CGL 210

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproduction/Developmental Toxicity Screening study according to OECD 421 and GLP (2013), oral administration (gavage) to rats, NOAEL for general systemic toxicity, for reproductive performance and fertility and for developmental toxicity is 1000 mg/kg bw.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012-2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

27 Jul 1995

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

certified by Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht Rheinland-Pfalz, 2009

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 160-250g
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5d
- Fasting: 16h before administration

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 Jul 2012 To: 17 Sep 2012 (sacrifice of parental females)

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

applied as a asolution

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): once a week
- Storage temperature of food: room temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water): miscible

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: maximum 2 weeks
- Proof of pregnancy: vaginal smear was sperm positive, or a copulation plug was observed referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): pregnant animals and litter together

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration control Analysis of the test substance preparations were performed in samples of all concentrations at the start of the administration period.

Duration of treatment / exposure:

The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females.

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Remarks:

Basis: actual ingested

Dose / conc.:

300 mg/kg bw/day

Remarks:

Basis: actual ingested

Dose / conc.:

1 000 mg/kg bw/day

Remarks:

Basis: actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on 28d study

Positive control:

without

Parental animals: Observations and examinations:

E SIDE OBSERVATIONS: Yes
- Time schedule: once or twice daily
- check for morbidity, pertinent behavioral changes and signs of overt toxicity were reported for affected animal

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The littering and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams. On weekdays (except public holidays) the parturition behavior of the dams was inspected in the afternoons in addition to the evaluations in the mornings.

BODY WEIGHT: Yes
- Time schedule for examinations: before the start of the administration period, on study day 0 (start of the administration period) and thereafter once a week at the same time of the day (in the morning).
- The following exceptions are notable for the female animals:
• During the mating period the parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20.
• Females with litter were weighed on the day of parturition (PND 0) and on PND 4.
• Females without a litter and without positive evidence of sperm in the vaginal smear were weighed weekly. These body weight data were solely used for the calculations of the dose volume. Therefore, these values are only documented in the Individual Tables (PART II).
• Females between PND 4 and sacrifice were weighed once a week (if necessary, for the calculation of the administration volume, body weight data will only be reported in the individual tables).

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
- The following exceptions were made:
• Food consumption was not determined during the mating period (male and female F0 animals).
• Food consumption of the F0 females with evidence of sperm was determined for GD 0-7, 7-14 and 14-20.
• Food consumption of F0 females, which gave birth to a litter was determined for PND 1-4.
Food consumption was not determined in females without positive evidence of sperm (during the mating period of dams used in parallel) and females without litter (during the lactation period of dams used in parallel) and in males after the premating period.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality up to day 4, presence of gross anomalies

GROSS EXAMINATION OF DEAD PUPS:
yes, all stillborn pups and those pups, which died ahead of schedule, were examined externally, eviscerated and their organs were assessed macroscopically

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals

GROSS NECROPSY
- organ weights: 1. Anesthetized animals, 2. Epididymides, 3. Testes
- tissue fixation: 1. All gross lesions 2. Cervix 3. Coagulating glands 4. Epididymides (modified Davidson’s solution) 5. Ovaries (modified Davidson’s solution) 6. Oviducts 7. Prostate gland 8. Seminal vesicles 9. Testes (modified Davidson’s solution) 10. Vagina 11. Uterus

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination and weighed, respectively:
1. Testes
2. Epididymides
3. Ovaries

Postmortem examinations (offspring):

SACRIFICE
These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: all pups were sacrificed on day 4 post partum

GROSS NECROPSY
All surviving pups (sacrificed on PND 4 under isoflurane anesthesia with CO2), all stillborn pups and those pups, which died ahead of schedule, were examined externally, eviscerated and their organs were assessed macroscopically. Dead pups, except those excessively cannibalized, were examined macroscopically.

Statistics:

Statistics of pathology: Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting pvalue was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the equal medians

Reproductive indices:

- Male reproduction data: Male mating index, Male fertility index
- Female reproduction and delivery data: Female mating index, Female fertility index, Gestation index, Live birth index, Post implantation loss

Offspring viability indices:

Pup number and status at delivery, Pup viability/mortality, Sex ratio, up body weight data

Clinical signs:

no effects observed

Description (incidence and severity):

No substance-related clinical signs were observed. Animal No. 116 (test group 1, 100 mg/kg bw/d) which did not deliver any pups showed a hard abdomen from gestation day 37 and in addition piloerection from gestation day 38 to gestation day 42. Due to the lack of a dose response relationship, this finding was assessed as being incidental.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No animal died prematurely in the present study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test substance-related changes in body weight or body weight gain were observed for male and female animal of test groups 1-3 (100, 300 and 1000 mg/kg bw/d) when compared to control groups.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test substance-related changes in food consumption were observed for male and female animals of test groups 1-3 (100, 300 and 1000 mg/kg bw/d) when compared to control groups.

Food efficiency:

not specified

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

not specified

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: 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

Description (incidence and severity):

The female mating index calculated after the mating period for F1 litter was 100% for all test groups. All sperm positive rats delivered pups with the exception of two animals, which did not become pregnant. The female fertility index was 90% in test groups 0-2 and 100 % in test group 3.
The male mating index was 100% in all test groups and the male fertility index was 90% in test groups 0-2 and 100% in test group 3. These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.

- The gestation index was 100% in all test groups
- The live birth index was 100% in all test groups
- The postimplantation loss was 2.61% in test group 0, 2.89% in test group 1, 4.45% in test group 2 and 5.52% in test group 3. These data reflect the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment-related adverse effects observed up to and including the highest dose level of 1000 mg/kg bw.

Critical effects observed:

no

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Description (incidence and severity):

The viability index indicating pup mortality during lactation (PND 0 - 4) was 100% for all test groups.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

no effects observed

Description (incidence and severity):

The sex distribution and sex ratios of live F1 pups on the day of birth and PND 4 did not show substantial differences between the control and the test substance-treated groups.

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

No test substance-related, adverse findings were noted

Dose descriptor:

NOAEL

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 treatment-related adverse effects observed up to and including the highest dose level of 1000 mg/kg bw.

Critical effects observed:

no

Reproductive effects observed:

no

Conclusions:

The NOAEL for general, systemic toxicity was 1000 mg/kg bw/d. The NOAEL for reproductive performance and fertility was 1000 mg/kg bw/d for the F0 parental rats.

Executive summary:

The test item was administered orally by gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (corn oil served as vehicle), 100 mg/kg bw/d, 300 mg/kg bw/d and 1000 mg/kg bw/d. The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females. A detailed clinical observation was performed in all animals. Body weights and food consumption were determined in F0 animals. All animals were assessed by gross pathology; weights of selected organs were recorded and a histopathological examination was performed.

Clinical examinations, reproductive performance, clinical pathology, histopathology and gross pathology did not reveal any finding in treated animals. Viability, sex ratio and body weight of the pups was not affected. Examination of the ovaries and the uterine content did not overt any effect on uterus weight, number of implantations or resorptions.

Under the conditions of this screening study, the oral administration of the test substance by gavage to male and female Wistar rats did not reveal signs of toxicity.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Sreening test according to OECD 421 and GLP, Klimisch 1

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Procedure and observations

In a GLP-compliant Reproduction/Developmental Toxicity Screening study according to OECD 421, the test item was administered orally by gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (corn oil served as vehicle), 100 mg/kg bw/d, 300 mg/kg bw/d and 1000 mg/kg bw/d. The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females. A detailed clinical observation was performed in all animals. Body weights and food consumption were determined in F0 animals. All animals were assessed by gross pathology; weights of selected organs were recorded and a histopathological examination was performed.

Clinical examinations, reproductive performance, clinical pathology, histopathology and gross pathology did not reveal any finding in treated animals. Viability, sex ratio and body weight of the pups was not affected. Examination of the ovaries and the uterine content did not overt any effect on uterus weight, number of implantations or resorptions.

 

Discussion

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration of the test substance by gavage to male and female Wistar rats did not reveal signs of toxicity. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity, for reproductive performance and fertility and for developmental toxicity is 1000 mg/kg bw.

Effects on developmental toxicity

Description of key information

Reproduction/Developmental Toxicity Screening study according to OECD 421 and GLP (2013), oral administration (gavage) to rats, NOAEL for general systemic toxicity, for reproductive performance and fertility and for developmental toxicity is 1000 mg/kg bw.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012-2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

27 Jul 1995

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

certified by Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht Rheinland-Pfalz, 2009

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

- Source: Charles River Wiga GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 160-250g
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5d
- Fasting: 16h before administration

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 Jul 2012 To: 17 Sep 2012 (sacrifice of parental females)

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

applied as a solution

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): once a week
- Storage temperature of food: room temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water): miscible

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration control Analysis of the test substance preparations were performed in samples of all concentrations at the start of the administration period.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1 from the same test group
- Length of cohabitation: over night for a maximum of 2 weeks
- Further matings after two unsuccessful attempts: not specified
- Verification of same strain and source of both sexes: not specified
- Proof of pregnancy: sperm in vaginal smear referred to as gestation day (GD) 0

Duration of treatment / exposure:

The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females.

Frequency of treatment:

daily

Duration of test:

56 days (from the beginning of administration period until sacrifice of parental females)

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Remarks:

Basis: actual ingested

Dose / conc.:

300 mg/kg bw/day

Remarks:

Basis: actual ingested

Dose / conc.:

1 000 mg/kg bw/day

Remarks:

Basis: actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on 28d study

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once or twice daily
- check for morbidity, pertinent behavioral changes and signs of overt toxicity were reported for affected animal

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The littering and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams. On weekdays (except public holidays) the parturition behavior of the dams was inspected in the afternoons in addition to the evaluations in the mornings.

BODY WEIGHT: Yes
- Time schedule for examinations: before the start of the administration period, on study day 0 (start of the administration period) and thereafter once a week at the same time of the day (in the morning).
- The following exceptions are notable for the female animals:
• During the mating period the parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20.
• Females with litter were weighed on the day of parturition (PND 0) and on PND 4.
• Females without a litter and without positive evidence of sperm in the vaginal smear were weighed weekly. These body weight data were solely used for the calculations of the dose volume. Therefore, these values are only documented in the Individual Tables (PART II).
• Females between PND 4 and sacrifice were weighed once a week (if necessary, for the calculation of the administration volume, body weight data will only be reported in the individual tables).

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
- The following exceptions were made:
• Food consumption was not determined during the mating period (male and female F0 animals).
• Food consumption of the F0 females with evidence of sperm was determined for GD 0-7, 7-14 and 14-20.
• Food consumption of F0 females, which gave birth to a litter was determined for PND 1-4.
Food consumption was not determined in females without positive evidence of sperm (during the mating period of dams used in parallel) and females without litter (during the lactation period of dams used in parallel) and in males after the premating period.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.

POST-MORTEM EXAMINATIONS: Yes
- Organ weights: 1. Anesthetized animals, 2. Epididymides, 3. Testes
- Tissue fixation: 1. All gross lesions 2. Cervix 3. Coagulating glands 4. Epididymides (modified Davidson’s solution) 5. Ovaries (modified Davidson’s solution) 6. Oviducts 7. Prostate gland 8. Seminal vesicles 9. Testes (modified Davidson’s solution) 10. Vagina 11. Uterus
- Histopathology: 1. Testes 2. Epididymides 3. Ovaries

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: No data
Examinations included:
- Number of implantations: Yes, to determine the number of implantation sites, the apparently non-pregnant uteri were stained for about 5 minutes in 1% ammonium sulfide solution according to the method of SALEWSKI. Then the uteri were rinsed carefully with 0.9% NaCl-solution. Thereafter the implantation sites were recorded for calculation of the postimplantation loss.

Blood sampling:

No

Fetal examinations:

No fetal examination, pup examiation included:
- External examinations: Yes: All stillborn pups, all pups that died before PND 4 and all pups sacrified on PND 4
- Soft tissue examinations: Yes: All stillborn pups, all pups that died before PND 4 and all pups sacrified on PND 4
- Skeletal examinations: Not specified
- Head examinations: Not specified
- Anogenital distance of all live rodent pups: Not determined

Statistics:

Statistics of pathology: Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting pvalue was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the equal medians

Indices:

- Male reproduction data: Male mating index, Male fertility index
- Female reproduction and delivery data: Female mating index, Female fertility index, Gestation index, Live birth index, Post implantation loss
- Offspring viability indices: Pup number and status at delivery, Pup viability/mortality, Sex ratio, Pup body weight data

Historical control data:

yes

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

not specified

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Number of abortions:

no effects observed

Description (incidence and severity):

The gestation index was 100% in all test groups.

Pre- and post-implantation loss:

effects observed, non-treatment-related

Description (incidence and severity):

The postimplantation loss was 2.61% in test group 0, 2.89% in test group 1, 4.45% in test group 2 and 5.52% in test group 3. These data reflect the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.

Total litter losses by resorption:

not examined

Early or late resorptions:

not examined

Dead fetuses:

no effects observed

Description (incidence and severity):

The live birth index was 100% in all test group

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

All sperm positive rats delivered pups with the exception of two animals, which did not become pregnant no implantation sites). The female fertility index was 90% in test groups 0-2 and 100 % in test group 3. The mean duration until sperm was detected (GD 0) was 3.5, 1.7, 3.5 and 2.8 days in test groups 0 - 3.

Other effects:

no effects observed

Description (incidence and severity):

The female mating index calculated after the mating period for F1 litter was 100% for all test groups.

Dose descriptor:

NOAEL

Remarks:

for systemic and developmental toxicity

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: No treatment-related adverse effects observed up to and including the highest dose level of 1000 mg/kg bw.

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Mean pup body weights/pup body weight changes of all pups in all test groups were comparable to the control group. Two female and one male runts were seen in test group 3 (1000 mg/kg bw/d). In test group 2 (300 mg/kg bw/d) one female runt was seen. One male and one female runt were seen in control group.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

The mean number of delivered F1 pups was 12.7 in test group 0, 11.8 in test group 1, 12.3
in test group 2 and 11.7 in test group 3.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

The sex distribution and sex ratios of live F1 pups on the day of birth and PND 4 did not
show substantial differences between the control and the test substance-treated groups

Changes in litter size and weights:

not specified

Anogenital distance of all rodent fetuses:

not examined

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

The viability index indicating pup mortality during lactation (PND 0 - 4) was 100% for all
test groups.

External malformations:

no effects observed

Skeletal malformations:

not specified

Visceral malformations:

no effects observed

Other effects:

no effects observed

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment-related adverse effects observed up to and including the highest dose level of 1000 mg/kg bw.

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

The NOAEL for general, systemic toxicity was 1000 mg/kg bw/d. The NOAEL for developmental toxicity in the F1 progeny was found to be 1000 mg/kg bw/d.

Executive summary:

The test item was administered orally by gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (corn oil served as vehicle), 100 mg/kg bw/d, 300 mg/kg bw/d and 1000 mg/kg bw/d. The duration of treatment covered a 2-week premating and a mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation and 2 weeks thereafter in females. A detailed clinical observation was performed in all animals. Body weights and food consumption were determined in F0 animals. All animals were assessed by gross pathology; weights of selected organs were recorded and a histopathological examination was performed.

Clinical examinations, reproductive performance, clinical pathology, histopathology and gross pathology did not reveal any finding in treated animals. Viability, sex ratio and body weight of the pups was not affected. Examination of the ovaries and the uterine content did not overt any effect on uterus weight, number of implantations or resorptions.

Under the conditions of this screening study, the oral administration of the test substance by gavage to male and female Wistar rats did not reveal signs of toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Sreening test according to OECD 421 and GLP, Klimisch 1

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available screening study is reliable and suitable for classification purposes under Regulation 1272/2008. No adverse effects were observed in a screening study for fertility and developmental toxicity (OECD 421). As a result, the substance is not considered to be classified for fertility or developmental toxicity under Regulation (EC) No. 1272/2008, as amended for the fourteenth time in Regulation (EC) No. 2020/217.