Sulfur in Pesticide Action and Metabolism - American Chemical Society

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

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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.

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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



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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

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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

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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


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

Sulfur in Pesticide Action and Metabolism - American Chemical Society

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