Registration Dossier

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: Guideline study; well-performed and well-documented
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
After 14 days of treatment the both male and female, animals were paired (1:1) for a maximum of 14 days. The subsequent morning onwards the vaginal smears of females were checked to confirm the evidence of mating. After the confirmation of the mating, females were separated and housed individually.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days for males, up to 54 days for females
Frequency of treatment:
once per day
Remarks:
Doses / Concentrations:
0, 100, 250, 750 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
piloerection, nasal discharge, eye closure at 250 and 750 mg/kg bw
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
only reproduction organs investigated
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant systemic effect up to highest applied dose. No effect on the reproduction organ and no effect on the reproduction performance.
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:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect found for all parameters related to developmental toxicity
Reproductive effects observed:
not specified

No mortality occurred in the control or any of the dose groups during the treatment period of this study.

At 250 and 750 mg/kg/day, signs of discomfort such as pushing the head through the bedding material and salivation were observed throughout the study in males and females. Occasionally, piloerection, nasal discharge and eye closure were also observed.

Food consumption and body weight and body weight gain were not affected by the treatment with the test item.

Gross pathological examination of male and females at scheduled necropsy did not revealed any treatment-related findings.

Absolute and relative weight of uterus, ovaries, testis, epididymides and prostate were not affected by the treatment with the test item.

The histopathologic examination of male and female reproductive organs did not indicate any test item-related changes. Two females of the control group, one female treated at 100 mg/kg/day, two females treated at 250 mg/kg/day and one female treated at 750 mg/kg/day were found not to be pregnant at terminal sacrifice. As there was no dose relationship, this was not considered to be treatment-related.

The litter weight was not affected by the treatment with the test item either at birth or on postnatal day 4.

No treatment related effect was observed on the total number of pups born per litter, and on the sex ratio. No external findings and no gross abnormalities were observed in pups at necropsy.

Fertility, delivery and viability indexes were similar within the group and were not indicative of any effect of the test item. Precoital interval and duration of the gestation were also not affected by the treatment with the test item.

Mean number of corpora lutea and of implantation sites were not considered to be affected by the treatment with the test item. Incidence of pre- and post-implantation losses was also not affected by the treatment with the test item.

Litter size and sex ratio were not affected by the treatment with the test item either at birth or on PND 4. Gross necropsy of dead pups revealed no treatment-related findings.

Conclusions:
The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 421. The NOAEL of 750 mg/kg bw, corresponding to highest applied dose, was obtained for parental and for developmental effects.
Executive summary:

The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 421. The rats were treated via gavage at doses of 0, 100, 250, and 750 mg/kg bw.

At doses of 250 and 750 mg/kg bw signs of discomfort were observed but no severe clinical signs. No effects were observed in food consumption and body weight. Macroscopic and histopathologic parameters and evaluation of litter data did not induce any test item-related effect.

The NOAEL of 750 mg/kg bw was obtained for parental and for developmental effects.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
One valid study for the reproduction toxicity; the obtained result is consistant with results obtained in repeated dose toxicity study and in developmental toxicity study.
Additional information

Short description of key information:
The registration substance was investigated for its reproduction toxicity according to the OECD guideline 421. Up to the highest applied dose of 750 mg/kg bw no significant effect was observed. The NOAEL of 750 mg/kg bw was observed for parental and fetal effects.

Justification for selection of Effect on fertility via oral route:
Guideline study; well-performed and well-documented

Effects on developmental toxicity

Description of key information
The registration substance was investigated for its developmetal toxicity according to OECD 414. No effect was found up to dose of 1000 mg/kg bw. The NOAEL of 1000 mg/kg bw was obtained. 
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-performed and well-documented study; recently performed Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
Mating was performed using a ratio of 1:2 (male to females).At the mornings, the vaginal smear of the female was checked. The day on which sperms were observed in the vaginal smear was considered as gestation day '0'. After getting 100 sperm positive females, the remaining females and males were discarded.
Duration of treatment / exposure:
Gestatation day 5-19
Frequency of treatment:
Once per day
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
There were no mortalities in any of the treated and control groups during the study.
There were no significant clinical signs indicative of significant systemic toxicity. There were moving the bedding and slight to severe salivation in 300 and 1000 mg/kg groups. These were assumed to be due to the local effect of test item treatment. There were also isolated incidences of alopecia, crust, half eye closure, abnormal breathing in treated groups. These were considered to be incidental.
There were no effects on body weight and body weight gain. There were no effects on terminal body weight and adjusted maternal body weight in test item treated groups compared to the corresponding control groups.
There was statistically significantly lower food consumption between GD 5-8 in the 1000 mg/kg group compared to control. Considering no effect on body weight and body weight gain, the minor effect on food consumption was not considered to be adverse.
There were no adverse effects on hematology and clinical biochemistry parameters. There were no statistically significant differences between the control and test item treated group females except for the statistically significantly lower mean ASAT value in 1000 mg/kg group compared to control. This finding was considered to have no toxicological relevance.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no effects of test item treatment on the parameters of prenatal data. There were no differences in mean gravid uterus weight, number of live foetuses, number of resorptions (early, late and total), number of foetuses (male, female and total foetuses), sex ratio and percent post implantation losses between the control and test item treated group. There were no dead foetuses in the control and test item treated groups.
There were no effects of test item treatment on litter data including mean foetus weight, total litter weight, male litter weight and female litter weight. There were no statistically significant differences between the control and the test item treated groups.
There were no external, craniofacial and skeletal abnormalities considered to be of toxicological relevance noted in any of the treated groups. The statistical analysis showed no significant changes.
The internal examinations of the foetal viscera by the free-hand-microdissection showed dose responsive increase in the incidence of “dilated ureter (bilateral)” in treated groups compared to control attaining statistical significance at HD group. However, this finding is normally seen greater in fetuses than in pups and is considered part of normal aspects of renal development supporting the idea that these changes are transient and considered as variations [1], [2]. Therefore, the finding was not considered to be an adverse effect.

The references used are,
1. Solecki R et al., (2003) Harmonization of rat fetal external and visceral terminology and classification. Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18–20 April 2002. Reprod Toxicol 17: 625-637
2. Teratology. 1972 Oct;6(2):191-6. "Apparent hydronephrosis" as a normal aspect of renal development in late gestation of rats: the effect of methyl salicylate. Woo DC, Hoar RM.

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Table: Findings of foetal viscera

 

Historical

[%]

Study 151945

[%]

Control

100 mg/kg bw

300 mg/kg bw

1000 mg/kg bw

Ureter B

0.25 ± 0.65, max 2.46

0.83

3.67

6.06

8.85

Ureter L

1.00 ± 1.18, max 4.44

8.33

4.59

9.09

8.85

Ureter R

0.46 ± 0.90, max 3.33

1.67

0.92

5.05

0.88

S

Dilated ureter either one sided or both sided

1.71

10.83

9.18

20.2

18.59

Conclusions:
The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 414. Pregnant rats were treated at dose up to 1000 mg/kg bw. No significant maternal and developmental toxicity was found. The NOAEL of 1000 mg/kg bw was obtained.
Executive summary:

The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 414. Pregnant rats were treated at dose up to 1000 mg/kg bw. No significant maternal and developmental toxicity was found. The NOAEL of 1000 mg/kg bw was obtained.

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:
One valid study for the developmental toxicity; the obtained result is consistant with results obtained in repeated dose toxicity study and in reproduction toxicity screening test.
Additional information

Justification for selection of Effect on developmental toxicity: via oral route:
Guideline study; well-performed and well-documented

Justification for classification or non-classification

With respect to toxicity to reproduction, one reproduction toxicity screening test and one developmental toxicity in rats are available. No effect was found up to highest applied dose of 750 mg/kg bw and 1000 mg/kg bw respectively. Further, no indication of reproduction organ toxicity is found in the 28 -day toxicity study (OECD 407).

No classification is warranted.

Additional information