Registration Dossier

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study conducted according to internationally recognised test methods.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Italy SpA
- Age at study initiation: 8-9 weeks
- Weight at study initiation: Males: 388-420 g; Females: 242-277 g
- Fasting period before study: No
- Housing: Polysulphone solid bottom cages, Group caged except for in pairs (1 male/1 female) for mating and females individually caged during gestation
- Diet (e.g. ad libitum): Mucedola 4RF21 pelleted diet available ad libitum
- Water (e.g. ad libitum): Municipal supply tap water available ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prepared daily by dissolution/suspension in corn oil.


VEHICLE
- Justification for use and choice of vehicle (if other than water): Substance is poorly soluble in water
- Concentration in vehicle: As required to achieve nominal dose, up to 25% w/v
- Amount of vehicle (if gavage): 2mL/kg
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 14 days (until sperm detected in vagina).
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): singly
- Any other deviations from standard protocol: None reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Proposed formulation procedure checked for concentration and homogeneity in the range from 20 to 200 mg/mL to confirm that the method was suitable. All levels were within 90-110% of nominal for concentration and the CV for homogeneity was < 10%. Stability after 24 hours at room temperature was verified in the range from 20 to 200 mg/mL and determined to be within acceptable limits (90-110% of nominal of concentration and CV for homogeneity < 10%).
Samples of the formulations, prepared on Weeks 1 and 6, were analysed to check for homogeneity and concentration. Results were within acceptable limits (90-110% of nominal for concentration and the CV for homogeneity was < 10%).
Duration of treatment / exposure:
Males: from 14 days before pairing for a total of approximetaly 6 weeks
Females: from 14 days before pairing to day 3 post partum (total of approximately 6 weeks)
Frequency of treatment:
Daily during treatment period
Remarks:
Doses / Concentrations:
0 (control), 100, 300and 1000 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
10 males & 10 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on data findings from structural analogues of the substance
- Rationale for animal assignment (if not random): Random, stratified body weight

Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for signs of ill health and moribund condition
- Cage side observations were included.: Yes - Daily, 2 or 3 times following dose administration

DETAILED CLINICAL OBSERVATIONS: Yes (functional observation battery)
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Males: Weekly; Females: days 0, 7, 14, 20, gestation days 0, 7, 14 and 20, post partum Days 1 and 4.

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 - Weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No - Not applicable as animals dosed by gavage

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No - Not applicable - Not a dietary study

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No - Not applicable as animals dosed by gavage:

Oestrous cyclicity (parental animals):
Examined pre-dose and during mating period
Sperm parameters (parental animals):
Parameters examined in P males/group : yes
- testis weight and microscopic pathology, epididymis weight and microscopic pathology

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

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals following approximately 6 weeks of treatment
- Maternal animals: All surviving animals day 4 post-partum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations of all organs & including the cervical, thoracic, and abdominal viscera. Pups: dead pups examined internally and externally. Live pups examined externally and sex confirmed by gonadal inspection..

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were weighed: adrenal glands, brain, epididymides, heart, kidney, liver, ovaries (with oviduct), spleen, testes, thymus.
The following tissues were prepared for microscopic examination: (5 males/5 females examined from high dose and control groups) - adrenal glands, bone marrow, brain, caecum, colon, duodenum, epididymides, heart, ileum, jejunum (including Peyer’s patches, kidneys, liver, Lungs (including mainstem bronchi), lymph nodes (cervical and mesenteric), ovaries with oviducts, pituitary gland, prostate gland, rectum, sciatic nerve, seminal vesicles with coagulating gland, spinal cord (cervical, thoracic and lumbar), spleen, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus and cervix, vagina.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination): Yes

GROSS NECROPSY
- Gross necropsy of dead pups consisted of external and internal examinations. Examination of live pups was limited to exernal examination.
Statistics:
For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data. Statistical analysis of histopathological findings was carried out by means of the non-parametric Kolmogorov-Smirnov test if n was more than 5. The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups was assessed by the non-parametric version of the Williams test. The criterion for statistical significance was p<0.05
Reproductive indices:
Copulation Index: No. of pairs with successful copulation/no. of pairs mated x 100
Fertility Index: No of males inducing pregnancy/No. of males paired x 100 and No. pregnant females/no. of pairs with successful copulation x 100
Offspring viability indices:
Pre-birth loss: (No. visible implantations - total litter size at birth)/No. visible implantations x 100
Pup loss at birth: (total litter size - live litter size)/total litter size x 100
Cumulative pup loss: (total litter size at birth - live litter size Day 4)/total litter size at birth x 100
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Salivation noted in animals treated at 1000 mg/kg following dosing
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No mortality occurred in the study. Clinical observations for neurotoxicity assessment (removal of animals from the home cage and open arena) did not reveal changes attributable to the tested substance. Salivation was the most relevant clinical sign, observed approximately 1 hour after dosing in high dose (1000 mg/kg b.w./day) main and recovery animals during the treatment phase of the study. This finding disappeared during the 2 week recovery period.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Body weight and body weight gain were unaffected by treatment. Food consumption was unaffected by treatment.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Measurements of oestrous cycle did not show differences between treated and control groups

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): See histopathology, below.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): Measurements of oestrous cycle, copulation plugs, copulatory index and fertility index did not show differences between treated and control groups. An increase in pre-coital interval was noted in 2 females dosed at 1000 mg/kg/day. Due to the low incidence, this finding was not considered to be of toxicological significance. No significant differences were observed in the number of implantation, corpora lutea, pre-implantation loss, total litter size, pre-birth loss and gestation length between control and treated groups.

ORGAN WEIGHTS (PARENTAL ANIMALS): A statistically significant decrease was noted in the absolute thymus weight of females treated at 1000 mg/kg/day (approximately 28%). A slight, statistically significant, increase was also noted in the relative kidney weight of males treated at 300 and 1000 mg/kg/day (approximately 10%) and in the relative kidney and liver weights of females of the recovery group treated at 1000 mg/kg/day (approximately 7%).

GROSS PATHOLOGY (PARENTAL ANIMALS): No treatment-related changes were noted in treated animals, both in main and recovery groups. Those changes that were observed were regarded as being incidental, having a comparable incidence in control and treated groups, and/or characteristically seen in untreated Sprague Dawley rats of the same age.

HISTOPATHOLOGY (PARENTAL ANIMALS): No treatment-related changes were noted in randomly selected animals from the control group and high dose (1000 mg/kg/day) group. Those changes that were observed were regarded as being incidental, having a comparable incidence in control and treated groups, and/or characteristically seen in untreated Sprague Dawley rats of the same age. Examples of such minimal, spontaneous, age-related changes included hepatic and heart inflammatory cell foci. In particular, two female rats treated at 1000 mg/kg/day exhibited mild atrophy of the thymic cortex. As this kind of change is sporadically seen in untreated female rats it was not considered as related to treatment.
A detailed qualitative evaluation of testes was performed on randomly selected control and high dose (1000 mg/kg/day) males. The evaluation took into account the tubular stages of the spermatogenic cycle, in order to identify potential treatment-related effects, such as: missing germ cell layers or types, retained spermatids, multinucleated or apoptotic germ cells and sloughing of spermatogenic cells into the lumen. PAS-H stained sections were used to identify the spermatogenic stages. Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages. Regular layering in the germinal epithelium was noted
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of effects on reproductive performance or sex organs
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
VIABILITY (OFFSPRING): No effects

CLINICAL SIGNS (OFFSPRING): No effects

BODY WEIGHT (OFFSPRING): No effects

GROSS PATHOLOGY (OFFSPRING): No effects

Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of effects on pup weight; sex ratio; survival index; viability index
Reproductive effects observed:
not specified

 

Reproductive performance

Dose level (mg/kg body weight/day

0

100

300

1000

Number of mated pairs

10

10

10

10

Number of pregnant animals

9

10

10

10

Copulation index – males (%)

100

100

80

100

Fertility index – males (%)

90

100

80

100

Copulation index – females (%)

100

100

100

100

Fertility index – females (%)

90

100

100

100

 

 

 

Developmental toxicity parameters

Dose level (mg/kg body weight/day

0

100

300

1000

Number of pregnant animals

9

10

10

10

Number of pregnant animals with live young

9

10

10

10

Gestation length (days)

22.11 ± 0.60

22.10 ± 0.57

22.30 ± 0.67

21.80 ± 0.42

Number of corpora lutea

13.67 ± 5.32

15.80 ± 3.29

15.40 ± 4.17

16.50 ± 1.58

Number of implantation sites

13.33 ± 5.24

15.00 ± 3.02

15.00 ± 3.83

16.50 ± 1.58

Pre-implantation loss (%)

2.09 ± 6.27

4.55 ± 7.64

2.10 ± 4.78

0.00 ± 0.00

Pre-birth loss (%)

7.28 ± 6.40

7.89 ± 5.58

10.17 ± 13.41

7.51 ± 6.29

 

 

 

 

 

Lactation day 0:

 

 

 

 

Number of pups born

12.56 ± 5.22

13.80 ± 2.86

13.80 ± 4.24

15.30 ± 2.06

Number of pups alive

12.56 ± 5.22

13.70 ± 2.95

13.80 ± 4.24

15.30 ± 2.06

Pup weight (g)

7.31 ± 1.21

7.14 ± 0.79

7.37 ± 0.83

6.93 ± 0.37

Sex ratio (% males)

47.07 ± 24.44

49.90 ± 12.47

52.01 ± 13.14

45.75 ± 14.51

 

 

 

 

 

Lactation day 4:

 

 

 

 

Number of live pups

12.22 ± 5.02

13.10 ± 2.64

13.70 ± 4.19

15.30 ± 2.06

Pup weight (g)

10.23 ± 2.58

9.79 ± 1.86

10.32 ± 1.80

9.30 ± 0.74

Sex ratio (% males)

46.61 ± 24.52

49.27 ± 12.38

51.71 ± 13.07

45.75 ± 14.51

 
Conclusions:
A repeated-dose toxicity combined with a reproductive/developmental toxicity screen conducted according to OECD Test Guideline No 422 found no adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg/day for both parent animals and offspring, this being the highest dose level investigated.
Executive summary:

A repeated-dose toxicity combined with a reproductive/developmental toxicity screen conducted according to OECD Test Guideline No 422 found no adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg/day for both parent animals and offspring, this being the highest dose level investigated.

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
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A repeated-dose toxicity combined with a reproductive/developmental toxicity screen conducted according to OECD Test Guideline No 422 found no adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg/day for both parent animals and offspring, this being the highest dose level investigated.

 

A two-generation reproductive toxicity study is required in accordance with Section 8.7.3 of Column 1, Annex IX. It is proposed to waive the need to conduct this study on the basis of the fact that a well-conducted OECD 422 combined repeat-dose and reproductive/developmental toxicity screening study is available on the substance. This study shows that the substance has no functional effect on the reproductive performance of both male and female rats. It provides adequate data to demonstrate the potential toxicity to reproduction of the substance to humans and to derive relevant DNELs for oral exposure.


Short description of key information:
Fertility - Rat: NO(A)EL - 1000 mg/kg/day

Justification for selection of Effect on fertility via oral route:
Single study available for evaluation

Effects on developmental toxicity

Description of key information
Developmental toxicity - rat: NO(A)EL 1000 mg/kg/day
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with current test methods and in compliance with GLP regulations
Qualifier:
according to guideline
Guideline:
other: OECD 422
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Italy SpA
- Age at study initiation: 8-9 weeks
- Weight at study initiation: Males: 388-420 g; Females: 242-277 g
- Fasting period before study: No
- Housing: Polysulphone solid bottom cages, Group caged except for in pairs (1 male/1 female) for mating and females individually caged during gestation
- Diet (e.g. ad libitum): Mucedola 4RF21 pelleted diet available ad libitum
- Water (e.g. ad libitum): Municipal supply tap water available ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prepared daily by dissolution/suspension in corn oil.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Proposed formulation procedure checked for concentration and homogeneity in the range from 20 to 200 mg/mL to confirm that the method was suitable. All levels were within 90-110% of nominal for concentration and the CV for homogeneity was < 10%. Stability after 24 hours at room temperature was verified in the range from 20 to 200 mg/mL and determined to be within acceptable limits (90-110% of nominal of concentration and CV for homogeneity < 10%).
Samples of the formulations, prepared on Weeks 1 and 6, were analysed to check for homogeneity and concentration. Results were within acceptable limits (90-110% of nominal for concentration and the CV for homogeneity was < 10%).
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Until mating observed (4 days/1 oestrus)
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: Individually
- Any other deviations from standard protocol: No
Duration of treatment / exposure:
Males: from 14 days before pairing for a total of approximetaly 6 weeks
Females: from 14 days before pairing to day 3 post partum (total of approximately 6 weeks)
Frequency of treatment:
Daily, 7 days/week
Duration of test:
Males: from 14 days before pairing for a total of approximetaly 6 weeks
Females: from 14 days before pairing to day 3 post partum (total of approximately 6 weeks)

Remarks:
Doses / Concentrations:
0, 100, 300 and 1000 mg/kg body weight
Basis:
nominal conc.
No. of animals per sex per dose:
10 males / 10 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on data findings from structural analogues of the substance
- Rationale for animal assignment (if not random): Random, stratified body weight
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for signs of ill health and moribund condition
- Cage side observations were included.: Yes - Daily, 2 or 3 times following dose administration

DETAILED CLINICAL OBSERVATIONS: Yes (functional observation battery)
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Males: Weekly; Females: days 0, 7, 14, 20, gestation days 0, 7, 14 and 20, post partum Days 1 and 4.

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 - Weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No - Not applicable as animals dosed by gavage

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No - Not applicable - Not a dietary study

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No - Not applicable as animals dosed by gavage

SACRIFICE
- Male animals: All surviving animals following 42 days of treatment
- Maternal animals: All surviving animals day 4 of lactation

GROSS NECROPSY:
Gross necropsy consisted of external and internal examinations of all organs & including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS:
The following tissues were weighed: adrenal glands, brain, epididymides, heart, kidney, liver, ovaries (with oviduct), spleen, testes, thymus.
The following tissues were prepared for microscopic examination:(5 males/5 females examined from high dose and control groups) - adrenal glands, bone marrow, brain, caecum, colon, duodenum, epididymides, heart, ileum, jejunum (including Peyer’s patches, kidneys, liver, Lungs (including mainstem bronchi), lymph nodes (cervical and mesenteric), ovaries with oviducts, pituitary gland, prostate gland, rectum, sciatic nerve, seminal vesicles with coagulating gland, spinal cord (cervical, thoracic and lumbar), spleen, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus and cervix, vagina.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows: Examined for external abnormalities and sex confirmation by gonadal inspection
- External examinations: Yes - all per litter
- Soft tissue examinations: Yes: - early decedents
- Skeletal examinations: No
- Head examinations: No
Statistics:
For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data. Statistical analysis of histopathological findings was carried out by means of the non-parametric Kolmogorov-Smirnov test if n was more than 5. The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups was assessed by the non-parametric version of the Williams test. The criterion for statistical significance was p<0.05.
Indices:
Copulation Index: No. of pairs with successful copulation/no. of pairs mated X 100
Fertility Index: No of pregnant females/no. of pairs with successful copulation X 100
Implantation index: No. of implantation sites/no. of corporea lutea X 100
Delivery index: No. of pups born/no. of implantation sites X 100
Gestation index: No. of females with live pups delivered/no. of pregnant females X 100
Nursing index: No. of females nursing live pups/no. of females with normal delivery X 100
Live birth index: No. of live pups at birth/no. of pups at birth X 100
Viability index: No. of live pups on d4/no.of live pups at birth
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No deaths occurred. Temporary increase in salivation after dosing was observed in animals treated at 1000 mg/kg/day.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Decreased body weight gain from day 7 to 14 of gestation observed in females treated at 500 mg/kg/day. No adverse effects on body weights in males. No effects on food consumption in either sex.

ORGAN WEIGHTS (PARENTAL ANIMALS): No effects

GROSS PATHOLOGY (PARENTAL ANIMALS): No effects

HISTOPATHOLOGY (PARENTAL ANIMALS): No effects
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Abnormalities:
not specified
Developmental effects observed:
not specified

Reproductive performance

Dose level (mg/kg body weight/day

0

100

300

1000

Number of mated pairs

10

10

10

10

Number of pregnant animals

9

10

10

10

Copulation index – males (%)

100

100

80

100

Fertility index – males (%)

90

100

80

100

Copulation index – females (%)

100

100

100

100

Fertility index – females (%)

90

100

100

100

Developmental toxicity parameters

Dose level (mg/kg body weight/day

0

100

300

1000

Number of pregnant animals

9

10

10

10

Number of pregnant animals with live young

9

10

10

10

Gestation length (days)

22.11 ± 0.60

22.10 ± 0.57

22.30 ± 0.67

21.80 ± 0.42

Number of corpora lutea

13.67 ± 5.32

15.80 ± 3.29

15.40 ± 4.17

16.50 ± 1.58

Number of implantation sites

13.33 ± 5.24

15.00 ± 3.02

15.00 ± 3.83

16.50 ± 1.58

Pre-implantation loss (%)

2.09 ± 6.27

4.55 ± 7.64

2.10 ± 4.78

0.00 ± 0.00

Pre-birth loss (%)

7.28 ± 6.40

7.89 ± 5.58

10.17 ± 13.41

7.51 ± 6.29

 

 

 

 

 

Lactation day 0:

 

 

 

 

Number of pups born

12.56 ± 5.22

13.80 ± 2.86

13.80 ± 4.24

15.30 ± 2.06

Number of pups alive

12.56 ± 5.22

13.70 ± 2.95

13.80 ± 4.24

15.30 ± 2.06

Pup weight (g)

7.31 ± 1.21

7.14 ± 0.79

7.37 ± 0.83

6.93 ± 0.37

Sex ratio (% males)

47.07 ± 24.44

49.90 ± 12.47

52.01 ± 13.14

45.75 ± 14.51

 

 

 

 

 

Lactation day 4:

 

 

 

 

Number of live pups

12.22 ± 5.02

13.10 ± 2.64

13.70 ± 4.19

15.30 ± 2.06

Pup weight (g)

10.23 ± 2.58

9.79 ± 1.86

10.32 ± 1.80

9.30 ± 0.74

Sex ratio (% males)

46.61 ± 24.52

49.27 ± 12.38

51.71 ± 13.07

45.75 ± 14.51

Conclusions:
In a repeat-dose toxicity combined with a screening study of reproductive toxicity conducted in accordance with OECD test methods, no adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg/day, this being the highest dose level investigated.
Executive summary:

In a repeat-dose toxicity combined with a screening study of reproductive toxicity conducted in accordance with OECD test methods,no adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg/day, this being the highest dose level investigated.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
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

A repeated-dose toxicity combined with a reproductive/developmental toxicity screen conducted according to OECD Test Guideline No 422 has been conducted on the substance itself. No adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index were found. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg/day for both parent animals and offspring, this being the highest dose level investigated.


Justification for selection of Effect on developmental toxicity: via oral route:
Single study available for evaluation

Justification for classification or non-classification

An OECD screening study of reproductive toxicity revealed no functional changes in fertility or reproductive performance.

In accordance with the criteria laid down in Regulation (EC) No. 1272/2008 no toxicologically significant effects are evident sufficient to warrant classification.

Additional information

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