detected

glutamic

acid

free

glue

+ +

++ ++*

Rat Cow

are also

t h e same

the glucuronides

a n dCl^CA

(Figure

in

o fthe

i s conjugated

in

5).

>=^1

C I

cr^-^-cooH Species

a n d- c i s - p e r m e t h r i n

as the corresponding

H

CK ^ - ^ - C O O H free glue + +

+

also glutamate conjugate of trans-QC\à Figure 5. Metabolites from acid moiety of (1RS, trzns)-permethrin and (IRS,tra.ns)-permethrin, rat and cow The and to

liberated in

the corresponding benzoic

rats, and in

alcohol moiety

[1 R S , c i s] - p e r m e t h r i n i s as a glycine

acid which

conjugate

as t h e glutamate cows

b u t absent

rats

+ -

• •

o f [1RS, t r a n s ] further

i s excreted in

6).

free glue + +

• +

oxidized free

rats

which i s t h e major

(Figure

Species free gly glue glut Rat Cow

part

andglucuronide

conjugate

in

on cleavage

t h e most

in

a n d cows

metabolite

3-Fhenoxybenzyl

4'

2'

++

+

+

Figure 6. Metabolites from the alcohol moiety of (1RS, transj-permetnrin and (1RS, cis)-permethrin, rat and cow alcohol amount the

i s excreted

sulfate

amount tive

in

appears The

shown

only

complete in

in

in

rats

cows

o f t h e k'-hydroxy

cowu r i n e

permethrin is

free

o f glucuronide

in

rats

a n dcows

only. acid,

a n dt h e s u l f a t e

in

pathway

i n c l u d i n g t h e 2k

F i g u r e 7. excreted

radiocarbon

except

i s present

trace

r a t metabolite, in

small

o f the 2 -hydroxy 1

deriva-

r a t urine.

metabolic

metabolites

andas a

T h em a j o r

This in

pathway

amounts

f o r 5 minor

f o r trans-

and c i s -

identified metabolites accounts

o f >1% o f t h e a d m i n i s t e r e d fecal

(5.)

f o r a l lpermethrin

metabolites

o fc i s -

permethrin.



Figure 7.

The complete metabolic pathway for trans- and cis-permethrin


1

h-» CO h-

So**

Ο

δ"

3" 2. 3

a

I

is

I

192

SYNTHETIC

PYRETHROIDS


Experimental Procedures for Bean and Cotton Plants and L CJPermethrin Metabolites in Plants Bean and cotton plants treated topically on the leaves and bean plants treated by stem injection with the h [-^C]preparations of [1RS ]-permethrin were held for up to 21 days in the greenhouse. The leaves were washed with methanolchloroform (2:1) and then extracted with this solvent mixture or the whole plants were extracted in the same manner. Plant metabolites were identified and analyzed by the methods used for the mammalian metabolites, except that β-glucosidase, cellulase and acid were employed for conjugate cleavage. An extract of bean plants Ik days after stem injection with [1RS,trans]-permethrin contains the parent compound, hydroxylated permethrin, the free dichlorovinyl acid and i t s hydroxy derivatives, phenoxybenzyl alcohol and phenoxybenzoic acid. These products appear as one spot in the n-butanolacetic acid-water solvent system (Figure 8) but they are resolved in the benzene (formic acid)-ether system. The products at Rf 0 Λ 7 and 0.6l are conjugates of hydroxylated permethrin while the Rf Ο.56 product is an unidentified conjugate from the acid moiety. The identified conjugates include the glycosides of the dichlorovinyl acid and of 3-phenoxybenzyl alcohol. Permethrin on bean and cotton leaves undergoes transcis isomerization to the extent of 6-13$ in 21 days. The penetrated portion yields metabolites similar to those found in the injected bean plants. In a l l cases, trans-permethrin is more rapidly metabolized than cis-permethrin. These preliminary results with plants indicate the importance of photodecomposition and metabolic oxidation and hydrolysis in the dissipation of permethrin residues. Abstract Permethrin metabolites excreted by rats and cows include 8 mono- and dihydroxy derivatives of the trans- and c i s esters, the acid moieties from ester cleavage and their 2-transand 2-cis-hydroxy derivatives, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid and i t s 2'- and 4'-hydroxy derivatives. These metabolites are excreted without conjugation or as glucuronides and glycine and glutamic acid conjugates of the carboxylic acids and as sulfates of the phenolic compounds. Permethrin on bean and cotton leaves undergoes t r a n s - c i s photoisomerization and the absorbed material yields hydroxy esters and their glycosides, hydrolysis products and their glycosides, and 3-phenoxybenzoic acid, trans-Permethrin generally undergoes more rapid biodégradation than c i s - p e r methrin, in part because of the greater hydrolysis rate of the trans- compound.


17.

GAUGHAN E T A L .

PermethHn

Permethrin HO-Permethrin

Permethrin HO-Permethrin C|)=\X OH CIvHO-, l C I M ^ O H V

193

Metabolism

0.81

0.81

HO-Permethrin glyc.-^0.6 I Unk. glyc. from acid-*>Q moiety 5

0.61 -^HO-Permethrin glyc.

6

0.47«*-H0-Permethrin glyc.

HO-Permethrin glyc.-*0.47 0.34«-glyc0^ glyc-K). 3 4


0 butonol-acetic acid-water (e ι ι) Figure 8.

Bean metabolites of (1RS, trans)-permethrin, stem injection

Acknowledgment s We thank Michael E l l i o t t for assistance and helpful suggestions. This study was supported in part by grants from: National Institutes of Health (2 FOI ES000U9); Agricultural Chemical D i v . , FMC Corp., Middleport, N.Y. ; Agricultural Chemicals D i v . , ICI United States I n c . , Goldsboro, N. C ; Sumitomo Chemical Co., Osaka, Japan; Roussel-Uclaf-Procida, Paris, France; Mitchell Cotts & Co. L t d . , London, England; Wellcome Foundation L t d . , London, England; National Research Development Corp., London, England. Literature Cited

1. Elliott, M., ACS Symp. Ser. (1977) this volume. 2. Elliott, M., Farnham, A. W., Janes, N. F., Needham, P. Η., Pulman, D. A., Stevenson, J. Η., Nature (1973) 2k6, 169. 3. Elliot, M., Farnham, A. W., Janes, IT. F., Needham, P. H., PuLbnan, D. Α., Pestic. Sci. (1975) 6, 537. k. Elliott, Μ., Janes, N. F., Pulman, D. Α., Gaughan, L. C, Unai, Τ·, Casida, J. E., J. Agr. Food Çhem. (1976) 2h, 270. 5. Gaugnâh, L. C, Unai, T., Casida, J. E., J. Agr. Food Chem. (1977) in press. 6. Unai, T., Casida, J. E., ACS Symp. Ser. (1977) this volume.


Permethrin Metabolism in Rats and Cows and in Bean and Cotton Plants

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