1-Propanaminium, 3-amino-N-(carboxymethyl)-N,N-dimethyl-, N-coco acyl derivs., hydroxides, inner salts

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology, when male and female Sprague Dawley rats were treated with test chemical orally for 90 days.

Link to relevant study records

Reference

Endpoint:

reproductive toxicity, other

Remarks:

sub chronic toxicity study

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data from secondary source

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD guideline 408

Principles of method if other than guideline:

Reproductive toxicity study of test material was performed on Sprague Dawley rats

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crl: CD(SD)BR)

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Age: 5/6 weeks
- Weight at study initiation: male : 115-174 g, female : 97-150 g

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled water

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS:Test material soluble in distilled water
DIET PREPARATION- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 250, 500, 1000 mg /kg-
Amount of vehicle (if gavage):10ml /kg bw
- Lot/batch no. (if required):
- Purity:

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

5 days/week

Details on study schedule:

No data available

Remarks:

0, 250, 500, 1000 mg /kg

No. of animals per sex per dose:

Total:800 mg/kg :
10 male and 10 female 250mg/kg:
10 male and 10 female: 500mg/kg
10 male and 10 female: 1000 mg/kg:
10 male and 10 female: 0 mg/kg

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: daily
BODY WEIGHT: Yes

Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes twice/week
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: Yes / No / No data: No data available
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:
OTHER:

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

Postmortem examinations (Parent Animal)
SACRIFICE :On day 92
GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS : yes

Postmortem examinations (offspring):

No data available

Statistics:

Levene´s test (body weight, body weight gain, food consumption), ANOVA, Dunnett´s test (both for multiple group comparisons), Student-Newman-Keul (organ weight, chlinical chemistry, hematology data organ/body weight ratio with each one factor treatment)

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment-related clinical signs were observed

Dermal irritation (if dermal study):

no effects observed

Mortality:

no mortality observed

Description (incidence):

There were no treatment-related mortalities

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment related effects on histopathology of testes, accessory sex organs, ovaries, uterus, prostate

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

organ weights and organ / body weight ratios

histopathology: non-neoplastic

Remarks on result:

other: No effects on reproductive organ

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

not measured/tested

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Conclusions:

No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology, When male and female Sprague Dawley rats were treated with test chemical orally for 90 days.

Executive summary:

A 90 days subchronic toxicity study of test chemical was performed according to OECD TG 408 on male and female Sprague-Dawley rats. The test material was dissolved in distilled water at dose levels of 0, 250, 500 or 1000 mg/kg-day and administered via oral gavage route once a day for 5 days/week in dose volume 10ml/kg bw in Sprague-Dawley rats 10/sex/dose was used in the study. All the animals were observed for Clinical signs and mortality daily. Body weight and food consumption were noted twice a week. On day 92, all the animals were sacrificed and Gross pathology and Histopathology were performed. There were no treatment-related mortalities in any test group. No effects on Body weight and food consumption were noted. No effects on testes and ovaries weights were noted. No treatment related effects on histopathology of testes, accessory sex organs, ovaries, uterus and prostate were noted. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology were observed, when male and female Sprague Dawley rats were treated with test chemical orally for 90 days.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from authoritative database

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Data available for the read across chemicals was reviewed to determine the reproductive toxicity of test chemical. The studies are as mentioned below:

Study 1: A 90 days subchronic toxicity study of test chemical was performed according to OECD TG 408 on male and female Sprague-Dawley rats. The test material was dissolved in distilled water at dose levels of 0, 250, 500 or 1000 mg/kg-day and administered via oral gavage route once a day for 5 days/week in dose volume 10ml/kg bw in Sprague-Dawley rats 10/sex/dose was used in the study. All the animals were observed for Clinical signs and mortality daily. Body weight and food consumption were noted twice a week. On day 92, all the animals were sacrificed and Gross pathology and Histopathology were performed. There were no treatment-related mortalities in any test group. No effects on Body weight and food consumption were noted. No effects on testes and ovaries weights were noted. No treatment related effects on histopathology of testes, accessory sex organs, ovaries, uterus and prostate were noted. Hence No Observed Adverse Effect Level (NOAEL) for reproductive toxicity was considered to be 1000 mg/kg/day, as no effects on reproductive organ weight and histopathology were observed, when male and female Sprague Dawley rats were treated with test chemical orally for 90 days.

 

Study 2: The prenatal developmental toxicity study following OECD guideline 414 was performed on female CD rats. Test material was soluble in water (aqua ad iniectabilia). Dose concentration were prepared at 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively) and administered in a dose volume of 10 ml/kg bw from day 5 to 19 of pregnancy once daily via gavage. 25 female rats /dose group were treated and 20 pregnant animals were evaluated. 20 rats (0, 330, 990 mg/kg bw group) and 21 rats (3300 mg/kg bw group) were evaluated for maternal toxicity. 1 male and 1 female were placed in one cage during the dark period. Mating was repeated until vaginal smear showed presence of sperm. All animals were observed for clinical signs, Body weight and food consumption daily. Also number of fetuses alive, Weight of fetuses, sex distribution of fetuses, skeletal anomalies (50 %) and soft tissue anomalies (50 %) were noted. One dam at 3300 mg/kg day died on gestation day 15 and in same dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility was noted. At≥990 mg/kg bw dose group, reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%) and reduced food consumption (up to 12 % gestation days 8, 10, 19), 4/20: ulcers, thickened mucosa were observed. At 3300 mg/kg bw dose group, reduced body weight (up to 17 % below control) and decreased body weight change, reduced food consumption up to 65% each day, reduced gravid uterus weight by 22% (caused by lowered fetal weights) and 20/21: thickened mucosa, greyish discolored in 2/21; ulcers (also in the prematurely deceased dam) were observed. The number of early, late and total resorptions was increased in the 3300 mg/kg bw group. Moreover the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in this dose group. A statistically significant reduction in fetal weights and number of viable fetuses as compared to the control was observed. At 3300 mg/kg bw dose group. No external, skeletal or soft tissue malformations and no external variations were seen in controls or in dosed groups. The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw) in the test group respectively. The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw). Hence, the NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean fetal body weight were considered to be secondary to maternal toxicity when female CD rats were treated with test chemical orally from day 5 - 19 of pregnancy.

Study 3: In a reproductive toxicity study, Sprague-Dawley female rats were treated with test chemical in the concentration of 0, 100, 300, or 1000 mg/kg/day orally by gavage in corn oil. No maternal mortality and clinical signs or behavioral changes were observed in treated female rats as compared to control. No effect on body weight and feed consumption changes were observed in treated female rats as compared to control. Similarly, no effect on reproductive parameters such as number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length was observed in treated rats. Ratio of male and female pups at the 1000 mg/ kg/day dose level was significantly different from the control group but was not considered treatment related. Slight but significant increase in relative liver weight of treated female rats was observed as compared to control. In addition, No effect on viability, fetal body weight and external malformations were observed in treated fetuses as compared to control. One fetus with bent limb bones, two fetuses from different mothers with microphthalmia and two other fetuses with omphalocele were observed at 1000 mg/kg/day and single fetus with multiple malformations were observed at 300 mg/kg/day in treated fetuses as compared to control. The incidence of developmental variations in the treated litters was not significantly increased over the control incidence. They occurred in low frequency and were distributed randomly across the test chemical treated and control groups. Therefore, NOAEL was considered to be 300 mg/kg bw for P generation and 1000 mg/kg for F1 generation when Sprague-Dawley female rats were treated with test chemical orally by gavage from day 6 to 15 of gestation.

Based on the data available from different studies, test chemical did not showed reproductive toxicity at dose concentration between 300- 1000mg/kg bw/day. Hence the test chemical is not likely to classify as a reproductive and developmental toxicant as per the criteria mentioned in CLP regulation.

Effects on developmental toxicity

Description of key information

The NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean foetal body weight were considered to be secondary to maternal toxicity when female CD were treated with test chemical orally from day 5 - 19 of pregnancy.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data from secondry source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Developmental toxicity study of test material was performed on female CD rats.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: CD

Details on test animals or test system and environmental conditions:

Age at day 0 of pregnancy: 8 - 9 weeks- Body weight at day 0 of pregnancy: 205 - 254 g

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

(aqua ad iniectabilia)

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS:Test material soluble in water (aqua ad iniectabilia)

DIET PREPARATION
- Rate of preparation of diet (frequency):- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0, 330, 990 or3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively)
- Amount of vehicle (if gavage):10ml /kg bw
- Lot/batch no. (if required)
:- Purity:

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: during the dark period.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- Any other deviations from standard protocol:

Duration of treatment / exposure:

15 days (from day 5 - 19 of pregnancy)

Frequency of treatment:

Daily

Duration of test:

20 days

Remarks:

0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively)

No. of animals per sex per dose:

Total:
1000 mg/kg : 25 female
95 mg/kg:25 female
286 mg/kg:25 female
950 mg/kg:25 female

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Maternal examinations:

Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: daily
BODY WEIGHT: Yes, Time schedule for examinations: daily
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes daily Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Compound intake calculated as time
-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations

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:

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data

Statistics:

Postmortem examinations (Parent Animal)
SACRIFICE : on days 20
GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS : yes

Indices:

No data available

Historical control data:

No data available

Clinical signs:

no effects observed

Description (incidence and severity):

At 3300 mg/kg bw dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

One dam at 3300 mg/kg day died on gestation day 15

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

>= 990 mg/kg bw dose group reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%). At 3300 mg/kg bw dose group reduced body weight (up to 17 % below control) and decreased body weight change were observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

>= 990 mg/kg bw dose group reduced food consumption (up to 12 % gestation days 8, 10, 19)and at 3300 mg/kg bw dose group up to 65% each day

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In 3300 mg/kg bw dose group reduced gravid uterus weight by 22% (caused by lowered fetal weights)

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At 990 mg/kg bw dose group 4/20: ulcers, thickened mucosa and in 3300 mg/kg bw dose group 20/21: thickened mucosa, greyish discoloured in 2/21; ulcers (also in the prematurely deceased dam) were observed.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

not specified

Pre- and post-implantation loss:

effects observed, treatment-related

Description (incidence and severity):

the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in the 3300 mg/kg bw dose group.

Total litter losses by resorption:

not specified

Early or late resorptions:

effects observed, treatment-related

Description (incidence and severity):

The number of early, late and total resorptions was increased in the 3300 mg/kg bw group.

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

95 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

mortality

organ weights and organ / body weight ratios

pre and post implantation loss

total litter losses by resorption

Remarks on result:

other: No toxic effects observed at given dose group

Abnormalities:

not specified

Localisation:

not specified

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

a statistically significant reduction in fetal weights as compared to the control was observed At 3300 mg/kg bw dose group

Description (incidence and severity):

a statistically significant reduction in number of viable fetuses as compared to the control was observed At 3300 mg/kg bw dose group

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

No external malformations and no external variations were seen in controls or in dosed groups.

Skeletal malformations:

no effects observed

Description (incidence and severity):

No skeletal were seen in controls or in dosed groups.

Visceral malformations:

no effects observed

Description (incidence and severity):

No soft tissue malformations were seen in controls or in dosed groups.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw). The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw)

Dose descriptor:

NOAEL

Effect level:

> 950 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

reduction in number of live offspring

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Remarks on result:

other: No developmental toxic effects observed

Abnormalities:

not specified

Localisation:

other: not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Conclusions:

The NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean foetal body weight were considered to be secondary to maternal toxicity when female CD were treated with test chemical orally from day 5 - 19 of pregnancy.

Executive summary:

The prenatal developmental toxicity study following OECD guideline 414 was performed on female CD rats. Test material was soluble in water (aqua ad iniectabilia). Dose concentration were prepared at 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively) and administered in a dose volume of 10 ml/kg bw from day 5 to 19 of pregnancy once daily via gavage. 25 female rats /dose group were treated and 20 pregnant animals were evaluated. 20 rats (0, 330, 990 mg/kg bw group) and 21 rats (3300 mg/kg bw group) were evaluated for maternal toxicity. 1 male and 1 female were placed in one cage during the dark period. Mating was repeated until vaginal smear showed presence of sperm. All animals were observed for clinical signs, Body weight and food consumption daily. Also number of fetuses alive, Weight of fetuses, sex distribution of fetuses, skeletal anomalies (50 %) and soft tissue anomalies (50 %) were noted. One dam at 3300 mg/kg day died on gestation day 15 and in same dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility was noted. At≥990 mg/kg bw dose group, reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%) and reduced food consumption (up to 12 % gestation days 8, 10, 19), 4/20: ulcers, thickened mucosa were observed. At 3300 mg/kg bw dose group, reduced body weight (up to 17 % below control) and decreased body weight change, reduced food consumption up to 65% each day, reduced gravid uterus weight by 22% (caused by lowered fetal weights) and 20/21: thickened mucosa, greyish discolored in 2/21; ulcers (also in the prematurely deceased dam) were observed. The number of early, late and total resorptions was increased in the 3300 mg/kg bw group. Moreover the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in this dose group. A statistically significant reduction in fetal weights and number of viable fetuses as compared to the control was observed. At 3300 mg/kg bw dose group. No external, skeletal or soft tissue malformations and no external variations were seen in controls or in dosed groups. The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw) in the test group respectively. The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw). Hence, the NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean fetal body weight were considered to be secondary to maternal toxicity when female CD rats were treated with test chemical orally from day 5 - 19 of pregnancy.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

950 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from authoritative database

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Data available for the read across chemicals was reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:

Study 1:

The prenatal developmental toxicity study following OECD guideline 414 was performed on female CD rats. Test material was soluble in water (aqua ad iniectabilia). Dose concentration were prepared at 0, 330, 990 or 3300 mg/kg-day (corresponding to 0, 95, 286, and 950 mg/kg-day active substance, respectively) and administered in a dose volume of 10 ml/kg bw from day 5 to 19 of pregnancy once daily via gavage. 25 female rats /dose group were treated and 20 pregnant animals were evaluated. 20 rats (0, 330, 990 mg/kg bw group) and 21 rats (3300 mg/kg bw group) were evaluated for maternal toxicity. 1 male and 1 female were placed in one cage during the dark period. Mating was repeated until vaginal smear showed presence of sperm. All animals were observed for clinical signs, Body weight and food consumption daily. Also number of fetuses alive, Weight of fetuses, sex distribution of fetuses, skeletal anomalies (50 %) and soft tissue anomalies (50 %) were noted. One dam at 3300 mg/kg day died on gestation day 15 and in same dose group 13/21 abdominal position, 2/21: pilo-erection, reduced motility was noted. At≥990 mg/kg bw dose group, reduction of the net weight change (carcass weight minus day 6 body weight) from day 6 onwards (23% and 67%) and reduced food consumption (up to 12 % gestation days 8, 10, 19), 4/20: ulcers, thickened mucosa were observed. At 3300 mg/kg bw dose group, reduced body weight (up to 17 % below control) and decreased body weight change, reduced food consumption up to 65% each day, reduced gravid uterus weight by 22% (caused by lowered fetal weights) and 20/21: thickened mucosa, greyish discolored in 2/21; ulcers (also in the prematurely deceased dam) were observed. The number of early, late and total resorptions was increased in the 3300 mg/kg bw group. Moreover the ratio of viable fetuses to implantation sites was decreased compared to the controls. This was due to a total post-implantation loss of two dams in this dose group. A statistically significant reduction in fetal weights and number of viable fetuses as compared to the control was observed. At 3300 mg/kg bw dose group. No external, skeletal or soft tissue malformations and no external variations were seen in controls or in dosed groups. The fetal incidence of the skeletal variations was 5 in the controls and 8 (330 mg/kg bw), 13 (990 mg/kg bw) and 6 (3300 mg/kg bw) in the test group respectively. The finding in the 990 mg/kg bw group was judged as incidental as no dose-relationship was noted. The skeletal retardations (fetal incidence) were 129 in the controls and 137 (330 mg/kg bw), 130 (990 mg/kg bw) and 125 (3300 mg/kg bw) in the dosed groups. No dose-related soft tissue variations were observed, as seen in the following fetal incidences: 8 (control), 12 (330 mg/kg bw), 10 (990 mg/kg bw) and 9 (3300 mg/kg bw). Hence, the NOAEL for maternal toxicity was 95 mg/kg bw/day and the NOAEL for reproductive and developmental toxicity was >950 mg/kg bw/day as the post-implantation loss and decreased mean fetal body weight were considered to be secondary to maternal toxicity when female CD rats were treated with test chemical orally from day 5 - 19 of pregnancy.

 

Study 2: The developmental toxicity study of test chemical was performed on female pregnant rats. The test material was administered in dose concentration 0, 30, 90 or 300 mg/kg bw on days 6 through 17 of gestation via gavage. Clinical signs, gestational body weights, food consumption, gravid uterine weight, total number of corpora lutea, implantation, early and late resorptions, were noted in dams while live and dead fetuses, sex, individual body weights of fetuses, visceral (50 %) and skeletal (50 %) abnormalities were observed in fetuses. No treatment-related effects on the incidence of fetal external, visceral, or skeletal malformations or developmental variations were observed among litters from dams in any of the treated groups. Hence the maternal and developmental no-observed-effect level (NOEL) was considered to be 300 mg/kg bw/d, the highest level, when female rats were treated with test chemical orally on days 6 through 17 of gestation.

 

Study 3: In a developmental toxicity reproductive toxicity was evaluated in Sprague-Dawley female rats by using test chemical in the concentration of 0, 100, 300, or 1000 mg/kg/day orally by gavage in corn oil. No maternal mortality and clinical signs or behavioral changes were observed in treated female rats as compared to control. No effect on body weight and feed consumption changes were observed in treated female rats as compared to control. Similarly, no effect number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length was observed in treated rats. Ratio of male and female pups at the 1000 mg/ kg/day dose level was significantly different from the control group but was not considered treatment related. Slight but significant increase in relative liver weight of treated female rats was observed as compared to control. In addition, No developmental parameter such as viability, fetal body weight and external malformations were observed in treated fetuses as compared to control. One fetus with bent limb bones, two fetuses from different mothers with microphthalmia and two other fetuses with omphalocele were observed at 1000 mg/kg/day and single fetus with multiple malformations were observed at 300 mg/kg/day in treated fetuses as compared to control. The incidence of developmental variations in the treated litters was not significantly increased over the control incidence. They occurred in low frequency and were distributed randomly across the test chemical treated and control groups. Therefore, NOAEL was considered to be 300 mg/kg bw for P generation and 1000 mg/kg for F1 generation when Sprague-Dawley female rats were treated with test chemical orally by gavage from day 6 to 15 of gestation.

Based on the data available from different studies, test chemical did not showed developmental toxicity at dose concentration between 300- 1000mg/kg bw/day. Hence the test chemical is not likely to classify as a reproductive and developmental toxicant as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation, the test chemical is not likely to classify as reproductive and developmental toxicant.