Biological and Chemical Behavior of ... - ACS Publications

6 Biological and Chemical Behavior of Perhalogenmethylmercapto Fungicides: Metabolism and in Vitro Reactions of Dichlofluanid in Comparison with Captan 1

Downloaded by UNIV LAVAL on July 13, 2014 | http://pubs.acs.org Publication Date: June 11, 1981 | doi: 10.1021/bk-1981-0158.ch006

I. S C H U P H A N , D. WESTPHAL , A. H A Q U E , and W. E B I N G Institut für Pflanzenschutzmittelforschung, Biologische Bundesanstalt, 1000 Berlin 33, Federal Republic of Germany

The f u n g i t o x i c N-perhalogenmethylmercapto moiety was introduced f o r p l a n t protection in 1950: The two f u n g i c i d e s captan(1) (N-(trichloromethylthio)-Δ tetrahydrophthalimide) and f o l p e t ( 2 ) (N-(trichloromet h y l t h i o ) p h t h a l i m i d e ) contain a p e r c h l o r i n a t e d methylt h i o group (1). About a decade l a t e r s u b s t i t u t i o n of f l u o r i n e f o r one of the c h l o r i n e s i n the perchloromethylmercapto moiety l e d to chemically r e l a t e d fun g i c i d e s (2,3) of which d i c h l o f l u a n i d ( 3 ) ((N-fluorodichloromethylthio)-N'-N'-dimethyl-N-phenyl s u l f o n y l diamide) was commerciallized. 4

>-S0 -N-S-CFCl 2

2

S t r u c t u r a l modifications i n the amide moiety or the methylmercapto group of these and r e l a t e d compounds r e s u l t i n changes i n chemical and b i o l o g i c a l a c t i v i t y . Thus, the r e a c t i v i t y of the t r i c h l o r o m e t h y l d e r i v a t i ves against 4-nitrothiophenol decreases i n the se quence 1, 2 and 4. A s i m i l a r trend holds true f o r the fluorodichloromethyl d e r i v a t i v e s 5, 6, and 3. The fluoroanalogues r e a c t 4-10 times f a s t e r with 4 - n i t r o thiophenol than the t r i c h l o r o d e r i v a t i v e s as shown i n Fig. 1 (3). The f l u o r o d i c h l o r o m e t h y l t h i o f u n g i c i d e s show s i m i l a r or greater f u n g i c i d a l activity than the t r i c h l o r o m e t h y l t h i o d e r i v a t i v e s (2). This may be rel a t e d to t h e i r increased r e a c t i v i t y against b i o l o g i cal thiols. 1

Current address: Max von Pettenkofer Institut, Bundesgesundheitsamt, 1000 lin 33, Federal Republic of Germany. 0097-6156/81/0158-0085$05.00/0 © 1981 American Chemical Society

In Sulfur in Pesticide Action and Metabolism; Rosen, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

Ber

86

SULFUR IN PESTICIDE ACTION AND METABOLISM

δ

Ο

1(1.9»104)

2 (1.5x 104)

|TYJN-S-CFCI Downloaded by UNIV LAVAL on July 13, 2014 | http://pubs.acs.org Publication Date: June 11, 1981 | doi: 10.1021/bk-1981-0158.ch006

2

5 (20x104)

C

>

|Tîr;N-s-CFci, 6 (8.2 x104)

H

3

Λ 4 ( 1 . 3 » 10*)

>

CH

>N-SO,-N-S-CFCI,

3 (5.2 χ 104)

Figure 1. Reaction rate constants K(l/mol · min) of perhalogenated methy capto derivatives in the reaction with 4-nitrothiophenol at25°C

The mode of a c t i o n of the t r i c h l o r o m e t h y l t h i o f u n g i c i d e s was studies i n Saccharomyces. Captan ex h i b i t e d l o s s of f u n g i t o x i c i t y i n the presence of sulfh y d r y l compounds (4;. In v i t r o r e a c t i o n products of captan with cysteine were reported to be tetrahydrophthalimide, hydrogen s u l f i d e , carbon d i s u l f i d e , t h i a z o l i d i n e - 2 - t h i o n e - 4 - c a r b o x y l i c a c i d and h y d r o c h l o r i c a c i d (4). From the r e s u l t s i t was concluded that the r e a c t i o n pathway involved thiophosgene as an unstable intermediate and i t followed that the f u n g i t o x i c pro p e r t i e s of captan were r e l a t e d to the trichloromethyl t h i o moiety. This proposal was substantiated by the f i n d i n g s that a v a r i e t y of t r i c h l o r o m e t h y l t h i o d e r i v a t i v e s had f u n g i c i d a l p r o p e r t i e s (5). Reaction of f o l p e t with t h i o l s and i t s mode of a c t i o n appear to be s i m i l a r to those of captan (6). The h a l f - l i f e of captan i n water i s reported to be about 12 hours, the r e a c t i o n products being carbon d i o x i d e , h y d r o c h l o r i c a c i d and s u l f u r (7). Although captan and f o l p e t are e x t e n s i v e l y used i n a g r i c u l t u r e , only one report on captan metabolism i n animals has been published (8). Urinary metabolites of o r a l l y - a d m i n i s t r a t e d captan were i d e n t i f i e d as t h i a z o l i d i n e - 2 - t h i o n e - 4 - c a r b o x y l i c a c i d , a s a l t of dithiobis-(methanesulphonic acid) and i t s disulphide monoxide (8). There are no reports con cerning metabolic studies i n higher p l a n t s . Captan i s mutagenic i n b a c t e r i a l assays such as the Salmonella typhimurium "Ames" assay (9,.10,21) and


6. SCHUPHAN ET AL.

Perhalogenmethylmercapto Fungicides

87

others (Λ2 Λ£). I t i s a questionable carcinogen i n mice, inducing duodenal tumors only a t extremely high (8,000-16,000 ppm) d i e t a r y l e v e l s (14) L i t t l e i s known of the b i o l o g i c a l and chemical behavior of the f l u o r o d i c h l o r o m e t h y l d e r i v a t i v e s . Riot o l y s i s of d i c h l o f l u a n i d r e s u l t s i n the formation of N,N-dimethyl-N -phenylsulphamide, phenyl isocyanate and isothiocyanates and dimethylamidosulfonyl c h l o r i d e ( . 1 5 ) · GC-MS a n a l y s i s a l s o i n d i c a t e s the presence of b i s - ( f l u o r o d i c h l o r o m e t h y l ) d i s u l f i d e and two ketones, the l a t t e r being a r t i f a c t s a r i s i n g from the solvent, acetone. D i c h l o f l u a n i d metabolism i n p l a n t s y i e l d s N,N-dimethyl-N -phenylsulphamide ( 1_6), but nothing i s 9

f


f

Figure 2.

Photolysis of dichlofluanid

known of the f a t e of the f l u o r o d i c h l o r o m e t h y l t h i o moiety. The b i o l o g i c a l and chemical behavior of the f l u o r i n e - c o n t a i n i n g d e r i v a t i v e s as compared to the t r i c h l o r o m e t h y l t h i o compounds i s of i n t e r e s t because c h l o r i n e - f l u o r i n e s u b s t i t u t i o n normally i n f l u e n c e s the behavior of organic compounds s i g n i f i c a n t l y . Thus, the formation of a f l u o r i n a t e d thiophosgene analogue intermediate might be of t o x i c o l o g i c a l importance. This r e p o r t w i l l mainly be concerned with the me t a b o l i c f a t e of d i c h l o f l u a n i d i n strawberries, captan i n spinach and s o i l as w e l l as i n v i t r o r e a c t i o n s of d i c h l o f l u a n i d with c e l l t h i o l s and the comparative be havior of metabolites i n the Ames assay.



88

Metabolism of ( f l u o r o d i c h l o r o i n Strawberries

C-methyl)Dichlofluanid


14 Spray a p p l i c a t i o n of formulated C - d i c h l o f l u a n i d (Euparen) to flowering strawberry plants i n a closed c o n t r o l l e d v e n t i l a t e d c u l t i v a t i n g system r e s u l t e d i n a recovery of 99 % radiocarbon a f t e r 36 days (Table I). TABLE I. Balance Account of C^c] D i c h l o f l u a n i d Radioa c t i v i t y a f t e r Spray A p p l i c a t i o n on Strawberry Plants under Closed Conditions R a d i o a c t i v i t y recovered from t o t a l a p p l i e d % Extractable Fruits

Sum

Unextractable

3.53 49.6

4.3 21.2

7.83 70.8

Roots

1.55

1.8

3.35

Soil

0.59

3.3

3-89

Leaves

co

5.95 0.01

2

COS Unknown volatile

0.04

Condensing water

3.59

Washing solutions

3.49

Total

98.95

The major amount of r a d i o a c t i v e m a t e r i a l (70%) was found i n leaves, 7.8% i n roots and s o i l and 6% as ' C0p« Bligh-Dyer e x t r a c t i o n of the leaves gave 49.6% of tne ^ C - l a b e l i n the chloroform and methanol-water l a y e r s while 21.2% was unextractable. F r u i t s c o n t a i ned 3.5% radiocarbon i n the chloroform and methanolwater f r a c t i o n s while 4.3% remained unextractable. A p a r a l l e l experiment i n a s i m i l a r chamber but with the top removed gave a recovery of 45% r a d i o 1


6. SCHUPHAN ET AL.

89


carbon. Leaves contained up to 36%, f r u i t s 3.1% and roots plus s o i l 5.7% of the a p p l i e d radiocarbon (Table I I ) . 1/f

TABLE I I . Balance Account of [ C] D i c h l o f l u a n i d Radioa c t i v i t y a f t e r Spray A p p l i c a t i o n on Strawberry Plants under Open Conditions R a d i o a c t i v i t y recovered from t o t a l a p p l i e d % Downloaded by UNIV LAVAL on July 13, 2014 | http://pubs.acs.org Publication Date: June 11, 1981 | doi: 10.1021/bk-1981-0158.ch006

Extractable

Sum

Unextractable

Fruits

2.84

0.21

3.05

Leaves

32.85 0.21

3.48 0.20

36.33 0.41

1.23

4.02

5.25

Roots Soil Washing solutions

0.18

45.22

Total

S p e c i a l a t t e n t i o n was given to the c h a r a c t e r i z a t i o n of the r a d i o a c t i v e metabolites found i n the strawberry f r u i t s where no parent compound was detect a b l e . U n i d e n t i f i e d , very p o l a r metabolites accounted f o r 83% of the m a t e r i a l while 3% was i d e n t i f i e d as t h i a z o l i d i n e - 2 - t h i o n e - 4 - c a r b o x y l i c a c i d by two-dimens i o n a l t h i n - l a y e r chromatography. Treatment with diazomethane allowed f o r GC-MS confirmation of the l a t t e r as the methylated d e r i v a t i v e s of the t h i a z o l i d i n e . B i s - ( f l u o r o d i c h l o r o m e t h y l ) d i s u l f i d e co-chromatographed with a l a b e l e d metabolite but i n s u f f i c i e n t mat e r i a l was a v a i l a b l e f o r confirmation by mass spectrometry . Leaves contained 55% of the l a b e l as the parent compound d i c h l o f l u a n i d , 35% as very p o l a r u n i d e n t i f i e d metabolites and 10% as t h i a z o l i d i n e - 2 - t h i o n e - 4 c a r b o x y l i c a c i d . A small amount (0.2%) was b i s - ( f l u o rodichloromethyl) d i s u l f i d e as confirmed by two dimais i o n a l t i c and MS. This amount i s probably l e s s than was a c t u a l l y present as the work up procedures were not optimized to detect such a r e l a t i v e l y v o l a t i l e



90

SULFUR

IN

PESTICIDE

ACTION

AND

METABOLISM

metabolite. The small amount (3.9%) of radioactivityfound i n s o i l and 3.4% found i n roots were very p o l a r and could not be characterized f u r t h e r even a f t e r dif f e r e n t enzymatic cleavage r e a c t i o n s or a c i d hydroly sis. The v o l a t i l e metabolites comprised 6% of the r a d i o a c t i v i t y . Carbon dioxide formed the main component. Other compounds, i n c l u d i n g carbonyl s u l f i d e , were de tected only i n traces below 0.04%. S p e c i a l attempts were made to i d e n t i f y carbonyl s u l f i d e as a metabolite of d i c h l o f l u a n i d because i t would help us understand the metabolic pathway. In a previous i n v e s t i g a t i o n i n t o the metabolism of captan, CSp was found as a metabolite (4), while i n a l a t t e r study, COS was reported ( 1 2 ) · V i l e s reagent (18) often used by many i n v e s t i g a t o r s f o r t h i s purpose, proved to be unsuitable because of the p o s s i b l e pre sence of carbon d i s u l f i d e . Both COS and CS give co l o r e d copper chelates that can not be q u a n t i t a t i v e l y separated by t i c . Furthermore, a n a l y s i s of the mixtu 1

2

2^NH

+

2 9= S

_

+ Cu

2+

*

—ν

\,

b (S) re by mass spectrometry i s f u t i l e because n e i t h e r de r i v a t i v e gives a molecular i o n . The formation of COS was proven by passing the a i r l e a v i n g the closed plant chamber through a mixture of d i i s o p r o p y l amine and 1,1,2,3-tetrachloropropene to give the thiocarbamate, t r i a l l a t e , as a r e a c t i o n product. .CI CI

The l a t t e r was i d e n t i f i e d by GC-MS. Using t h i s tech nique, 0.005% of the t o t a l a p p l i e d r a d i o a c t i v i t y was shown to be COS. The low y i e l d may have been due to h y d r o l y s i s of COS to HpS and C0p. The proposed metaoolic patnway i n strawberries i s shown i n Figure 3 . Five compounds: mixed d i s u l f i d e , s u l f i d e , s u l f e n i c a c i d , thiophosgene and the GSH-rea c t i o n product have not been i d e n t i f i e d as a straw berry metabolite but t h e i r involvement i s very l i k e l y based on the formation of b i s - ( f l u o r o d i c h l o r o m e t h y l )


6.

SCHUPHAN ET AL.

:N-SO,-N-S-C-F

Perhalogenmeîhylmercapto

Fungicides

91

^N-sa-NH + R - S - S - C ; F

+ RSH

^

'

Cl

-R-S-S-R

? Hydrolysis

Dichlof luanid

^HO-S^F

Cl

-0

F^C-S-S-CrF

H-S-C?F α

cr

-HCKF)

9, CI HO-S-C-F δ *CI Λ

rJ&Y°"

G,u

!^î_ci-*c-a(F)

S

^*Y>

ci

/-HCKFJ>|,H„0

#


Ο

^

'

S=*C=0

o=c=o

Figure 3.

14

Proposed metabolism of [ C] dichlofluanid in strawberries

disulfide, thiazolidine-2-thione-4-carboxylic acid and carbonyl s u l f i d e . Fluorodichloromethane sulfonic a c i d co-chromatographed with p o l a r metabolites i s o l a ted from leaves. D e r i v a t i z a t i o n v i a i t s s u l f o c h l o r i d e and r e a c t i o n with cyclohexene or c y c l o h e x y l i s o n i t r i l e f a i l e d to give d e r i v a t i v e s i n s u f f i c i e n t y i e l d f o r GC-MS confirmation. Metabolism of ( t r i c h l o r o - ^ C - m e t h y l ) Captan i n S p i nach and S o i l Our i n i t i a l studies on the metabolic pathway of captan i n spinach point to s i m i l a r i t i e s with d i c h l o f l u a n i d metabolism i n strawberries. Preplanting t r e a t ment of s o i l with ^ C - c a p t a n followed by spinach c u l t i v a t i o n f o r 34 days i n a closed c o n t r o l l e d v e n t i l a ted c u l t i v a t i n g system r e s u l t e d i n a recovery of 87% radiocarbon (Table I I I ) . The major amount (49%) was found i n the s o i l , 19% i n the spinach and 19% as car bon dioxide. Bligh-Dyer e x t r a c t i o n of the spinach ga ve 7.4% of the ^ C - l a b e l i n the chloroform and metha-


92

SULFUR

IN

PESTICIDE

ACTION

AND

METABOLISM

TABLE I I I . Balance Account of [^C] Captan R a d i o a c t i v i t y a f t e r S o i l A p p l i c a t i o n Followed by Spinach Culture under Closed Conditions R a d i o a c t i v i t y recovered from t o t a l a p p l i e d

Sum

% Extractable Spinach

7.4 30.7


Soil co

Unextractable 11.5 18.0

18.9 48.7 19.2

2

COS

0.02

Unknown volatile

0.18

Condensing water

0.07

Washing solutions

0.04

Total

87.1

nol-water l a y e r s while 11.5% was unextractable. Ext r a c t i o n of the s o i l showed that nearly a l l the ext r a c t a b l e r a d i o a c t i v i t y (30.7%) was i n the chloroform phase while 18% was unextractable. In spinach, 1.3% of the extractable r a d i o a c t i v i t y was found to be the parent compound while 3% was b i s - ( t r i c h l o r o m e t h y l ) d i s u l f i d e and 5.2% was thiazolidine-2-thione-4-carboxyl i c a c i d . At l e a s t eleven other products were present. These materials were very polar and could not be f u r ther c h a r a c t e r i z e d . Captan accounted f o r 84% of the extractable r a d i o a c t i v i t y i n s o i l . None of the polar s o i l metabolites could be i d e n t i f i e d . In V i t r o

Studies

To obtain f u r t h e r information concerning the degradation mechanism of the fluorodichloromethyl moiety,



6. SCHUPHAN ET AL.

Perhalogenmethyîmercapto Fungicides

93

r e a c t i o n s were c a r r i e d out between d i c h l o f l u a n i d and glutathione or cysteine. These r e a c t i o n s were p e r f o r med a t the 0.01 mmol l e v e l i n a 1:1 mixture of water/ methanol. Molar r a t i o s of d i c h l o f l u a n i d and g l u t a t h i o ne reacted immediately to form a very p o l a r d e r i v a t i ve. Time dependent t i c a n a l y s i s of the r e a c t i o n reveal e d that the radiocarbon r e t a i n e d a t the o r i g i n d i s appeared w i t h i n two hours i n the r e a c t i o n mixture but a compound i d e n t i c a l i n t i c behavior to d i c h l o f l u a n i d was formed. The odor of mercapto compounds was e v i dent. R a d i o a c t i v i t y from the o r i g i n on the t i c p l a t e s was l o s t i n open a i r w i t h i n 24 hours. Performing t h i s r e a c t i o n a t 40 C i n a closed system f i t t e d with traps f o r COS and COp absorption and passing nitrogen through i t , 2-4% CoS and 18 to 22% C0« were evolved a f t e r 16 hours. A two molar excess or glutathione released up to 40% of COp and 5% of COS. The same experiments c a r r i e d out with cysteine ave 30-35% C ° o Using a two molar cysteine excess, 0 to 70% of COp were released. The remaining r a d i o a c t i v i t y i n the r e a c t i o n mixture consisted p a r t l y of t h i a z o l i d i n e - 2 - t h i o n e - 4 - c a r b o x y l i c a c i d . In a l l experiments, 5 to 10% of the r a d i o a c t i v i t y was l o s t , poss i b l y due to formation of b i s - ( f l u o r o d i c h l o r o m e t h y l ) d i s u l f i d e . This assumption i s based on odor comparison between the d i s u l f i d e and the r e a c t i o n mixture. The degradation mechanism proposed from these r e s u l t s (Figure 4) include s h o r t - l i v e d intermediates #

»-CySH

>N-SO N-S F

Ô

CI

ON-SOfNH

CyS-S-C-F CI -CyS-SCy • CySH •Dichlof l u a n i d

^ O H S N. t

s

S

ma-

ci-*6-ci(F)-H-^i 2!±£!£!i. Uc

H

-HCI(F)

KM -HCI(F)

I+

CI -

1

pic-s-s-ci CI CI — '

χ

~ ·

H0 2

s=c=o - H 2 S j*H 0

o*c=o 2

Figure 4.

14

In vitro reactions of [ C] dichlofluanid with cysteine


94

SULFUR

IN

PESTICIDE

ACTION

AND

METABOLISM

not y e t detected but necessary to understand the metab o l i c pathway. These unstable metabolites are analogous to those postulated as a r e s u l t of i n v i t r o plus i n vivo studies of captan metabolism (4,8j. In the case of d i c h l o f l u a n i d metabolism the question a r i s e s whether f l u o r i n e influences the formation of these assumed s h o r t - l i v e d intermediates. Thiophosgene espec i a l l y i s assumed to play the major part i n the mode of a c t i o n of captan. Whether thiophosgene or i t s monofluoro analogue i s involved i n the degradation pathway of d i c h l o f l u a n i d i s not c l e a r .


Mutagenicity

Studies

I t i s w e l l known that captan i s a strong mutagen i n the Ames ( 9 , . 1 2 , 2 1 ) other b a c t e r i a l assays (12, 13) with or without metabolic a c t i v a t i o n . In contrast, we have found that d i c h l o f l u a n i d and two of i t s metab o l i t e s , t h i a z o l i d i n e - 2 - t h i o n e - 4 - c a r b o x y l i c a c i d and b i s - ( f l u o r o d i c h l o r o m e t h y l ) d i s u l f i d e are not mutagen i c to Salmonella typhimurium TA 100. Thiophosgene i s not mutagenic when d i s s o l v e d i n dimethyl s u l f o x i d e p r i o r to t e s t i n g , but gives p o s i t i v e r e s u l t s (2 r e vertants/nmole) when tested a f t e r d i s s o l v i n g i n ethylene g l y c o l dimethyl ether or tetrahydrofuran. This i n d i c a t e s that thiophosgene i s hydrolyzed by the hydroscopic dimethyl s u l f o x i d e before i n t e r a c t i n g with the b a c t e r i a . Surprisingly, bis-(trichloromethyl) disulfide was found to be as strong a mutagen as captan, and l i k e captan and f o l p e t , d i d not need metabolic a c t i v a t i o n (Figure 5). Comparing these r e s u l t s with the negative response obtained from d i c h l o f l u a n i d and b i s - ( f l u o r o d i c h l o r o m e t h y l ) d i s u l f i d e i t can be strongl y i n f e r r e d that the f l u o r i n e atom has a fundamental i n f l u e n c e on the mutagenic a c t i v i t y of these compounds. Indeed, the t r i c h l o r o m e t h y l t h i o d e r i v a t i v e of d i c h l o f l u a n i d i s mutagenic (Figure 6) even i n the absence of microsomal a c t i v a t i o n . In contrast, compounds (5) and (6), the monofluoro analogues of captan and f o l p e t do n o t show mutagenic a c t i v i t i e s with and without metabolic a c t i v a t i o n . L i k e the other f l u o r o containing d e r i v a t i v e s they have some bactericid a l potency i n higher concentrations which i s comp l e t e l y l o s t through microsome (S-9mix) a d d i t i o n . The mutagenic potency of b i s - ( t r i c h l o r o m e t h y l ) d i s u l f i d e may be of great s i g n i f i c a n c e i n the f u r t h e r evaluation of captan. I t has been reported (190 and confirmed by us that the d i s u l f i d e i s an impurity i n t e c h n i c a l captan. Moreover, vide supre, i t was found a n c i


6. SCHUPHAN ET AL.


95

20001 / (*S9 )

160CM

S120CH ο υ £ 800

oc 400


Φ

100 nMoles

~gÔ

Figure 5.

Mutagenic activity of captan and bis-(trichloromethyl) disulfide with S. typhimurium TA 100

140CM 8 120(H (+S9)

2100CH Φ c ο g 800

CH, r H

_

>S0 -N-S-C Cl. 2

Ô

~ βοσ

φ > φ Œ

400 200 H

20

Figure 6.

40

>heOf^-S-CFCl

60 80 nMoles

2

100

120

140

Negative response of dichlofluanid in comparison with its tr analog assayed with S. typhimurium TA 100



96

as a metabolite i n spinach a f t e r s o i l a p p l i c a t i o n of captan and i n strawberries a f t e r p l a n t a p p l i c a t i o n (20,19). Acknowledgement Supported i n part by the Ministerium f u r F o r schung und Technologie and the Deutsche Forschungsgemeinschaft. Literature Cited


1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

DBP 887 506 (17.August 1950): Standard O i l Development DBP 1193 498 (3.November 1960): Farbenfabriken Bayer A.G. K ü h l e , E.; Klauke, E.; Grewe, F., Angew. Chem., 1964, 76, 807. Lukens, R.J.; S i s l e r , H . D . , Phytopathology, 1958, 48, 235. Lukens, R.J., In "Fungicides". E d i t o r : Torgeson, D. C., 1969, 2, 396. New York and London: Acad. Press. S i e g e l , M . R . , J. Agric. Food Chem., 1970, 18, 823. Wolfe, N.L.; Zepp, R . G . ; Doster, J.C.; Hollis, R.C., J. A g r i c . Food Chem., 1976, 24, 1041. DeBaun, J.R.; M i a u l l i s , J.B.; Knarr, J.; M i h a i l o v s k i , Α . ; Menn, J.J., Xenobiotica, 1974, 4, 101. M a r s h a l l , T.C.; Dorough, H.W.; Swim, H.E., J. A g r i c . Food Chem., 1976, 24, 560. McCann, J.; Choi, E.; Yamasaki, E.; Ames, B . N . , Proc. Nat. Acad. S c i . USA, 1975, 72, 5135. F i e s o r , G . ; Bordas, S.; Stewart, S.J., Mutation Research, 1978, 51, 151. Legator, M . S . ; K e l l y , F.J.; Green, S.; Oswald, E.J., Ann. N.Y. Acad. Sci., 1969, 160, 344. Bridges, B . A . ; Mottershead, R . P . ; Rothwell, M . A . ; Green, M . H . L . , C h e m . - B i o l . I n t e r a c t i o n s , 1972, 5, 77. National Cancer I n s t i t u t e 1977; Bioassay of cap tan f o r p o s s i b l e c a r c i n o g e n i c i t y , CAS No.133-06-2, NCI-CG-TR-15 Technical Report Series No. 15. C l a r k , T . ; Watkins, D . A . M . , P e s t i c . Sci., 1978, 9, 225. Vogeler, K . ; Niessen, Η . , Pflanzenschutznachr. Bayer, 1967, 20, 534. Sommers, E.; Richmond, D . V . ; P i c k a r d , J.Α., Na t u r e , 1967, 215, 214. V i l e s , F.J., J. Ind. Hyg. T o x . , 1940, 22, 188. Wilkes, P . S . , B u l l . Environm. Contam. T o x i c o l . , 1979, 23, 820. Westphal, D . ; Schuphan, I . ; Haque, Α . ; Ebing, W., manuscript i n p r e p a r a t i o n .

RECEIVED January 29, 1981. In Sulfur in Pesticide Action and Metabolism; Rosen, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

Biological and Chemical Behavior of ... - ACS Publications

Recommend Documents