O-isobutyl ethylthiocarbamate

Endpoint summary

Description of key information

Oral repeated dose toxicity

NOAEL for Repeated dose oral toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested).This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.

The database include a set of 91 chemicals that have been evaluated for their repeated dose oral toxicity potential.

Inhalation repeated dose toxicity

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.

NOAEL rat            

250 mg/kg bw/day

÷1.15 m3/kgbw

÷20m3/rat

NOAECrat    10.87 mg/m3

Dermal repeated dose toxicity

The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day for Dithiocarbamates

On a molecular weight scaled basis, the NOAELwould be 158.18 mg/kg bw(300x 161.26) /305.84 = 158.18 mg/kg bwThe NOAEL was 158.18 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin.

Dithiocarbamates are related compounds to Thionocarbamate.

The NOAEL was 158.18 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin

Justification for selection of repeated dose toxicity dermal - local effects endpoint:  

The generic modification from the NOAELtest (in mg/kg of body weight) to NOAELmodified (in mg/cm2/day) will be

NOAELin mg/cm2 = ((dose in mg/kg bw)x (average animal weight in kg)) / Treated surface in cm2)

NOAELtest* 2.4/127= NOAELmodified  

The highest dose not causing irritation/corrosion was 158.18 mg/kg bw in twenty-one day dermal toxicity study in rabbits of Edwards et al.,1989, the modified dose descriptor would be NOAELmodified =158.18 mg/kg*2.4 kg/127cm2=2.99 mg/cm2

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

Remarks:

other: QSAR model

Type of information:

(Q)SAR

Adequacy of study:

key study

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:Accepted HESS QSAR method for chemicals properties assessment.. This method is relevant for Repeated dose oral toxicity endpoints in mammals.

Qualifier:

according to guideline

Guideline:

other: QSAR Toolbox Version 3.3.5.17

Principles of method if other than guideline:

The profiler was developed by National Institute of Technology and Evaluation (NITE) in the contract research project “Development of Hazard Assessment Techniques by using Structure-activity Method (FY2007-FY2011)” by New Energy and Industrial Technology Development

GLP compliance:

no

Remarks:

not applicable HESS QSAR method for chemicals properties assessment.

Limit test:

no

Species:

rat

Strain:

other: QSAR model

Sex:

male/female

Route of administration:

other: QSAR model

Vehicle:

other: QSAR model

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

QSAR model

Duration of treatment / exposure:

QSAR model

Frequency of treatment:

QSAR model

Remarks:

Doses / Concentrations:

Basis:
other: QSAR model

No. of animals per sex per dose:

QSAR model

Control animals:

other: QSAR model

Details on study design:

The profiler contains category boundaries to be expected to induce similar toxicological effects in repeated dose oral toxicity. These category boundaries were developed based on repeated dose toxicity test data in the database of Hazard Evaluation Support System (HESS). Justification for each category (mechanistic or empirical information) is described.

Observations and examinations performed and frequency:

This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
The database include a set of 91 chemicals that have been evaluated for their repeated dose oral toxicity potential.

Other examinations:

This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
The database include a set of 91 chemicals that have been evaluated for their repeated dose oral toxicity potential.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Details on results:

In the present study, NOAEL for Repeated dose oral toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested).

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: In the present study, NOAEL for Repeated dose oral toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested).

Critical effects observed:

not specified

See attached QSAR study report

Conclusions:

In the present study, NOAEL for Repeated dose oral toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested).This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
The database include a set of 91 chemicals that have been evaluated for their repeated dose oral toxicity potential.

Executive summary:

Profiling results:

-DNA binding by OECD-No alert found

-Est rogen Receptor Binding-Non binder, non cyclic structure

-OECD HPV Chemical Categories-Not categorized

-Protein binding by OECD-No alert found

-Protein binding potency-Not possible to classify according to these rules (GSH)

-Superfragments-No superfragment

Repeated dose (HESS) NOAEL Repeated dose oral toxicity 250 mg/kg bw/day

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

NOAEL for Repeated dose oral toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested).This grouping method contains simple categories for Repeated dose oral toxicity. This method is relevant for Repeated dose oral toxicity endpoints in mammals.
The database include a set of 91 chemicals that have been evaluated for their repeated dose oral toxicity potential.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

10.87 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Inhalation repeated dose toxicity
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
250 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 10.87 mg/m3

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

10.87 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Inhalation repeated dose toxicity
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL rat
250 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECrat 10.87 mg/m3

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

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.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

Data about the area covered by the test material and occlusion are not reported.

GLP compliance:

not specified

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Interfauna U.K. Ltd., Huntingdon, Cambridgeshire, England- Age at study initiation: 10-12 weeks on arrival- Weight at study initiation: fehlt noch- five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

TEST SITE- Area of exposure: no dataREMOVAL OF TEST SUBSTANCE- Washing (if done): with water- Time after start of exposure: 6 hTEST MATERIAL- Amount(s) applied (volume or weight with unit): 100, 300, 1000 mg/kg bw/day - For solids, paste formed: Yes. Powder was moistened with water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

purity of ziram was analysed

Duration of treatment / exposure:

21 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:100, 300, 1000 mg/kg bw/dayBasis:nominal per unit body weight

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Positive control:

no

Observations and examinations performed and frequency:

CLINICAL SIGNS- Time schedule: once dailyMORTALITY - Time schedule: once dailyDERMAL IRRITATION- Time schedule for examinations: Prior to the first application and subsequent daily (erythema and eschar / oedema formation) .BODY WEIGHT - Time schedule for examinations: Prior to dosing and then once weekly. FOOD CONSUMPTION- Time schedule for examinations: Once weekly.HAEMATOLOGY- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.- Animals fasted: Yes - Parameters: haematocrit, erythrocyte count, haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, platelet count, total leukocyte count, differential leukocyte count, cell morphology, thrombotestCLINICAL CHEMISTRY- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.- Animals fasted: Yes- Parameters: glucose, blood urea nitrogen, creatinine, total bilirubin, total cholesterol, alanine aminotransferase (GPT), aspartate aminotransferase (GOT), alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride, albumin, total protein, albumin/globulin ratio

Sacrifice and pathology:

ORGAN WEIGHTSFrom all animals sacrificed at termination.- Organs: adrenals, liver, kidneys, testes with epididymides/ovariesGROSS AND HISTOPATHOLOGYAll animals were sacrificed at study termination and a gross pathological examination was performed.- Histopathology: from all animals of the control and highest dose group- Organs: abnormal tissue, skin (treated and untreated), kidneys, liver

Statistics:

All analyses were carried out separately for male and female.The following tests were used for food and water consumption, bodyweight, relative organ weight and clinical pathology data:- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.- Analyses of variance were followed by a Student’s ‘t’ test and Williams’ test for a dose-related response, although only the one thought most appropriate for the response pattern observed has been reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).Where appropriate for organ weight data, analysis of covariance was used in place of analysis of variance.

Clinical signs:

no effects observed

Dermal irritation:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAINBodyweight losses or reduced bodyweight gain was observed in females dosed at 1000 mg/kg bw/day. FOOD CONSUMPTIONReduction was measured for females dosed at 1000 mg/kg bw/day in week 1. Food consumption was also reduced in the following weeks but did not achieve statistical significance.HAEMATOLOGYSignificant lower lymphocyte counts for females dosed at 1000 mg/kg bw/day.CLINICAL CHEMISTRYLiver enzymes GOT and GPT were increased in females dosed at 1000 mg/kg bw/day and in case of GOT also at 300 mg/kg bw/day.Increased levels of bilirubin amongst females and cholesterol amongst both sexes dosed at 1000 mg/kg bw/day were also observed.GROSS PATHOLOGYIncreased incidence of irregular cortical scarring of the kidney in all groups was not considered to be treatment-related.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Dose descriptor:

NOAEL

Effect level:

158.18 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

On a molecular weight scaled basis, the NOAELwould be 158.18 mg/kg bw

(300x 161.26.24) /305.84 = 158.18 mg/kg bw

Conclusions:

On a molecular weight scaled basis, the NOAELwould be 158.18 mg/kg bw(300x 161.26) /305.84 = 158.18 mg/kg bwThe NOAEL was 158.18 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin.
Dithiocarbamates are related compounds to Thionocarbamate.

Executive summary:

Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

158.18 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The NOAEL was 158.18 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

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.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

Data about the area covered by the test material and occlusion are not reported.

GLP compliance:

not specified

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Interfauna U.K. Ltd., Huntingdon, Cambridgeshire, England- Age at study initiation: 10-12 weeks on arrival- Weight at study initiation: fehlt noch- five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

TEST SITE- Area of exposure: no dataREMOVAL OF TEST SUBSTANCE- Washing (if done): with water- Time after start of exposure: 6 hTEST MATERIAL- Amount(s) applied (volume or weight with unit): 100, 300, 1000 mg/kg bw/day - For solids, paste formed: Yes. Powder was moistened with water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

purity of ziram was analysed

Duration of treatment / exposure:

21 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:100, 300, 1000 mg/kg bw/dayBasis:nominal per unit body weight

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Positive control:

no

Observations and examinations performed and frequency:

CLINICAL SIGNS- Time schedule: once dailyMORTALITY - Time schedule: once dailyDERMAL IRRITATION- Time schedule for examinations: Prior to the first application and subsequent daily (erythema and eschar / oedema formation) .BODY WEIGHT - Time schedule for examinations: Prior to dosing and then once weekly. FOOD CONSUMPTION- Time schedule for examinations: Once weekly.HAEMATOLOGY- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.- Animals fasted: Yes - Parameters: haematocrit, erythrocyte count, haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, platelet count, total leukocyte count, differential leukocyte count, cell morphology, thrombotestCLINICAL CHEMISTRY- Time schedule for collection of blood: For all animals at Day 20. For specified animals procedure was repeated on Day 22.- Animals fasted: Yes- Parameters: glucose, blood urea nitrogen, creatinine, total bilirubin, total cholesterol, alanine aminotransferase (GPT), aspartate aminotransferase (GOT), alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride, albumin, total protein, albumin/globulin ratio

Sacrifice and pathology:

ORGAN WEIGHTSFrom all animals sacrificed at termination.- Organs: adrenals, liver, kidneys, testes with epididymides/ovariesGROSS AND HISTOPATHOLOGYAll animals were sacrificed at study termination and a gross pathological examination was performed.- Histopathology: from all animals of the control and highest dose group- Organs: abnormal tissue, skin (treated and untreated), kidneys, liver

Statistics:

All analyses were carried out separately for male and female.The following tests were used for food and water consumption, bodyweight, relative organ weight and clinical pathology data:- If the data consisted predominantly of one particular value (relative frequency of the mode exceeds 75%), the proportion of animals with values different from the mode was analysed by appropriate methods. Otherwise:- Bartlett’s test was applied to test for heterogeneity of variance between treatments. Where significant (at the 1% level) heterogeneity was found, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.- If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out. If significant heterogeneity of variance was present, and could not be removed by a transformation, the Kruskal-Wallis analysis of ranks was used.- Analyses of variance were followed by a Student’s ‘t’ test and Williams’ test for a dose-related response, although only the one thought most appropriate for the response pattern observed has been reported. The Kruskal-Wallis analyses were followed by the non-parametric equivalents of the ‘t’ test and Williams’ test (Shirleys’ test).Where appropriate for organ weight data, analysis of covariance was used in place of analysis of variance.

Clinical signs:

no effects observed

Dermal irritation:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

BODY WEIGHT AND WEIGHT GAINBodyweight losses or reduced bodyweight gain was observed in females dosed at 1000 mg/kg bw/day. FOOD CONSUMPTIONReduction was measured for females dosed at 1000 mg/kg bw/day in week 1. Food consumption was also reduced in the following weeks but did not achieve statistical significance.HAEMATOLOGYSignificant lower lymphocyte counts for females dosed at 1000 mg/kg bw/day.CLINICAL CHEMISTRYLiver enzymes GOT and GPT were increased in females dosed at 1000 mg/kg bw/day and in case of GOT also at 300 mg/kg bw/day.Increased levels of bilirubin amongst females and cholesterol amongst both sexes dosed at 1000 mg/kg bw/day were also observed.GROSS PATHOLOGYIncreased incidence of irregular cortical scarring of the kidney in all groups was not considered to be treatment-related.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Dose descriptor:

NOAEL

Effect level:

158.18 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

not specified

On a molecular weight scaled basis, the NOAELwould be 158.18 mg/kg bw

(300x 161.26.24) /305.84 = 158.18 mg/kg bw

Conclusions:

On a molecular weight scaled basis, the NOAELwould be 158.18 mg/kg bw(300x 161.26) /305.84 = 158.18 mg/kg bwThe NOAEL was 158.18 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin.
Dithiocarbamates are related compounds to Thionocarbamate.

Executive summary:

Ziram (purity 98.5%) was applied to the intact skin of groups of five male and five female New Zealand white rabbits, weighing 2.2-2.6 kg, daily for 21 consecutive days at doses of 0, 100, 300, or 1000 mg/kg bw per day. The test substance was moistened with distilled water and maintained on the backs of the rabbits for 6 h each day, after which the dressings were removed and the treated skin washed with tap-water at 30-40°C and gently blotted dry. No dermal reaction to the treatment was observed at any dose. Significant losses in body weight or low body-weight gain and reduced food consumption were recorded for female rabbits receiving 1000 mg/kg bw. The number of lymphocytes was reduced in both males and females at 1000 mg/kg bw, and alanine and aspartate transaminase activities were increased at 300 and 1000 mg/kg bw. At the highest dose, significantly increased levels of bilirubin were found in females and of cholesterol in animals of each sex. The NOAEL was 300 mg/kg bw per day, on the basis of decreased body weight, body-weight gain, food consumption, and number of lymphocytes and increased bilirubin and cholesterol levels at 1000 mg/kg bw per day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2.99 mg/cm²

Study duration:

subchronic

Species:

rat

Quality of whole database:

The generic modification from the NOAELtest (in mg/kg of body weight) to NOAELmodified (in mg/cm2/day) will be
NOAELin mg/cm2 = ((dose in mg/kg bw)x (average animal weight in kg)) / Treated surface in cm2)
NOAELtest* 2.4/127= NOAELmodified
The highest dose not causing irritation/corrosion was 158.18mg/kg bw in twenty-one day dermal toxicity study in rabbits of Edwards et al.,1989, the modified dose descriptor would be NOAELmodified =158.18 mg/kg*2.4 kg/127cm2=2.99 mg/cm2

Justification for classification or non-classification

Based on the hazard assessment O-isobutyl ethylthiocarbamate (IBETC) in section 2.1 and 2.2. in IUCLID 6., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99) and according to the criteria described in Directive 67/548 and in the CLP Regulation:

 

Directive 67/548

Repeated dose toxicity R33 Danger of cumulative effects. T; R48/23 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation. T; R48/23/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin. T; R48/23/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. T; R48/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin. T; R48/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed. T; R48/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure if swallowed. Xn; R48/20 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation. Xn; R48/20/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin. Xn; R48/20/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. Xn; R48/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin. Xn; R48/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed. Xn; R48/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure if swallowed

CLP

Repeated dose toxicity STOT Rep. Exp. 1 STOT Rep. Exp. 2 H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H373: May cause damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

It is concluded that the substance O-isobutyl ethylthiocarbamate (IBETC) does not meet the criteria to be classified for human health hazards for Repeated dose toxicity

 

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