O-isobutyl ethylthiocarbamate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Dithiocarbamates are related compounds to Thionocarbamate.

Objective of study:

metabolism

Qualifier:

according to guideline

Guideline:

EPA OPP 85-1 (Metabolism and Pharmacokinetics)

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.36 (Toxicokinetics)

Deviations:

yes

Remarks:

Distribution was not investigated.

GLP compliance:

yes

Radiolabelling:

yes

Remarks:

14C-Ziram

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River, US
- Age at study initiation: 44 days (m); 51 days (f)
- Weight at study initiation: 149-169 g (m); 145-162 g (f)

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Duration and frequency of treatment / exposure:

Single and multiple (15 days daily) application

Remarks:

Doses / Concentrations:
Single: 15 and 352 mg/kg
Multiple: 15 mg/kg (14x nonradiolabeled; 1x radiolabeled)

No. of animals per sex per dose / concentration:

5

Control animals:

yes, concurrent vehicle

Details on dosing and sampling:

- Tissues and body fluids sampled: air, urine, faeces, blood, several organs

The CO2 trapping solution and the volatile traps were collected at 0-4, 4-8, 8-12, and 12-24 h following administration of the radiolabeled Ziram and daily thereafter for a total of 4 days. Urine and faeces samples were collected at 0-6, 6-12, and 12-24 hours after the radiolabeled dose and daily thereafter for a total of 7 days. Urine and faeces were collected in plastic containers surrounded by ice. At the end of the collection period, the animals were anesthetized with halothane and exsanguinated by cardiac puncture. Blood (2 to 5 mL) was collected and weighed in heparinized tubes and saved for radioanalysis. After sacrifice the cages were washed with a 1.0% trisodium phosphate solution which was saved for analysis.

Details on absorption:

The mean 14C recovery ranged from 79% to 92% of the total doses administered.

Details on distribution in tissues:

The mean total radioactivity retained in the tissues and carcasses ranged from 1.11% to 1.92% of the total dose administered. For the low dose groups, the residue levels in the blood and tissues ranged from 0.05 to 2.5 ppm (µg 14C-Ziram equivalents/g sample). The highest levels were found in blood, liver, kidney, heart, lungs, spleen and thyroid gland.

Details on excretion:

The majority of the radioactivity was found in urine (17% to 35%), faeces (9% to 18%), and expired air (36% to 53%). The rate of elimination was relatively fast; the majority of the radioactivity was eliminated within 48 hours after dosing.
No apparent sex-related differences were observed for 14C elimination or distribution for any of the treated groups.

Metabolites identified:

yes

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
Dithiocarbamates are related compounds to Thionocarbamate .
The mean total radioactivity retained in the tissues and carcasses ranged from 1.11% to 1.92% of the total dose administered. For the low dose groups, the residue levels in the blood and tissues ranged from 0.05 to 2.5 ppm (µg 14C-Ziram equivalents/g sample). The highest levels were found in blood, liver, kidney, heart, lungs, spleen and thyroid gland.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Data waiving:

other justification

Justification for data waiving:

other:

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Isobutyl alcohol is reagents used in the manufacture of O-isobutyl ethylthiocarbamate.Therefore, the health effects of Isobutyl alcohol need to be considered in the assessment of O-isobutyl ethylthiocarbamate .

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

In an effort to understand the elimination kinetics of aliphatic alcohols found in alcoholic beverages, research was conducted with human subjects.
Test subjects consumed isobutanol in an ethanol/water vehicle over a two hour time period. Blood and urine samples were collected prior to consumption, at the end of the two-hour consumption period, at one, two, eight (urine only), and nine hours after the end of the exposure period.

GLP compliance:

no

Radiolabelling:

no

Species:

other: human

Strain:

not specified

Sex:

not specified

Route of administration:

other: oral by drinking

Vehicle:

other: orange juice

Duration and frequency of treatment / exposure:

2 hours followed by 9 hours of post exposure

Remarks:

Doses / Concentrations:
not specified

No. of animals per sex per dose / concentration:

not specified

Control animals:

not specified

Positive control reference chemical:

None.

Metabolites identified:

yes

Details on metabolites:

isobutyraldehyde and isobutyric acid
The blood concentrations of isobutanol, isobutyraldehyde, and isobutyric acid were approximately 4, 4, and 17 µmol/L at the end of the consumption period, clearly demonstrating that isobutyric acid was the major metabolite of isobutanol metabolism. While the addition of ethanol to the test beverage definitely altered the rate of isobutanol metabolism (via a competition for metabolic enzymes), the presence of ethanol did not affect how isobutanol was metabolized. Blood levels of isobutanol decreased over the next two hours while the isobutyraldehyde levels slowly increased in the blood. Isobutyric acid levels also decreased after the end of the consumption period. Urinary concentrations of isobutanol peaked at the one-hour postexposure time point. Urinary levels of isobutyraldehyde peaked at the eight hour post-exposure time point. Urinary levels of isobutyric acid peaked at the end of the two-hour exposure period. Urinary levels of propionaldehyde roughly followed those for isobutyraldehyde with peak levels of approximately 8 µmol/L. Urinary levels of propionic acid rose after the exposure period ended with plateau levels between 2 and 8 hours of approximately 60 µmol/L. Urinary levels of succinic acid roughly followed the propionic acid urinary elimination curve with peak levels of approximately 30 µmol/L. A diagram was provided in the paper describing the further metabolism of isobutyric acid, ending with propionic acid. The formation of succinic acid from propionic acid is proposed based on the known intermediate metabolism of propionic acid via the citric acid cycle

The blood concentrations of isobutanol, isobutyraldehyde, and isobutyric acid were approximately 4, 4, and 17 µmol/L at the end of the consumption period, clearly demonstrating that isobutyric acid was the major metabolite of isobutanol metabolism. While the addition of ethanol to the test beverage definitely altered the rate of isobutanol metabolism (via a competition for metabolic enzymes), the presence of ethanol did not affect how isobutanol was metabolized. Blood levels of isobutanol decreased over the next two hours while the isobutyraldehyde levels slowly increased in the blood. Isobutyric acid levels also decreased after the end of the consumption period. Urinary concentrations of isobutanol peaked at the one-hour postexposure time point. Urinary levels of isobutyraldehyde peaked at the eight hour post-exposure time point. Urinary levels of isobutyric acid peaked at the end of the two-hour exposure period. Urinary levels of propionaldehyde roughly followed those for isobutyraldehyde with peak levels of approximately 8 µmol/L. Urinary levels of propionic acid rose after the exposure period ended with plateau levels between 2 and 8 hours of approximately 60 µmol/L. Urinary levels of succinic acid roughly followed the propionic acid urinary elimination curve with peak levels of approximately 30 µmol/L. A diagram was provided in the paper describing the further metabolism of isobutyric acid, ending with propionic acid. The formation of succinic acid from propionic acid is proposed based on the known intermediate metabolism of propionic acid via the citric acid cycle

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
No bioaccumulation potential based on study results for Isobutyl alcohol
Isobutyl alcohol is reagents used in the manufacture of O-isobutyl ethylthiocarbamate.Therefore, the health effects of Isobutyl alcohol need to be considered in the assessment of O-isobutyl ethylthiocarbamate .

Reference 4

Endpoint:

dermal absorption in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction:US EPA accepted QSAR method for chemicals properties assessment.

Qualifier:

no guideline required

Principles of method if other than guideline:

Using the DERMWIN v2.01 QSAR model

GLP compliance:

no

Remarks:

not applicable to QSAR models

Radiolabelling:

no

Species:

other: QSAR model,

Strain:

other: QSAR model,

Sex:

not specified

Type of coverage:

other: QSAR model

Vehicle:

other: QSAR model

Duration of exposure:

not applicable to QSAR models

Doses:

not applicable to QSAR models

No. of animals per group:

not applicable to QSAR models

Control animals:

no

Details on study design:

not applicable to QSAR models

Details on in vitro test system (if applicable):

not applicable to QSAR models

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

A QSAR model predicts that the permeability of O-isobutyl ethylthiocarbamate (IBETC) to human skin is quite low. The permeability coefficient was determined to be 0.00487 mg/cm2, which is around 1% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)=00.0663 cm/hr

A QSAR model predicts that the permeability of O-isobutyl ethylthiocarbamate (IBETC)  to human skin is quite low. The permeability coefficient was determined to be   0.00487 mg/cm2, which is around 1% of the skin penetration rate.

Predicted dermally absorbed coefficient was determined to be Kp (est)=00.0663 cm/hr  

Conclusions:

A QSAR model predicts that the permeability of O-isobutyl ethylthiocarbamate (IBETC) to human skin is quite low. The permeability coefficient was determined to be 0.00487 mg/cm2, which is around 1% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)=00.0663 cm/hr

Executive summary:

A QSAR model predicts that the permeability of O-isobutyl ethylthiocarbamate (IBETC)  to human skin is quite low. The permeability coefficient was determined to be   0.00487 mg/cm2, which is around 1% of the skin penetration rate.

Predicted dermally absorbed coefficient was determined to be Kp (est)=00.0663 cm/hr  

Reference 5

Endpoint:

dermal absorption in vivo

Type of information:

other: published dara

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Dithiocarbamates are related compounds to Thionocarbamate.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Deviations:

yes

Remarks:

Recovery was not in the required range. Volatile 14C-compounds were not collected.

GLP compliance:

yes

Radiolabelling:

yes

Remarks:

(14C)-Ziram

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

- Source: Charles River Laboratories, Wilmington, Massachusetts, US
- Weight: 237-267 g (Individual data of control group not reported)

Type of coverage:

open

Vehicle:

water

Duration of exposure:

0.5, 1, 2, 4, 10 and 24 h

Doses:

1.2, 9.9, 57.1% (w/v)

No. of animals per group:

4 per timepoint

Control animals:

yes

Signs and symptoms of toxicity:

no effects

Dermal irritation:

not examined

Absorption in different matrices:

see Table 6_2-1

Total recovery:

see Table 6_2-1

Dose:

0.086 mg/cm²

Parameter:

percentage

Absorption:

28.5 %

Remarks on result:

other: 24 h

Dose:

0.95 mg/cm²

Parameter:

percentage

Absorption:

30.7 %

Remarks on result:

other: 24 h

Dose:

7.25 mg/cm²

Parameter:

percentage

Absorption:

4.89 %

Remarks on result:

other: 24 h

Table A6_2-1:     Mean recovery of radioactivity from male rats following a single dermal application of (^14C)-ziram
Parameter /Tissue	1.07 mg/rat						11.9 mg/rat						90.6 mg/rat
	[%] of administered dose
	0.5 h	1 h	2 h	4 h	10 h	24 h	0.5 h	1 h	2 h	4 h	10 h	24 h	0.5 h	1 h	2 h	4 h	10 h	24 h
Skin rinse	75.22	85.35	78.90	74.64	70.07	70.53	72.39	69.03	67.03	60.71	72.33	68.79	101.96	99.79	99.73	97.20	100.26	93.49
Skin cell cover	0.06	0.08	0.12	0.12	0.26	0.60	0.02	0.04	0.05	0.06	0.14	0.16	0.04	0.06	0.18	0.26	0.15	0.35
Skin enclosure	0.10	0.14	0.33	0.20	0.07	0.35	0.42	0.17	0.31	0.17	0.09	0.43	1.02	1.44	1.02	0.22	1.03	1.26
Total nonabsorbed dose	75.38	85.57	79.35	74.96	70.40	71.48	72.83	69.24	67.39	60.94	72.56	69.38	103.02	101.29	100.93	97.68	101.44	95.10
Urine	ND	ND	0.01^a	0.02	0.06^a	0.16	ND	ND	0.01	0.01	0.02	0.05	ND	ND	ND	0.01	0.01	0.01
Faeces	ND	ND/NS	ND	ND/NS	ND	0.01	ND/NS	ND/NS	ND/NS	ND/NS	ND/NS	0.01^a	ND/NS	0.01^c	ND/NS	ND/NS	ND/NS	ND
Cage wash	ND	ND	ND	ND	ND	0.02^b	ND	ND	0.01^c	ND	ND	ND	ND	ND	ND	ND	ND	ND
Cage wipe	ND	ND	0.01^a	0.01	0.01	0.01	ND	0.01^c	0.01^c	0.01^b	0.01	0.01	0.01^c	0.01^b	ND	0.01^b	ND	0.01^b
Total excreted	ND	ND	0.01	0.02	0.06	0.18	ND	0.01	0.01	0.01	0.02	0.05	0.01	0.01	ND	0.01	0.01	0.01
Carcass	ND	ND	ND	ND	0.08	0.14	ND	ND	0.01	ND	ND	0.03	ND	ND	ND	ND	ND	ND
Skin	5.63	3.18	4.57	5.05	7.88	3.79	3.04	3.48	5.67	9.93	8.86	4.46	0.56	0.93	1.11	1.48	1.44	1.52
Total absorbed dose	5.63	3.18	4.57	5.07	8.02	4.11	3.04	3.48	5.68	9.93	8.88	4.54	0.56	0.93	1.11	1.48	1.44	1.52
Total recovery	81.01	88.75	83.92	80.03	78.42	75.59	75.87	72.72	73.07	70.87	81.44	73.92	103.58	102.22	102.04	99.16	102.88	96.62
NS    Not sampled ND   Not detectable ^a      Mean of three animals ^b      Mean of two animals ^c      Mean of one animal

 

Table A6_2-2:     Concentations of radioactivity in blood from male rats following a single dermal application of (^14C)-ziram
Dose level	µg ziram/g
	0.5 h	1 h	2 h	4 h	10 h	24 h
1.07 mg	0.002	ND	ND	ND	0.002	0.006 .006
11.9 mg	ND	ND	ND	ND	ND	ND
90.6 mg	ND	ND	ND	ND	ND	ND
ND    Not detectable

 

Conclusions:

Dithiocarbamates are related compounds to Thionocarbamate.
Less than 0.3% of the administered radiolabel was retained in the carcass and was eliminated in the excreta within 24 h after exposure.
The mean amount absorbed (sum of radiolabel in urine, carcass, and skin at the test site) by 24 h was 29% of the administered dose in animals at 1.1 mg, 31% in those at 12 mg, and 5% for those at 91 mg, indicating non-linear dermal absorption.

Executive summary:

Less than 0.3% of the administered radiolabel was retained in the carcass and was eliminated in the excreta within 24 h after exposure. The mean amount absorbed (sum of radiolabel in urine, carcass, and skin at the test site) by 24 h was 29% of the administered dose in animals at 1.1 mg, 31% in those at 12 mg, and 5% for those at 91 mg, indicating non-linear dermal absorption.

Description of key information

O-isobutyl ethylthiocarbamate has not bioaccumulation potential.

 

The chemical belongs to the thiocarbamate group. In general, thiocarbamates are absorbed via the skin, mucous membranes, respiratory and gastrointestinal tracts, with rapid elimination via expired air and urine. Thiocarbamates are also rapidly metabolised, producing either mercapturic acid compounds or compounds that enter the carbon metabolic pool.

 

As a general rule, thiocarbamates can be absorbed by theorganism via the skin, mucous membranes, and the respiratory andgastrointestinal tracts.  They are eliminated quite rapidly,mainly via expired air and urine.

 

Two  major  pathways  exist  for  the  metabolism  ofthiocarbamates in mammals.  One is via sulfoxidation  andconjugation with glutathione. The conjugation product is thencleaved to a cysteine derivative, which is metabolized to amercapturic acidcompound. The second route is oxidation of thesulfur to a sulfoxide, which is then oxidized to a sulfone, orhydroxylation to compounds that enter the carbon metabolic pool.

 

In plants, thiocarbamates are rapidly metabolized in typicaloxidation reactions, e.g., thiol sulfur oxidation to the corres-ponding sulfoxides, reactive intermediates that are capable of reacting with sulfhydryl groups (as in glutathione, cysteine)to form conjugates. Onhydrolysis, mercaptans, carbon dioxide,and alkylamines may be formed.

 

While thiocarbamates and their metabolic products can befound in certain organs, such as liver and kidneys, accumulationdoes not take place because of their rapid metabolism.

 

Therefore testing for Basic toxicokinetics does not need to be performed.

References

World Health Orgnization Geneva, 1988,THIOCARBAMATE PESTICIDES - A GENERAL INTRODUCTION

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

1