Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
Non-ER binder due to non-cyclic molecular structure. Isopropyl Ethyl Thionocarbamate (IPETC ) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%)  and propan-2-ol (1%-5%) have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore  Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol  does not cause reproductive toxicity.
Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type
Type of information:
experimental study
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:
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc, Kingston facility, Stone Ridge, New York.
- Age at study initiation: (P) 8 wks; (F1) 8 wks
- Weight at study initiation: (P) Males: 265.5-331.9 g; Females: 175.2-228.4 g; (F1) Males: 265.2-265.4 g; Females: 181.1-181.2 g
- Fasting period before study: None
- Housing: stainless steel and wire mesh cage, individually housed, except during the first week of quarantine, during mating, and during lactation
- Diet (e.g. ad libitum): Purina certified rodent chow ad libitum
- Water (e.g. ad libitum): automatic watering system, ad libitum (Elizabethtown Water Company, Elizabeth, New Jersey)
- Acclimation period: 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24.4°C
- Humidity (%): 40 to 70 %
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: June 13, 1990 To: April 15, 1992
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Undiluted test material was thoroughly miscible in carrier (RO water) prior to dispensing. Test material dosing solutions were prepared at 6-15 day intervals, in consideration of laboratory scheduling/ Dosing solutions were aliquoted on or prior to the first scheduled day of dosing. Aliquoted dosing solutions were stored in the Compound Preparation Department refrigerator. Unused portions were returned to the Compound Preparation Lab for disposal.

DIET PREPARATION
not administered in diet

VEHICLE
- Justification for use and choice of vehicle (if other than water): vehicle used was water
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: when pregnant or 7 days had elapsed (then cohabited with a different male)
- Proof of pregnancy: copulatory plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: yes 3 attempts
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of isopropyl alchohol dose solutions in reverse osmosis water were analyzed by Gas Chromatography for concentration verification.
Duration of treatment / exposure:
All P1 and F1 (P2) male and female animals received test or control material daily for at least 10 weeks prior to mating, throughout the mating period, and until the day prior to euthanasia. Additionally, P1 and F1 (P2) females received test or control material during gestation, lactation, and until the day prior to euthanasia, following weaning of their offspring on day 21 postpartum. F1 neonates prior to selection for mating received test or control material beginning on postnatal day 21.
Frequency of treatment:
daily
Details on study schedule:
- F1 parental animals not mated until 11 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: 15 weeks
Remarks:
Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
30/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): random
Positive control:
no
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: morning and afternoon


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to selecton, first day of dosing and weekly thereafter until euthanasia (males) or weekly until post partum day 21 (females)


BODY WEIGHT: Yes
- Time schedule for examinations: prior to selecton, first day of dosing and weekly thereafter until euthanasia (males) or weekly until post partum day 21 (females)
Oestrous cyclicity (parental animals):
not reported
Sperm parameters (parental animals):
not reported
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, and physical abnormalities.


GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals as soon as possible after the last litters in each generation were produced.
- Maternal animals: All surviving animals after the last litter of each generation was weaned.


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations.


HISTOPATHOLOGY / ORGAN WEIGHTS
The following organs and tissues were prepared for microscopic examination: liver, kidney, vagina, uterus, ovaries, testes, epididymides, seminal vesicles, prostate, pituitary, liver, and any abnormal tissue
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations macroscopic and microscopic examination


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations
Statistics:
The following parameters were analyzed statistically for significant differences: mean body weights; mean food consumption; mean organ weights; mean relative organ weights
Reproductive indices:
calculated
Offspring viability indices:
calculated
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Free of any observable abnormalities
1 death in control and 1 death in mid dose group considered to be incidental. 2 deaths in high dose group, cause of death was not determined

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
no significant differences

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
no significant differences


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
no significant differences


ORGAN WEIGHTS (PARENTAL ANIMALS)
Mean absolute and relative liver weights in high dose P1 males were statistically significantly increased compared to controls. In females, relative liver weight was increased in the mid-dose and high-dose groups and relative kidney weight was increased in the high dose group.


GROSS PATHOLOGY (PARENTAL ANIMALS)
no significant effects

HISTOPATHOLOGY (PARENTAL ANIMALS)
no significant effects
Dose descriptor:
NOAEL
Remarks:
offspring toxicity
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reduced body weights and increased mortality at 1000 mg/kg bw/day
Remarks on result:
other: Generation: F1/F2 (migrated information)
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
VIABILITY (OFFSPRING)
Increased mortality was observed in high-dose F1 offspring compared with controls from postnatal Days 0 to 2. Several F1 weanlings died or were euthanized prior to P2 selection; 1 each in the low- and mid-dose groups, and 18 in the high-dose group.

CLINICAL SIGNS (OFFSPRING)
no significant effects

BODY WEIGHT (OFFSPRING)
High dose F1 male body weights were significantly lower on postnatal days 0 and 1 compared to controls.


GROSS PATHOLOGY (OFFSPRING)
No significant effects

HISTOPATHOLOGY (OFFSPRING)
No significant effects
Dose descriptor:
NOAEL
Remarks:
parental
Generation:
F1
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: increased organ weights at 1000 mg/kg bw/day
Dose descriptor:
NOAEL
Remarks:
reproductive
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed at highest dose
Reproductive effects observed:
not specified
Conclusions:
NOAEL-500 mg/kg bw/day. Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Endpoint:
reproductive toxicity, other
Remarks:
other: repeated dose toxicity, subchronic
Type of information:
experimental study
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:
Butan-1-ol (Butyl alcohol) is both reagents used in the manufacture of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol. Therefore, Butan-1-ol (Butyl alcohol) need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Principles of method if other than guideline:
Four groups of male and female rats (30/sex/group) were administered daily by gavage 0, 30, 125 or 500 mg/kgbw/d for either 6 or 13 weeks.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, U.S.A.
- Age at study initiation: 36-37 d
- Mean weight at study initiation: males 90 g, females 86 g
- Housing: individually
- Diet (e.g. ad libitum): Purina Certiofied Rodent Laboratory Chow #5002 (pellet)
- Water (e.g. ad libitum): filtered municipal water
- Acclimation period: 7 days before the pretreatment week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 1
- Humidity (%): 48 +/- 9
- Photoperiod (hrs dark / hrs light): 12:12
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions of butanol in deionized water were used.

VEHICLE
- Concentration in vehicle: not specified
- Amount of vehicle (if gavage): 10 ml/kg was the constant dosing volume
Details on mating procedure:
no mating
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 (interim sacrifice) or 13 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 30, 125, 500 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
30
Control animals:
yes, concurrent vehicle
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly


FOOD CONSUMPTION: Yes
-Time schedule: Food consumption was recorded weekly


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmic examination was conducted prior to treatment and during week 13 before final necropsy.
- Dose groups that were examined: no data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: before the start of the study, during week 6 and during week 13
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 males and 10 females
- parameters: hemoglobin ( HGB), hematocrit (PCV), erythrocyte count (RBC), mean cell volume (MCV), mean cell hemoglobin (MCH),mean cell hemoglobin concentration (MCHC) total and differential leucocyte counts (WBC), estimated platelet count (PLT)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before the start of the study, during week 6 and during week 13
- Animals fasted: No data
- How many animals: 10 males and 10 females
- parameters: alkaline phosphatase (Alk phos) blood urea nitrogen (BUN), glutamate pyruvate transaminase (SGPT), glutamate oxalacetate transaminase (SGOT), glucose (Gluc), total protein (TP), albumin (Alb), A/G ratio (calculated), globulin (calculated), total bilirubin (Tot. bili.), sodium (Na), potassium (K ), chloride (Cl), calcium (Ca), inorganic phosphate (Phos), carbon dioxide (TCO2), total serum cholesterol (Chol), creatinine.


URINALYSIS: Yes
- Time schedule for collection of urine: before the start of the study, during week 6 and during week 13
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- parameters: pH, specfic gravity, glucose, protein, ketones, bilirubin, urobilinogen, microscopy of sediment
Postmortem examinations (parental animals):
At the interim and final sacrifice, testes (with epididymes) and ovaries were weighed. Testis (with epididymis), ovary, uterus and cervix were part of the histological examinations.
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): Ataxia and hypoactivity (lasting less than 1 h) were observed 2 to 3 minutes after dosing in both sexes of the high-dose group (500 mg/kg bw/d) during the final 6 weeks of dosing. Such ataxia and hypoactivity are typically seen following high oral doses of alcohols. The rapid induction/remission of these effects and the reported increased incidence after the interim kill may be due to the fact that personnel were able to collect post-dose observations more quickly since fewer animals required dosing.
No significant changes between treated groups and controls were observed concerning mortality (three rats were found dead or sacrificed in extremis, but these deaths could not be attributed to the test article.).
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS) : no significant changes between treated groups and controls were observed
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): no significant changes between treated groups and controls were observed
ORGAN WEIGHTS (PARENTAL ANIMALS): no treatment-related effects

GROSS PATHOLOGY (PARENTAL ANIMALS): no treatment-related effects

HISTOPATHOLOGY (PARENTAL ANIMALS): no treatment-related effects
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed on reproductive organs
Clinical signs:
not examined
Mortality / viability:
not examined
Sexual maturation:
not examined
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified
Conclusions:
NOAEL-500 mg/kg bw/day. Butan-1-ol (Butyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Executive summary:

NOAEL-500 mg/kg bw/day.Butan-1-ol (Butyl alcohol)as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol  and propan-2-ol .

Endpoint:
reproductive toxicity, other
Remarks:
QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
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 Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Qualifier:
according to guideline
Guideline:
other: QSAR Toolbox Version 3.3.5.17
Principles of method if other than guideline:
This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
GLP compliance:
no
Remarks:
not applicable. QSAR model,Estrogen Receptor Binding method, relevant for reproductive toxicity endpoints in fish and mammals.
Limit test:
no
Species:
other: fish (trout) and mammals.
Strain:
other: QSAR model
Sex:
not specified
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Parental animals: Observations and examinations:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
Isopropyl Ethyl Thionocarbamate (IPETC ) have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Isopropyl Ethyl Thionocarbamate (IPETC ) does not cause reproductive toxicity.

1.1. CAS number:141-98-0
1.2. Other regulatory numbers: Not reported
1.3. Chemical name(s):
ethyl-thiocarbamic acid o-isopropyl ester
carbamothioic acid, ethyl-, o-(1-methylethyl) ester
o-isopropyl ethylthiocarbamate
o-propan-2-yl ethylcarbamothioate
carbamic acid, ethylthio-, o-isopropyl ester
1.3. Structure codes:
a. SMILES: CCCNC(=S)OC(C)C
1.4. 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
-US-EPA New Chemical Categories-Not categorized

Dose descriptor:
other: Relative ERBA (Estrogen Receptor Binding Affinity)
Effect level:
< -3 other: Log RBA(Relative Binding Affinities )
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
clinical signs
body weight and weight gain
water consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive performance
other: see 'Remark'
Remarks on result:
other: Generation: QSAR model (migrated information)
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Isopropyl Ethyl Thionocarbamate (IPETC ) have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Isopropyl Ethyl Thionocarbamate (IPETC ) does not cause reproductive toxicity.

1.1. CAS number:
141-98-0
1.2. Other regulatory numbers: Not reported
1.3. Chemical name(s):
ethyl-thiocarbamic acid o-isopropyl ester
carbamothioic acid, ethyl-, o-(1-methylethyl) ester
o-isopropyl ethylthiocarbamate
o-propan-2-yl ethylcarbamothioate
carbamic acid, ethylthio-, o-isopropyl ester
1.3. Structure codes:
a. SMILES: CCCNC(=S)OC(C)C
1.4. 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
-US-EPA New Chemical Categories-Not categorized

Dose descriptor:
other: Relative ERBA (Estrogen Receptor Binding Affinity)
Generation:
F1
Effect level:
< -3 other: Log RBA(Relative Binding Affinities )
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
sexual maturation
clinical signs
mortality
body weight and weight gain
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: neoplastic
other:
Remarks on result:
other: Non-ER binder due to non-cyclic molecular structure.
Reproductive effects observed:
not specified

This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.

 

Non-binder, impaired OH or NH2 group

Non-binder without OH or NH2 group

Non-binder, non-cyclic structure

Non-binder, MW > 500

Non-binder, non-cyclic structure– chemicals without cycles and MW =<500

Non-ER binder due to non-cyclic molecular structure.

 

Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .

Popular among these are the “four phase” assessment that includes Comparative Molecular Field Analysis (CoMFA) and the Common Reactivity Pattern Approach (COREPA)

Since the RE-binding is a receptor mediated event, particular organic functional groups, size and shape are critical to binding potency.

Isopropyl Ethyl Thionocarbamate (IPETC ) have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Isopropyl Ethyl Thionocarbamate (IPETC ) does not cause reproductive toxicity.

Conclusions:
Non-ER binder due to non-cyclic molecular structure. Isopropyl Ethyl Thionocarbamate (IPETC ) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol does not cause reproductive toxicity.
Executive summary:

Non-ER binder due to non-cyclic molecular structure. Isopropyl Ethyl Thionocarbamate (IPETC ) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol does not cause reproductive toxicity.

1.1. CAS number: 141-98-0

1.2. Other regulatory numbers: Not reported

1.3. Chemical name(s):

ethyl-thiocarbamic acid o-isopropyl ester

carbamothioic acid, ethyl-, o-(1-methylethyl) ester

o-isopropyl ethylthiocarbamate

o-propan-2-yl ethylcarbamothioate

carbamic acid, ethylthio-, o-isopropyl ester

1.3. Structure codes:

a. SMILES: CCCNC(=S)OC(C)C

1.4. 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

-US-EPA New Chemical Categories-Not categorized

Endpoint:
reproductive toxicity, other
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 Estrogen Receptor Binding QSAR method for chemicals properties assessment.. This method is relevant for reproductive toxicity endpoints in fish and mammals.
Qualifier:
according to guideline
Guideline:
other: Estrogen Receptor Binding method
Principles of method if other than guideline:
This grouping method contains simple categories for estrogen receptor (ER) binding. This method is relevant for reproductive toxicity endpoints in fish and mammals.
GLP compliance:
no
Remarks:
not applicable. QSAR model
Limit test:
no
Species:
other: fish and mammals.
Strain:
other: QSAR model
Sex:
not specified
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Remarks:
Doses / Concentrations:

Basis:
other: QSAR model
Control animals:
not specified
Parental animals: Observations and examinations:
Estrogen receptor (ER) binding is a molecular initiating event much like protein binding that leads to a series of adverse outcomes, which are typically considered reproductive and development hazards. It is an endpoint where several comprehensive databases exist, which has lead to the development of several approaches for using (Q)SARs to predict ER-binding and possible endocrine disruption .
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
QSAR model
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: QSAR model
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
QSAR model
Reproductive performance:
no effects observed
Description (incidence and severity):
QSAR model
No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Isopropyl Ethyl Thionocarbamate (IPETC) (CAS# 141-98-0 ) and respectively Reaction mass of O-isopropyl ethylthiocarbamate (98%) and n-butanol (1%) and propan-2-ol (1%) )and therefore Isopropyl Ethyl Thionocarbamate (IPETC) does not cause reproductive toxicity.
Dose descriptor:
other: QSAR model
Effect level:
< -3 other: Log RBA(Relative Binding Affinities )
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
other: No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Isopropyl Ethyl Thionocarbamate (IPETC) (CAS# 141-98-0 ) and respectively Reaction mass of O-isopropyl ethylthiocarbamate (98%) and n-butanol (1%) and propan-2-ol (1%)
Remarks on result:
other: Generation: QSAR model (migrated information)
Clinical signs:
no effects observed
Description (incidence and severity):
QSAR model
Mortality / viability:
no mortality observed
Description (incidence and severity):
QSAR model
Body weight and weight changes:
no effects observed
Description (incidence and severity):
QSAR model
Sexual maturation:
no effects observed
Description (incidence and severity):
QSAR model
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
QSAR model
Gross pathological findings:
no effects observed
Description (incidence and severity):
QSAR model
Histopathological findings:
no effects observed
Description (incidence and severity):
QSAR model
No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Isopropyl Ethyl Thionocarbamate (IPETC) (CAS# 141-98-0 ) and respectively Reaction mass of O-isopropyl ethylthiocarbamate (98%) and n-butanol (1%) and propan-2-ol (1%) )and therefore Isopropyl Ethyl Thionocarbamate (IPETC) does not cause reproductive toxicity.
Dose descriptor:
other: Relative ERBA (Estrogen Receptor Binding Affinity)
Generation:
F1
Effect level:
< -3 other: Log RBA(Relative Binding Affinities )
Based on:
other: Estrogen receptor (ER) binding
Sex:
not specified
Basis for effect level:
clinical signs
mortality
body weight and weight gain
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
other: No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Isopropyl Ethyl Thionocarbamate (IPETC) (CAS# 141-98-0 ) and respectively Reaction mass of O-isopropyl ethylthiocarbamate (98%) and n-butanol (1%) and propan-2-ol (1%)
Remarks on result:
other: No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Isopropyl Ethyl Thionocarbamate (IPETC)
Reproductive effects observed:
not specified

No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Isopropyl Ethyl Thionocarbamate (IPETC) (CAS# 141-98-0 ) and respectively Reaction mass of O-isopropyl ethylthiocarbamate (98%) and n-butanol (1%) and propan-2-ol (1%) )and therefore Isopropyl Ethyl Thionocarbamate (IPETC) does not cause reproductive toxicity.

Conclusions:
No binding to Estrogen Receptor Alpha (Log RBA >-3) for the Isopropyl Ethyl Thionocarbamate (IPETC) (CAS# 141-98-0 ) and respectively Reaction mass of O-isopropyl ethylthiocarbamate (98%) and n-butanol (1%) and propan-2-ol (1%) )and therefore Isopropyl Ethyl Thionocarbamate (IPETC) does not cause reproductive toxicity.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
21.74 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15m3/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 500 mg/kg bw/day
÷1.15m3/kgbw
÷20m3/rat
NOAECrat 21.74 mg/m3
Effect on fertility: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
12.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
 corrected dermal NOAEL=   oral NOAEL
500 mg/kg bw/day x 0.025 kg =                  
 NOAELrat  = 12.5 mg/kg bw/day
Additional information

Oral exposure

 

NOAEL-500 mg/kg bw/day. Propan-2-ol (Isopropyl alcohol) as a main constituent ofReaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol  and propan-2-ol .

 

NOAEL-500 mg/kg bw/day.Butan-1-ol (Butyl alcohol)as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol  and propan-2-ol .

 

Non-ER binder due to non-cyclic molecular structure. Isopropyl Ethyl Thionocarbamate (IPETC )as a main constituent ofReaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%)have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol does not cause reproductive toxicity.

 

Inhalation exposure:

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15m3/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            500 mg/kg bw/day

÷1.15m3/kgbw

÷20m3/rat

NOAECrat   = 21.74 mg/m3

 

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

500 mg/kg bw/day x 0.025 kg =                  

 NOAELrat  = 12.5 mg/kg bw/day

 

 


Short description of key information:
There are conclusive but not suffcient data for the classification of substance Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol with regard to reproduction.
Non-ER binder due to non-cyclic molecular structure. Isopropyl Ethyl Thionocarbamate (IPETC ) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) have a molecular weight of less than 500, but do not possess a cyclic structure is reported to non-binders to the receptor and therefore Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol does not cause reproductive toxicity.
It is concluded that the substance Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol does not meet the criteria to be classified for human health hazards for Reproductive toxicity

Effects on developmental toxicity

Description of key information
There are conclusive but not suffcient data for the classification of substanceReaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol   with regard to Developmental toxicity / teratogenicity 
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
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 DART QSAR method for chemicals properties assessment.. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.
Qualifier:
according to guideline
Guideline:
other: QSAR Toolbox Version 3.3.5.17
Principles of method if other than guideline:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.
GLP compliance:
no
Remarks:
not applicable DART QSAR method for chemicals properties assessment..
Limit test:
no
Species:
rat
Strain:
other: QSAR model
Route of administration:
other: QSAR model
Vehicle:
other: QSAR model
Details on exposure:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential. These chemicals were grouped into 25 different categories, and 129 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
QSAR model
Duration of treatment / exposure:
QSAR model
Frequency of treatment:
QSAR model
Duration of test:
QSAR model
Control animals:
other: QSAR model
Maternal examinations:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential. These chemicals were grouped into 25 different categories, and 129 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.
Fetal examinations:
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential. These chemicals were grouped into 25 different categories, and 129 sub-categories, based on defined receptor binding and chemical properties, and when known, their MOA. Data is separated into two types of endpoints: developmental and reproductive toxicity. Detailed information for the effect associated with observed data is available in the metadata information of the database.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No adverse effects on the highest dose tested according the DART QSAR method for chemicals properties assessment..
This grouping method contains simple categories for Developmental and Reproductive toxicity. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals. The database include a set of 716 chemicals (664 positive, 16 negative, and 36 with insufficient data) that have been evaluated for their DART potential.
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Fetal body weight changes:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Basis for effect level:
other:
Remarks on result:
other: No adverse effects on the highest dose tested according the DART QSAR method for chemicals properties assessment.. This method is relevant for Developmental and Reproductive toxicity endpoints in mammals.
Abnormalities:
not specified
Developmental effects observed:
not specified

See attached background material and QSAR study report

Conclusions:
NOAEL for developmental toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested) for Isopropyl Ethyl Thionocarbamate (IPETC) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol and does not cause developmental toxicity.
Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)


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

Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Justification for type of information:
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC.
- Age at study initiation: Female rats = 10 weeks of age on Gestational Day 0
- Weight at study initiation: 213.6 - 274.6 g on Gestational Day 0
- Housing: Males were housed singly in solid bottom polycarbonate cages (5" x 11 1/2" x 7"), non-mated females were group housed (maximum 3/cage), and mated females were singly housed in solid bottom polycarbonate cages (6" x 19" x 10 1/2") with stainless steel wire lids
- Diet (e.g. ad libitum): #5002 Purina Certified Rodent Chow ad libitum
- Water (e.g. ad libitum): Deionized/filtered tap water ad libitum
- Acclimation period: 7-day quarantine period


ENVIRONMENTAL CONDITIONS
- Temperature: Reported in the study as 72.0 ± 0.5 °F (approximately 22.2 ºC)
- Humidity (%): . Mean relative humidity = 59.0 ± 0.55% with a range of 46.7 - 70.0%
- Photoperiod (hrs dark / hrs light): 12 hours: 12 hours
Route of administration:
oral: gavage
Vehicle:
other: deionized/distilled water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The concentration of isopropanol in the dosing solutions varied with dose. Dilutions of isopropanol in deionized/distilled water were formulated independently for each concentration and were prepared in a quantity sufficient for the period of dosing.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
An aliquot of each formulation of isopropanol and vehicle was analyzed to verify the concentration of the test compound. Dosing formulations with assayed values of 90-110% of the nominal concentration were considered to be suitable for use in these studies. Personnel, other than the laboratory supervisor and those involved in analysis of dosage formulations for isopropanol concentration, were not informed of the formulation concentrations until all laboratory work had been completed.

For analysis of the dosing formulations, triplicate 0.100 mL samples of the vehicle control solution (deionized/distilled water) and of the dosing formulations were pipetted into separate GC auto-sampler vials each containing 0.80 mL of methanol. An 0.10 mL aliquot of the internal standard solution, 0.493 g of butanol/mL of water was added for each vial. The samples were mixed and analyzed by gas chromatography. Standards encompassing the range of dosing formulation concentrations were prepared in the same way and also analyzed.
Details on mating procedure:
- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: Individual females were placed in the home cage of singly housed males (i.e., 1:1)
- Length of cohabitation: Overnight
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Gestational Days 6 through 15
Frequency of treatment:
Single-dose administration
Duration of test:
From Feb. 26, 1990 to March 28, 1990
No. of animals per sex per dose:
25 females/group
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily on Gestational Day 0-5 (prior to dosing period) and on Gestational Day 16-20 (after dosing period) and twice daily, at dosing and 1-2 hours after dosing, throughout the dosing period (Gestational Day 6 through 15).

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: At sacrifice, the body, liver and uterus of each sperm-positive female were weighed
Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Analyses of Variance(ANOVA) and Bartlett’s test for homogeneity of variance. A one-tailed test (i.e., Williams’ Test and/or Dunnett’s Test) was used for all pairwise comparisons except that a two-tailed test was used for maternal body and organ weight parameters, maternal food consumption, fetal body weight, and percent males per litter. Nominal scale measures were analyzed by Chi-Square Test for Independence for differences among treatment groups.
Indices:
Not reported
Historical control data:
Not reported
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No pregnant surviving female aborted, delivered early or was removed from study. Two females (8%) died in the 1200 mg/kg bw/day group and one female (4%) died in the 800 mg/kg bw/day group. Maternal body weights were equivalent across all groups and for all timepoints. The statistically reduced maternal weight gain (Gestational Days 0-20) in the 1,200 mg/kg bw/day group was likely due to significantly reduced gravid uterine weights. Corrected maternal weight gain for Gestational Days 0-20 was statistically equivalent across all groups. There were no treatment related clinical signs apparent in maternal animals. Maternal food consumption was statistically equivalent across all groups for all intervals evaluated although a significant downward trend for Gestational Days 6-9 and 6-15 (treatment period) with no significant pairwise comparisons was evident.
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Fetal body weight changes:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
A total of 22-25 litters were evaluated per group. No litter was fully resorbed. All gestational parameters were equivalent across groups, including pre- and post-implantation loss. Fetal body weights/litter were significantly reduced in the 800 and 1,200 mg/kg bw/day groups. There were no treatment-related increased incidences in individual or pooled external, visceral, skeletal or total fetal malformations or variations.
Basis for effect level:
other:
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
There were no adverse maternal or developmental effects at 400 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats.
Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Executive summary:

There were no adverse maternal or developmental effects at 400 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats.

Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Justification for type of information:
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
number of animals was 15/group instead of 20/group
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Denver, PA
- Age at study initiation: 5.5 months
- Weight at study initiation: 2750 to 3800 g
- Fasting period before study: not reported
- Housing: singly in stainless steel cages with mesh flooring (Hoeltge, Inc., Cincinnati, OH)
- Diet (e.g. ad libitum): #5322 Purina Certified Rabbit Chow ad libitum
- Water (e.g. ad libitum): deionized/filtered tap water ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.3 to 20.6 °C
- Humidity (%): 42.3 to 60.0%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light


IN-LIFE DATES: From: March 13, 1990 To: April 27, 1990
Route of administration:
oral: gavage
Vehicle:
other: deionized/distilled water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prior to formulation of study dosing solutions, aliquots of formulations of isopropanol in vehicle, bracketing the range of concentrations to be used in this study, were assayed for homogeneity, stability and dose level verification. Dosing formulations were homogeneous and stable for at least 49 days under refrigerated conditions. Aliquots sufficient for one day of dosing per dose group were stored in containers with septum seal caps, used for one day of dosing and then appropriately disposed of. To prepare dosing formulations, isopropanol was dissolved in deionized/distilled water according to the following formula: Concentration (mg/mL) = Dose level (mg/kg)/Dose volume (2 mL/kg).

The concentration of isopropanol in the dosing solutions varied with dose. Dilutions of isopropanol in deionized/distilled water were formulated independently for each concentration and were prepared in a quantity sufficient for the period of dosing. An aliquot of each formulation of isopropanol and vehicle was analyzed to verify the concentration of the test compound. Dosing formulations with assayed values of 90-110% of the nominal concentration were considered to be suitable for use in these studies. Personnel, other than the laboratory supervisor and those involved in analysis of dosage formulations for isopropanol concentration, were not informed of the formulation concentrations until all laboratory work had been completed. For analysis of the dosing formulations, triplicate 0.100 mL samples of the vehicle control solution (deionized/distilled water, CAS No. 7732-18-5) and of the dosing formulations, 80.0, 160.0 and 240.0 mg/mL, were pipetted into separate GC auto sampler vials each containing 0.80 mL of methanol. An 0.10 mL aliquot of the internal standard solution, 0.250-0.251 g of t-butanol/mL of water, was added to each vial. The samples were mixed and analyzed by gas chromatography (Hewlett Packard 5890A Gas Chromatograph, Waters 840 data system). Standards encompassing the range of dosing formulation concentrations were prepared and analyzed in the same way. The capillary column was J&W DB-I (30 m x O.32 mm ID), 5 micron film with the injection solvent methanol:water (4:1).


DIET PREPARATION
- Rate of preparation of diet (frequency): not applicable
- Mixing appropriate amounts with (Type of food): not applicable
- Storage temperature of food: 12.8-15.6 °C


VEHICLE
- Justification for use and choice of vehicle (if other than water): not applicable
- Concentration in vehicle: 0, 60, 120, and 240 mg/mL mixture
- Amount of vehicle (if gavage): 2 mL/kg bw
- Lot/batch no. (if required): not provided
- Purity: not provided
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
An aliquot of each formulation of isopropanol and vehicle was analyzed to verify the concentration of the test compound. Dosing formulations with assayed values of 90-110% of the nominal concentration were considered to be suitable for use in these studies. For analysis of the dosing formulations, triplicate 0.100 mL samples of the vehicle control solution (deionized/distilled water, CAS No. 7732-18-5) and of the dosing formulations, 80.0, 160.0 and 240.0 mg/mL, were pipetted into separate GC auto sampler vials each containing 0.80 mL of methanol. An 0.10 mL aliquot of the internal standard solution, 0.250-0.251 g of t-butanol/mL of water, was added to each vial. The samples were mixed and analyzed by gas chromatography (Hewlett Packard 5890A Gas Chromatograph, Waters 840 data system). Standards encompassing the range of dosing formulation concentrations were prepared and analyzed in the same way. The capillary column was J&W DB-I (30 m x O.32 mm ID), 5-micron film with the injection solvent methanol:water (4:1).
Details on mating procedure:
- Impregnation procedure: artificial insemination
- Verification of same strain and source of both sexes: No. Test animals consisted of female New Zealand (NZW) rabbits supplied by Hazleton Research Products, Inc., Denver, PA. Male rabbits of the same strain and originally from the same supplier were obtained from the laboratory's (RTI) breeding colony and used to provide semen samples.
- Proof of pregnancy: On gestation day 30, approximately one to one and a half days before expected parturition, all surviving maternal animals were killed and the pregnancy status of the rabbits was confirmed by uterine examination
Duration of treatment / exposure:
From day 6 to 18 of gestation.
Frequency of treatment:
Daily
Duration of test:
from the start of the test (i.e., animals in cages) to necropsy
No. of animals per sex per dose:
A total of 15 females per dose were treated; 2 females in the 120 mg/kg bw/day dose group were not pregnant at sacrifice.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on a range-finding study in pregnant rabbits performed at RTI (RTI STUDY CODE: RbgO-ISPT). The highest dose level was chosen to induce overt maternal toxicity, but not to cause a weight loss greater than 20% when compared to concurrent controls, nor to cause greater than 10% maternal mortality. The low dose was selected to be a maternal/developmental no-observable-adverse-effect level (NOAEL). The mid-dose was halfway between the high and low doses.
- Rationale for animal assignment (if not random): Animals were assigned to treatment groups by a stratified randomization method designed to provide uniform mean body weights across dose groups at the initiation of the study.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily on gestation days 0-5 (prior to dosing) and 19-30 (after dosing period); twice daily at dosing and 1-2 hours after dosing, throughout the dosing period (gestation days 6 through 18).
- Cage side observations checked in table No. 3 were included.


DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15, 18, 24, and 30.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 30
- Organs examined: thoracic and abdominal cavities, and organs; liver and uterus weights obtained.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: dead and live fetuses
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistics:
Parametric statistical procedures were applied to selected measures. Appropriate General Linear Models (GLM) procedures (SAS Institute Inc., 1985a, 1985b) for the proposed Analyses of Variance (ANOVA) were employed. Prior to GLM analysis, an arcsine-square root transformation was performed on all litter-derived percentage data (Snedecor and Cochran, 1967) and Bartlett’s test for homogeneity of variance (alpha level = 0.001) was performed on all data to be analyzed by ANOVA (Winer, 1962). GLM analysis was used to determine the significance of the dose-response relationships (Test for Linear Trend), and to determine whether significant dose effects had occurred for selected measures (ANOVA). When a significant (p<0.05) main effect for dose occurred, Williams’ Multiple Comparison Test (Williams, 1971; 1972) and/or Dunnett’s Multiple Comparison Test (Dunnett, 1955; 1964) was used to compare each exposed group to the vehicle control group for that measure. A one-tailed test (i.e., Williams’ Test and/or Dunnett’s Test) was used for all pairwise comparisons except that a two-tailed test was used for maternal body and organ weight parameters, maternal food consumption, fetal body weight, and percent males per litter. Nominal scale measures were analyzed by Chi-Square Test for Independence for differences among treatment groups, and by a test for linear trend on proportions (Snedecor and Cochran, 1967). When Chi-Square revealed significant (p<0.05) differences among groups, then a one-tailed Fisher’s Exact Probability Test was used for pair wise comparisons between each treated group and the vehicle control group.
Indices:
Dams: pregnancy; corpora lutea; implantation sites per litter; percent preimplantation loss; live fetuses per litter; total and percent: resorptions per litter, litters with resorptions, late fetal deaths per litter, litters with late fetal deaths, nonlive implants per litter, litters with nonlive implants, adversely affected implants per litter; male and female fetuses per litter; average fetal body weight per litter; average male fetal body weight per litter; and average female fetal body weight per litter.
Historical control data:
Large historical databases for reproductive performance and prevalence of spontaneous malformations in 200 control rabbit litters are available from studies conducted at RTI, as well as from historical data on 1,142 New Zealand White rabbit control litters summarized across teratology studies from 11 pharmaceutical companies or biological research organizations by the Middle Atlantic Reproduction and Teratology Association (Woo and Hoar, 1982).
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Profound maternal toxicity at 480 mg/kg/day, expressed as 26.7% mortality, reduced body weight gain during the treatment period and for the gestational period corrected for the contribution of the gravid uterus, reduced food consumption during the treatment period and relatively severe clinical signs of toxicity. At 240 and 120 mg/kg/day, the only findings were transient, relatively mild and nonspecific clinical signs of toxicity.
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
480 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no demonstrable developmental toxicity at a dose resulting in significant maternal toxicity (480 mg/kg/day) or at doses with only relatively mild and transient clinical signs of toxicity (240 and 120 mg/kg/day).
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No adverse maternal effects were noted at 120 or 240 mg/kg. All gestational parameters were equivalent across groups. No evidence of increased
teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to NZW rabbits.
Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Executive summary:

No adverse maternal effects were noted at 120 or 240 mg/kg. All gestational parameters were equivalent across groups. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to NZW rabbits. Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .

Endpoint:
developmental toxicity
Type of information:
experimental study
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:
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 426 (Developmental Neurotoxicity Study)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. Raleigh, NC
- Age at study initiation: 9 weeks on gestation day 0
- Weight at study initiation: 174-197 g on gestation day 0
- Fasting period before study: None
- Housing: singly caged in solid bottom polycarbonate cages with stainless steel wire lids
- Diet (e.g. ad libitum): 5002 Purina certified rodent chow was available ad libitum
- Water (e.g. ad libitum): tap water in polycarbonate bottles was available ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-75 (20 - 24ºC)
- Humidity (%): 40-70
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light):12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS

Vehicle was deionized/distilled water
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
no
Details on mating procedure:
Male and female animals were paired at Charles River Laboratories Inc on July 10, July 24, August 7, and September 11, 1990, and were determined to have mated by the obsevation of a copulatory plug on the morning of the following day. The plug-positive female rats were delievered to Research Triangle Institute on the day a copulatory-plug was found which was designated gestation day 0.
Duration of treatment / exposure:
dministered from day 6 of gestation to day 21 post natal
Frequency of treatment:
daily
Duration of test:
Administered from day 6 of gestation to day 21 post natal
No. of animals per sex per dose:
64 females/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Review from 4 previous studies
- Rationale for animal assignment (if not random): sperm postive female rats were assigned to treatment groups by a stratified randomization method designed to provide uniformed mean body wieghts accross dose groups
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily on gestation days 0-5 and twice daily through dosing period gestation day 6 to post natal day 21


BODY WEIGHT: Yes
- Time schedule for examinations: maternal body weights were measured on gestation days 0, 6, 9, 12, 15, 18, 20 and on post natal days 0, 4, 7, 13, 17, and 21


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No
Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
A combination of categorical, analysis of variance, survival time, and repeated measures techniques were used.
Indices:
Not reported
Historical control data:
Not reported
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal and developmental toxicity was noted at 700 and 1,200 mg/kg/day, with no indication of teratogenicity at any dose tested.
Dose descriptor:
NOAEL
Effect level:
700 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
A total of 22-25 litters were evaluated per group. No litter was fully resorbed. All gestational parameters were equivalent across groups, including pre- and post-implantation loss. Fetal body weights/litter were significantly reduced in the 700 and 1,200 mg/kg bw/day groups. There were no treatment-related increased incidences in individual or pooled external, visceral, skeletal or total fetal malformations or variations.
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
There were no adverse maternal or developmental effects at 700 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats.
Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Executive summary:

There were no adverse maternal or developmental effects at 700 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats.

Propan-2-ol (Isopropyl alcohol)as a main constituent ofReaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol  and propan-2-ol .

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
17.39 mg/m³
Study duration:
subacute
Species:
rabbit
Quality of whole database:
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15m3/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 400 mg/kg bw/day
÷1.15m3/kgbw
÷20m3/rat
NOAECrat 17.39 mg/m3
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
For dermal exposure we taken that:
-the average weight of rats is 250g (200-300g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg
 corrected dermal NOAEL=   oral NOAEL
400 mg/kg bw/dayx0.025 kg =                  
 NOAELrat  = 10 mg/kg bw/day
Additional information

Oral exposure

NOAEL for developmental toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested) for Isopropyl Ethyl Thionocarbamate (IPETC) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol and does not cause developmental toxicity.Developmental & Reproductive Toxicity (DART): Not known precedent reproductive and developmental toxic potential (DART scheme v.1.0)

There were no adverse maternal or developmental effects at 400 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats. Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .

No adverse maternal effects were noted at 120 or 240 mg/kg. All gestational parameters were equivalent across groups. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to NZW rabbits. Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .

There were no adverse maternal or developmental effects at 700 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats.

Propan-2-ol (Isopropyl alcohol)as a main constituent ofReaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol  and propan-2-ol .

In the study of Nakaura S, et al. 1984, the NOAEL for maternal toxicity of zinc bis(diethyldithiocarbamate) was 125 mg/kg bw/day (Based on clinical signs of toxicity and mortality at the next dose level) and the NOAEL for developmental toxicity was 250 mg/kg bw/day (No adverse effects on the highest dose tested) .Dithiocarbamates are related compounds toThionocarbamates.

Dermal exposure:

For dermal exposure we taken that:

-the average weight of rats is 250g (200-300g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.025 kg

 corrected dermal NOAEL=   oral NOAEL

400 mg/kg bw/dayx0.025 kg =                  

 NOAELrat  = 10 mg/kg bw/day

Inhalation exposure:

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15m3/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            400 mg/kg bw/day

÷1.15m3/kgbw

÷20m3/rat

NOAECrat    17.39 mg/m3

Justification for classification or non-classification

Based on the hazard assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol in section 2.1 and 2.2. in IUCLID 5.4., 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” and according to the criteria described in Directive 67/548 and in the CLP Regulation:

Directive 67/548

Toxicity to reproduction/development

Repr. Cat. 1; R61 May cause harm to the unborn child.

Repr. Cat. 2; R61 May cause harm to the unborn child.

Repr. Cat. 3; R63 Possible risk of harm to the unborn child.

Toxicity to reproduction/fertility

 Repr. Cat. 1; R60 May impair fertility.

Repr. Cat. 2; R60 May impair fertility.

Repr. Cat. 3; R62 Possible risk of impaired fertility

 

CLP

Reproductive toxicity

Repr. 1A

Repr. 1B

Repr. 2

H360: May damage fertility or the unborn child <state specific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

H361: Suspected of damaging fertility or the unborn child <state specific effect if known> <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

 

 

It is concluded that the substance Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol does not meet the criteria to be classified for human health hazards for Reproductive toxicity

 

 

Additional information