Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

The administration of the test material to Wistar rats by oral gavage, at dose levels of 100, 300 and 1000 mg/kg/day, resulted in no treatment-related clinical signs, changes in the body weights, feed consumption and microscopic effects in male and female animals. No treatment-related effects on reproduction! development such as mating index, fertility index, gestation length, pre-natal loss, postnatal loss, sex ratio and offspring growth and development were observed. Therefore, a 'No Observed Effect Level' (NOEL) for reproductive toxicity is considered to be the high dose employed in the study i.e. 1000 mg/kg/day.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 03, 2019 to November 21, 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room Temperature (20 to 30°C)
Stability under test conditions: Stable
Solubility and stability of the test substance in the vehicle: Stability of dose formulation at 10 mg/ml, 100 mg/ml was checked at 0 and 6 hours period. The dose formulations were found to be stable up to 6 hours.
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Recommended by the guidelines
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animal Breeding , RCC Laboratories India Private Limited
- Females (if applicable) nulliparous and non-pregnant: [yes]
- Age at study initiation: 13-15 wks
Body weight at first dosing Males = 299.0 to 338.5 grams, Females = 249.5 to 283.3 grams.
- Housing:
Initially (acclimatization and randomization period), all animals were housed in groups of three / two per polycarbonate cages (approximate internal dimensions of 365 mm x 202 mm x 180 mm height) with corn cob/paddy husk bedding. Results of analyses for contaminants were archived at RCC Laboratories India Private Limited. After randomization, males and females were housed individually. During the mating phase, animals were housed on one male: one female basis within each dose group.
After successful mating, the females were returned to their original cages and housed individually during gestation and lactation
- Diet :Teklad Certified Global 14% Protein Rodent Maintenance Diet from Envigo (Lot Number – 2014C-012919MA) was provided ad libitum.
- Water : ad libitum
- Acclimation period:11 days under laboratory conditions
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.7 to 23.0°C
- Humidity (%): 57 to 67 %,
- Air changes (per hr): Above 10
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark.
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Concentration in vehicle: The Low dose (10 mg/mL), Intermediate dose (30.0 mg/mL) and High dose (100 mg/mL).
- Amount of vehicle (if gavage): 10 mL/kg body weight.

VEHICLE

- Concentration in vehicle: 10 ml/kg body weight Vehicle Control group were treated with Distilled water (10 mL/kg body weight).
- Amount of vehicle (if gavage): (10 mL/kg body weight).
Details on mating procedure:
- M/F ratio per cage: 1:1 (one male to one female) mating was used in this study.
- Proof of pregnancy: Sperm in vaginal plug referred to as [day 0] of pregnancy
- After successful mating each pregnant female was caged (how): After successful mating, the females were returned to their original cages and housed individually during gestation and lactation
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical method was validated and the detector response was found to be linear (r2 = 0.9992) in the range of 5.21 mg/ 10 mL to 18.99 mg/ 10 mL concentration.
The accuracy and precision obtained in the dose preparation were within recovery concentration (i.e. mean recovery for T1 and T2 levels were 99.496% and 99.304%).
The test item was found to be stable at 6th hour sample at room temperature. The stability concentration was obtained in all the dose groups were in agreement with the target concentration (i.e. ranged between 91% to 103%).
The recovered content was found homogeneously distributed in the suspension at concentrations 10 mg/mL, 30 mg/mL and 100 mg/mL for the test item.
The recovered content obtained in all the dose groups was in agreement with the target concentration (i.e. ranged between 93.83% to 99.58%).
Duration of treatment / exposure:
Males were dosed for a minimum of four weeks (day 0 to day 28). This includes two weeks prior to mating, mating and post mating period.
Females were dosed throughout the study this includes two weeks prior to mating, the variable time to conception, the duration of pregnancy and thirteen days after delivery up to and including the day before scheduled necropsy.
Frequency of treatment:
Once Daily, Seven days a week
Dose / conc.:
100 mg/kg bw/day
Remarks:
Low
Dose / conc.:
300 mg/kg bw/day
Remarks:
Intermediate
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
High dose
No. of animals per sex per dose:
12 males and 12 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels of 0 (Vehicle control), 100 (Low), 300 (Intermediate) and 1000 (High) mg/kg body weight are selected based on the results of RCC Study No. 153.


Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily during the acclimatization and treatment, gestation, lactation period (Twice daily on initial three days as per raw data), animals were observed for clinical signs.
Twice daily during the acclimatization and treatment period animals were checked for mortality/ viability.
Females showing no evidence of copulation were sacrificed 26 - 41 days after the last day of the mating period. i.e. 26 and some on 41.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual animal was weighed at the time of receipt, randomization, on the first day of dosing, once weekly thereafter and at termination.
Pregnant females were weighed on days 0, 7, 14 and 20 and within 24 hours of parturition (day 1 post-partum) and days 4 and 13 post-partum.
Live pups were weighed within 24 hours of parturition (day 1 post-partum), on day 4 and day 13 post-partum.
Oestrous cyclicity (parental animals):
Estrous cycle was monitored for 14 days during the pre-exposure period to select the study females with regular estrous cyclicity.
Sperm parameters (parental animals):
Testes, Epididymides, Seminal vesicles with coagulating glands, Prostate gland, Levator ani plus bulbocavernosus muscle complex and Cowper’s glands and glans penis
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes


PARAMETERS EXAMINED
The following parameters were examined in offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples in male pups]

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities.



Postmortem examinations (parental animals):
SACRIFICE
- Male animals and Maternal animals: All surviving animals were sacrificed at the end of the observation period using carbon dioxide asphyxiation and examined macroscopically for any gross abnormalities or pathological changes, especially the organs of the reproductive system.


GROSS NECROPSY
There were no treatment related macroscopic findings in males, females and in pups.
One incidence of bilateral small sized testes, epididymides, seminal vesicles, coagulating glands, cowpers gland and small sized prostate was observed in a group 4 male animal (Animal number 78). All these changes were considered incidental as it was single incidence of the lesion.

HISTOPATHOLOGY / ORGAN WEIGHTS
There were no treatment related microscopic findings in testes and epididymides in males and in ovaries in females at high dose. Single incidence of absence of spermatids in seminiferous tubules of testes, aspermia in epididymides and atrophy of prostate, seminal vesicle, coagulating glands and cowpers gland were observed in animal number 78 of high dose group and considered as incidental findings
Organs weights
No significant difference was observed in absolute and relative organ weights in treatment groups in male and female animals compared with control group.
No significant difference was observed in absolute and relative organ weights in treatment group pups when compared with control group.
Postmortem examinations (offspring):
SACRIFICE
These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

No abnormality was observed attributable to treatment in any of the pups in low, mid and high dose groups.

Statistics:
Statistical analysis was performed using statplus program.
ANOVA, T -TEST, Normality and homogenicity test was performed
Reproductive indices:
Mating performance and Fertility:
No treatment-related effects were detected on mating performance. All the female animals of control, low, intermediate and high dose group showed positive evidence of mating. No significant difference was observed in the pre-coital interval of female animals between control, low, intermediate and high dose group.
No treatment related effects on the oestrous cycle was observed.
Mating index for all the groups was 100% (as confirmed by presence of sperm in the vaginal smear).
The pregnancy index for the control and low dose groups is 83.33% and for the intermediate dose and high dose groups is 75%, respectively.
Of the litters born, litter sizes at birth and subsequently on days 1 and 4 post-partum was comparable to controls.
There were no treatment-related effects observed on the fertility of treated animals.
Gestation and Parturition:
There were no differences in gestation length. The gestation length for treated females was comparable to controls. All animals showed gestation lengths between 19 to 23 days. The parturition index was 100% in control and all treatment dose groups.
Offspring viability indices:
Litter Responses:
Pre natal & Post natal loss
The pre and post natal losses in all treated groups were comparable with control group.
Litter Size and Live birth:
Of the litters delivered in all the treatment groups, litter size at birth and subsequently on Day 1 and 4 post-partum were comparable to controls. No significant difference in live birth was noted between control and treated groups.
No nipple retention was observed in any of the male pups from control and treated groups.
Sex ratio:
No significant difference in sex ratio was observed in any of the treated groups when compared with control group.
Offspring Growth and Development:
Offspring body weights on day 1, 4 and 13 were recorded. No significant changes in the offspring body weight of low, Intermediate and high dose groups were observed on day 1, 4 and 13 when compared with control group.

Litter weights
No significant changes were observed in the litter weights on day 1, 4 and 13 post-partum between control and treated groups.
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs were observed in the control group (0 mg/kg bodyweight), low dose group (100 mg/kg body weight), intermediate dose group (300 mg/kg body weight) and high dose groups (1000 mg/kg body weight) in both male, female animals and in pups
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were no mortalities observed in control group (0 mg/kg bodyweight), low dose group (100 mg/kg body weight), intermediate dose group (300 mg/kg body weight) and high dose group (1000 mg/kg body weight) animals in premating, mating, gestations and lactation periods. Cannibalism of pups were observed in the control (Dam No.18), in low dose (Dams No.43 & 48), in intermediate dose (Dam No. 69) and in high dose (Dam No. 85) groups on day of parturition (Day 1 of Lactation Period).
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No significance difference in the body weight and body weight gain (%) was observed in low, intermediate and high dose group male animals when compared with control group.
No significance difference in the body weight and body weight gain (%) was observed in low, intermediate and high dose group female animals when compared with control group during Pre-mating and gestation.
However, significant marginal increase in the body weight was observed in intermediate dose (G3) and high dose (G4) when compared with control group (G1) in females during lactation day 13.
This effect was not considered to be test item related. The variations in the body weight gain were considered incidental as there was no dose dependency and the change was sporadic in nature
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Description (incidence and severity):
No adverse effects in food consumption were observed in the treated group animals when compared with control group.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically relevant findings in thyroxine (T4) and thyroid stimulating hormone (TSH) levels were observed in parent animals (males, females).
Significant increase was observed in high dose (G4) when compared to low dose (G2) and intermediate dose (G3) in combined pups TSH on PND-4.
Significant decrease was observed in intermediate dose (G3) when compared to control (G1) in combined pups TSH on PND-13.
The changes observed in the clinical biochemistry parameters are marginal, not clinically significant and could not be attributed to the test item administration as these values were within biological variation
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related microscopic findings in testes and epididymides in males and in ovaries in females at high dose. Single incidence of absence of spermatids in seminiferous tubules of testes, aspermia in epididymides and atrophy of prostate, seminal vesicle, coagulating glands and cowpers gland were observed in animal number 78 of high dose group and considered as incidental findings.
Histopathological findings: neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No treatment related effects on the oestrous cycle was observed.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Detailed histological examination was performed on testes using PAS-H stain with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure and epididymides of male animals and ovaries of female animals in order to identify treatment related effects.
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were detected on mating performance. All the female animals of control, low, intermediate and high dose group showed positive evidence of mating. No significant difference was observed in the pre-coital interval of female animals between control, low, intermediate and high dose group.
No treatment related effects on the oestrous cycle was observed.
Mating index for all the groups was 100% (as confirmed by presence of sperm in the vaginal smear).
The pregnancy index for the control and low dose groups is 83.33% and for the intermediate dose and high dose groups is 75%, respectively.
Of the litters born, litter sizes at birth and subsequently on days 1 and 4 post-partum was comparable to controls.
There were no treatment-related effects observed on the fertility of treated animals
Gestation and Parturition:
There were no differences in gestation length. The gestation length for treated females was comparable to controls. All animals showed gestation lengths between 19 to 23 days. The parturition index was 100% in control and all treatment dose groups.
Key result
Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food efficiency
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
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:
no effects observed
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:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
other: No effects were observed in pups
Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day
Treatment related:
no

TABULAR SUMMARY REPORT OF EFFECTS ON REPRODUCTION/DEVELOPMENT

Parameters

Group 1

Group 2

Group 3

Group 4

Pairs started (N)

12

12

12

12

Females showing evidence of copulation (N)

12

12

12

12

Females achieving pregnancy (N)

10

10

9

9

Conceiving Days 1 - 5 (N)

10

9

11

11

Conceiving Days ≥ 6 (N)

2

3

1

1

Pregnancy = 19 Days (N)

1

1

1

0

Pregnancy = 20 Days (N)

0

0

0

0

Pregnancy = 21 Days (N)

1

1

0

2

Pregnancy = 22 Days (N)

2

3

3

2

Pregnancy = 23 Days (N)

6

5

5

5

Dams with live young born (N)

10

10

9

9

Dams with live young at Day 4 post partum (N)

10

10

9

9

Implants/dam (mean)

7.8

8.0

9.1

7.6

Live pups/dam at  birth (mean)

7.70

7.70

9.00

7.44

Live pups/dam at Day 4 (mean)

7.50

7.50

8.89

7.33

Sex ratio % males at Day 1 post partum

49.33

54.67

40.00

51.52

Sex ratio % males at Day 4 post partum

49.33

54.67

40.00

51.52

Pup weight at Day 1 -Combined (g, mean)

4.94

4.99

4.98

5.07

Pup weight at Day 4 - Combined (g, mean)

10.16

10.27

10.27

10.39

Pup weight at Day 1 Male  (g, mean)

5.12

5.13

5.18

5.22

Pup weight at Day 4 Male  ((g, mean)

10.39

10.56

10.43

10.76

Pup weight at Day 1 Female (g, mean)

4.75

4.82

4.86

4.91

Pup weight at Day 4 Female (g, mean)

9.94

9.91

10.16

9.99

ABNORMAL PUPS (Based on gross finding)

Dams with 0 (N)

10

10

9

9

Dams with 1 (N)

0

0

0

0

Dams with 2 (N)

0

0

0

0

Dams with more than 2 abnormal pups (N)

0

0

0

0

 

 

TABULAR SUMMARY REPORT OF EFFECTS ON REPRODUCTION/DEVELOPMENT

 

Parameters

Group 1

Group 2

Group 3

Group 4

LOSS OF OFFSPRING  

Pre-natal (Implantations minus live births) 

Females with 0 (N)

9

8

8

8

Females with 1 (N)

1

1

1

1

Females with 2 (N)

0

1

0

0

Females with 3 (N)

0

0

0

0

Females with >4 (N)

0

0

0

0

Post-natal (live births minus alive at post natal Day 4) 

Females with 0 (N)

9

8

8

8

Females with 1 (N)

0

2

1

1

Females with 2 (N)

1

0

0

0

Females with 3 (N)

0

0

0

0

Females with >4 (N)

0

0

0

0

Post-natal (live births minus alive at post natal Day 13) 

Females with 0 (N)

9

8

8

8

Females with 1 (N)

0

2

1

1

Females with 2 (N)

1

0

0

0

Females with 3 (N)

0

0

0

0

 

Conclusions:
The administration of the test item to Wistar rats by oral gavage, at dose levels of 100, 300 and 1000 mg/kg/day, resulted in no treatment-related clinical signs, changes in the body weights, feed consumption and microscopic effects in male and female animals. No treatment-related effects on reproduction/ development such as mating index, fertility index, gestation length, pre-natal loss, post-natal loss, sex ratio and offspring growth and development were observed. Therefore, a ‘No Observed Effect Level’ (NOEL) for reproductive toxicity is considered to be the high dose employed in the study i.e.1000 mg/kg/day.
No Observed Effect Level (NOEL) for Reproduction / Developmental Toxicity : 1000 mg/kg body weight
Executive summary:

During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights.

Males were sacrificed on Day 29, followed by the sacrifice of all females on Day 14 post-partum.Pups were sacrificed on Day 13 postpartum. Macroscopy at termination was performed for all animals.

Male and female animals were screened for T4 and TSH parameters from each dose group. Selected offspring were also screened for T4 and TSH parameters from each dose and control group.

Wet weights of organs were recorded for testes, epididymis, seminal vesicles with coagulating glands, prostate gland,levator ani plus bulbocavernosus muscle complex; cowper’s glands and glands penis from males; and ovaries, uterus with cervix from females.

Histopathology was performedon the preserved organs for epididymis, testes and ovaries of control and high dose groups. Histopathology was not extended to the other dose groups since no test item related lesions were observed in the high dose group.

 

RESULTS

Analytics

Homogeneity and dose concentration Analysis revealed acceptable levels of A.I. content in the prepared dose formulations.

Mortality:

There were no mortalities observed in control group (0 mg/kg bodyweight), low dose group (100 mg/kg body weight), intermediate dose group (300 mg/kg body weight) and high dose group (1000 mg/kg body weight) animals in premating, mating, gestations and lactation periods. Cannibalism of pups were observed in the control (Dam No.18), in low dose (Dams No.43 & 48), in intermediate dose (Dam No. 69) and in high dose (Dam No. 85) groups on day of parturition (Day 1 of Lactation Period).

Clinical Signs:

No clinical signs were observed in the control group (0 mg/kg bodyweight), low dose group (100 mg/kg body weight), intermediate dose group (300 mg/kg body weight) and high dose groups (1000 mg/kg body weight) in both male, female animals and in pups.

Body Weight:

No significance difference in the body weight and body weight gain (%) was observed in low, intermediate and high dose group male animals when compared with control group. 

No significance difference in the body weight and body weight gain (%) was observed in low, intermediate and high dose group female animals when compared with control group during Pre-mating and gestation. 

However, significant marginal increase in the body weight was observed in intermediate dose (G3) and high dose (G4) when compared with control group (G1) in females during lactation day 13.

This effect was not considered to be test item related. The variations in the body weight gain were considered incidental as there was no dose dependency and the change was sporadic in nature.

Feed Consumption:

No adverse effects in food consumption were observed in the treated group animals when compared with control group.

Clinical Biochemistry:

No toxicologically relevant findings in thyroxine (T4) and thyroid stimulating hormone (TSH) levels were observed in parent animals (males and females) individually.

 

 

Mating performance and Fertility:

No treatment-related effects were detected on mating performance. All the female animals of control, low, intermediate and high dose group showed positive evidence of mating. No significant difference was observed in the pre-coital interval of female animals between control, low, intermediate and high dose group.

No treatment related effects on the oestrous cycle was observed. 

Mating index for all the groups was 100% (as confirmed by presence of sperm in the vaginal smear).

The pregnancy index for the control and low dose groups is 83.33% and for the intermediate dose and high dose groups is 75%, respectively.

Of the litters born, litter sizes at birth and subsequently on days 1 and 4 post-partum was comparable to controls.

There were no treatment-related effects observed on the fertility of treated animals.

Gestation and Parturition:

There were no differences in gestation length. The gestation length for treated females was comparable to controls. All animals showed gestation lengths between 19 to 23 days. The parturition index was 100% in control and all treatment dose groups.

Litter Responses:

Pre natal & Post natal loss

The pre and post natal losses in all treated groups were comparable with control group. 

Litter Size and Live birth:

Of the litters delivered in all the treatment groups, litter size at birth and subsequently on Day 1 and 4 post-partum were comparable to controls. No significant difference in live birth was noted between control and treated groups.

No nipple retention was observed in any of the male pups from control and treated groups.

Sex ratio:

No significant difference in sex ratio was observed in any of the treated groups when compared with control group.

Offspring Growth and Development:

Offspring body weights on day 1, 4 and 13 were recorded. No significant changes in the offspring body weight of low, Intermediate and high dose groups were observed on day 1, 4 and 13 when compared with control group.


Litter weights

No significant changes were observed in the litter weights on day 1, 4 and 13 post-partum between control and treated groups.

Organ weight:

No significant difference was observed in absolute and relative organ weights in treatment groups male and female animals when compared with control group.

No significant difference was observed in absolute and relative organ weights in treatment group pups when compared with control group.

Macroscopic findings

There were no treatment related macroscopic findings in males, females and in pups.

One incidence of bilateral small sized testes,epididymides, seminal vesicles, coagulating glands, cowpers gland and small sized prostatewas observed inagroup4male animal(Animal number78). All these changes were considered incidentalas it was single incidence of the lesion.

Microscopic findings

There were no treatment related microscopic findings in testes and epididymides in males and in ovaries in females at high dose. Single incidence of absence of spermatids in seminiferous tubules of testes, aspermia in epididymides and atrophy of prostate, seminal vesicle, coagulating glands and cowpers gland were observed in animal number 78 of high dose group and considered as incidental findings.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Experimental exposure time per week (hours/week):
168
Species:
rat
Quality of whole database:
reliable without restriction

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available

Justification for classification or non-classification

No classification

The NOAEL in a reproductive screening study according to OECD TG 421 was 1000 mg/kg.

Additional information