Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No effects on fertility became obvious in a one-generation reproduction toxicity study on rats following parameters of OECD 416.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Version / remarks:
1983
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Version / remarks:
2001
Deviations:
yes
Remarks:
no selection of F1 weanlings for further treatment
Principles of method if other than guideline:
This one-generation reproduction toxicity study was not only performed according to OECD 415 (1983), but also parameters of OECD 416 of 2001 were included taking into account the updated guideline requirements.
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Crl:(Wi)WU BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) 5-6 wks
- Weight at study initiation: (P) Males: 87 - 144 g; Females: 88 - 124 g
- Fasting period before study: none
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +- 2
- Humidity (%): 55 +- 5
- Air changes (per hr): 10 at minimum
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: March 2002 To: August 2002
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
The test item was blended (using a mixing granulator) with diet used (Provimi Kliba 3883.9.25). To minimize dust formation 1 % peanut oil (DAB 10) was added. The amounts of the test item were calculated on the basis of an content of 91 % instead of 92 %, which is based on an effor. The diet mixtures were prepared once a week.
Details on mating procedure:
F0 animals were pretreated with the test item for about 10 weeks up to the cohabitation period. Within the weeks 8-10 of this premating period investigations on estrus cycle were performed. The females were cohoused with males at a maximum of 12 times during the 3-week mating period. Insemiated females were not further co-housed. Insemination was established by investigating vaginal smears prepared in the morning.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability and homogeneity of the test item in the diet was analytically proven prior to the study for 50 ppm, 100, and 10000 ppm. Accuracy check was done for all doses.
Duration of treatment / exposure:
10 weeks before mating, and during mating (up to 3 weeks) for males, plus during pregnancy and up to weaning of pups to an age of 4 weeks for females - all together about 20 weeks for females and 13 weeks for males.
Frequency of treatment:
continuously via diet
Details on study schedule:
After a gestation period of about 22 days litters were born and the dams were allowed to rear them. If necessary, gour days after birth the F1 litters were reduced (culled) to eight pups according to random lists. If possible, four male and four female pups remained per litter. At an age of 4 weeks the pups were necropsied. F0 females were also killed at that time. F0 males were killed after the mating period partly in the course of spermatological investigations.
Dose / conc.:
100 mg/kg diet
Remarks:
according to an actual dose of 7 mg/kg bw/day for males and 11 mg/kg bw/day for females
Dose / conc.:
900 mg/kg diet
Remarks:
according to an actual dose of 66 mg/kg bw/day for males and 89 mg/kg bw/day for females
Dose / conc.:
8 100 mg/kg diet
Remarks:
according to an actual dose of 880 mg/kg bw/day for males and 1069 mg/kg bw/day for females
No. of animals per sex per dose:
25
Control animals:
yes, plain diet
Details on study design:
dose selection was based on results of a subacute toxicity study in Wistar rats with 100 -1000 ppm in the diet.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined: Yes, weekly; the daily food intake per animal is calculated
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Oestrous cyclicity (parental animals):
Within the weeks 8-10 of the 10 week premating period investigations on estrus cycle were performed by taking vaginal smears.
Sperm parameters (parental animals):
Parameters examined in [P] male parental generations:
weight: testes, seminal vesicles with coagulation glands, prostate, epididymides
spermatologcial investigations: in all living F0 males of the control and high dose group:
spermatozoa motility and viability, spermatozoa morphology, quantitative determination of spermatozoa in epididymis, quantitative determination of homogenization resistant spermatid heads in the testis,
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.

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;
Postmortem examinations (parental animals):
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

ORGAN WEIGHT: Yes
brain, pituitary gland, liver, kidneys, adrenals, spleen, thyroid, uterus, seminal vesicles with coagulation glands, prostate, epididymides, testes and ovaries
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
ORGAN WEIGHTS:
brain, spleen thymus, uterus weights were determined in the first male and female living F1 weanling of each litter
Statistics:
yes, several tests
Reproductive indices:
insemination index, fertility index, gestation index, rearing index,
Offspring viability indices:
live birth index, viability index, lactation index
Description (incidence and severity):
at 900 and 8100 ppm an increasing number of rats exhibited food spillage; at 8100 ppm feces excretion was increased and reduced reactivity and/or piloerection was recorded for some rats
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
severe body weight depression at 8100 ppm in both sexes
Description (incidence and severity):
at 8100 ppm females consumed slightly more diet per animal than controls probably due to food spillage
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
incidences for insemination, fertility, gestation, viability and rearing as well as the means for the duration of pregnancy and percentage of males born were not affected;
The mating performance was unchanged up to 900 ppm. At 8100 ppm rats need a slightly prolonged time up to their matings.
Number of implantation sites (per litter 13.20 in control versus 9.91 in high dose or total 264 versus 218 in high dose) and pups born (231 versus 181) were significantly reduced at 8100 ppm.
Dose descriptor:
NOEL
Effect level:
100 mg/kg diet
Based on:
test mat.
Remarks:
according to 7 mg/kg bw/day in males and 11 mg/kg bw/day in females
Sex:
female
Basis for effect level:
other: no effects at this dose
Dose descriptor:
NOAEL
Effect level:
900 mg/kg diet
Based on:
test mat.
Remarks:
according to 66 mg/kg bw/day in males and 89 mg/kg bw/day in females
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
gross pathology
Dose descriptor:
NOAEL
Effect level:
900 mg/kg diet
Based on:
test mat.
Remarks:
according to 89 mg/kg bw/day
Sex:
female
Basis for effect level:
other: slightly prolonged time up to mating and number of implantation sites and pups born significantly reduced at 8100 ppm
Dose descriptor:
NOAEL
Effect level:
8 100 mg/kg diet
Based on:
test mat.
Remarks:
according to 880 mg/kg bw/day in males and 1069 mg/kg bw/day in females
Sex:
male/female
Basis for effect level:
other: no effects on reproductive performance
Lowest effective dose / conc.:
8 100 mg/kg diet
System:
gastrointestinal tract
Description (incidence and severity):
from 900 ppm onwards an increasing number of pups without a milk spot (pups affected: 0/0/4/15) and more smaller (pups affected: 0/2/6/1) and or thin (pups affected: 0/5/3/24) were found
Mortality / viability:
no mortality observed
Description (incidence and severity):
Birth weight and pup weight development, number of implantation sites and pups born, litter size at birth, clinical appearance and lactation index were not influenced negatively by the treatment up to 900 ppm and were significantly reduced at 8100 ppm.
Description (incidence and severity):
organ weight measurements in pups revealed no remarkable changes up to 900 ppm; at 8100 ppm absolute and/or relative organ weight changes due to the body weight depressen were evident for each organ.
Description (incidence and severity):
no test substance-related gross pathological findings were observed in F1 offsprings up to 900 ppm; as a correlate to depressed body weight development an increase in number of thin pups were observed at necropsy in the 8100 ppm group
no malformation became obvious
Description (incidence and severity):
at no point effects on the skeletal development of the pups or weanlings were observed up to 8100 ppm
Description (incidence and severity):
Birth weight, pup weight development, number of implantation sites and pups born, litter size at birth, clinical appearance and lactation index were not influenced negatively by the treatment up to 900 ppm and were significantly reduced at 8100 ppm.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
900 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: pup birth weight, pup weight development, number of implantation sites and pups born, litter size at birth, clinical appearance and lactation index were significantly affected at 8100 ppm
Critical effects observed:
not specified
Lowest effective dose / conc.:
8 100 mg/kg diet
System:
other: general toxicity
Reproductive effects observed:
no
Executive summary:

A one-generation study was performed with the test item to evaluate possible effects to the entire reproduction process in Wistar rats. The study followed OECD 416 with the exception that there was no selection of F1 weanlings for further treatment.

The test item was administered to groups of 25 male and 25 female rats each at concentrations of 0 (control), 100, 900, and 8100 ppm in their diet (actual doses: 7, 66, 880 mg/kg/day (males) or 11, 89, 1069 mg/kg/day (females)).

Parental FO animals were pretreated over about 10 weeks and allowed to mate over a period of up to three weeks. F1 pups were nursed up to an age of four weeks.

Clinical signs, body weights, food intake, mating performance, fertility, duration of pregnancy, estrus cycling and sperm parameters were examined in FO rats. Litter size, percentage of males bom and pup weight at birth as weil as viability, rearing, lactation, clinical signs and body weight gain were studied in F1 offspring. Necropsies were done in all rats and implantation sites were recorded in FO females. Selected organs were weighed in FO and F1 rats.

There were no changes in mortality of FO rats up to 8100 ppm. At 900 and 8100 ppm an increasing number of rats exhibited food spillage. At 8100 ppm more FO rats exhibited a reduced or increased feces excretion as weil as some females showed macroscopically a thickened wall of the duodenum and/or a dilated cecum indicating changes in intestinal digestion and/or peristaltic by the treatment. Furthermore, some 8100 ppm rats exhibited a reduced reactivity and/or piloerection. These effects are clearly attributed to the treatment.

There was a severe body weight depression at 8100 ppm in both sexes. Accordingly, there were some 8100 ppm females showing emaciation at their necropsy.

There were no other gross findings in FO rats in relation to the treatment. At 8100 ppm females a sligthtly higher food intake per animal was measured than in controls and the body weight related food intake was distinctly increased in both sexes.

At 8100 ppm there were increased relative testis weights as weil as reduced weights of ovaries and uteri (each absolute and relative and ps0.05) in FO rats. The liver weights of FO rats were not toxicologically changed up to 900 ppm. At 8100 ppm significantly reduced absolute liver weights occurred in both sexes. The sperm parameter data of 8100 ppm FO males were comparable with those of the control group.

No changes in estrus cycling due to the treatment could be detected up to 8100 ppm. The indices for insemination, fertility, gestation, viability and rearing as well as the means for the duration of pregnancy and percentage of males born were not affected at levels of up to 8100 ppm. At 8100 ppm rats needed a slightly prolonged time until their successful matings.

The pup birth weight, pup weight development, number of implantation sites and pups born, litter size at birth, clinical appearance and lactation index were not influenced negatively by the treatment up to 900 ppm and significantly affected at 8100 ppm. At this dose more pups lacking a milk spot, smaller and/or thin pups were observed during lactation and at necropsy and changes in absolute and/or relative organ weight due to the body weight depression were evident for each organ.

The skeletal development of the pups or weanlings was unaffected at dose levels of up to 8100 ppm at any time point.

Thus, the dietary concentration of 100 ppm is established as the no observed (adverse) effect level (NOEL = NOAEL) for the parent animals. The NOEL for the

reproduction parameters was 900 ppm. The fertility was unchanged up to 8100 ppm.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
880 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Additional information

A one-generation study was performed with the test item to evaluate possible effects to the entire reproduction process in Wistar rats. The study followed OECD 416 with the exception that there was no selection of F1 weanlings for further treatment. The test item was administered to groups of 25 male and 25 female rats each at concentrations of 0 (control), 100, 900, and 8100 ppm in their diet (actual doses: 7, 66, 880 mg/kg/day (males) or 11, 89, 1069 mg/kg/day (females)). Parental FO animals were pretreated over about 10 weeks and allowed to mate over a period of up to three weeks. F1 pups were nursed up to an age of four weeks.

There were no changes in mortality of FO rats up to 8100 ppm. At 8100 ppm more FO rats exhibited a reduced or increased feces excretion as well as some females showed macroscopically a thickened wall of the duodenum and/or a dilated cecum indicating changes in intestinal digestion and/or peristaltic by the treatment. Furthermore, some 8100 ppm rats exhibited a reduced reactivity and/or piloerection. These effects are clearly attributed to the treatment.

There was a severe body weight depression at 8100 ppm in both sexes.

At 8100 ppm there were increased relative testis weights as well as reduced weights of ovaries and uteri (each absolute and relative and ps0.05) in FO rats. At 8100 ppm significantly reduced absolute liver weights occurred in both sexes.

No changes in estrus cycling due to the treatment could be detected up to 8100 ppm. The indices for insemination, fertility, gestation, viability and rearing as well as the means for the duration of pregnancy and percentage of males born were not affected at levels of up to 8100 ppm. At 8100 ppm rats needed a slightly prolonged time until their successful matings.

The pup birth weight, pup weight development, number of implantation sites and pups born, litter size at birth, clinical appearance and lactation index were significantly affected at 8100 ppm. At this dose more pups lacking a milk spot, smaller and/or thin pups were observed during lactation and at necropsy and changes in absolute and/or relative organ weight due to the body weight depression were evident for each organ.

The skeletal development of the pups or weanlings was unaffected at dose levels of up to 8100 ppm at any time point.

Thus, the dietary concentration of 100 ppm is established as NOEL for general toxicity of the parent animals. The NOEL for the reproduction parameters was 900 ppm. The fertility was unchanged up to 8100 ppm.

Effects on developmental toxicity

Description of key information

no developmental toxicity observed in a rat OECD 414 study

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
1998
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: analytically confirmed
- Homogeneity and stability of the test substance in the solvent/vehicle: analytically confirmed
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: none
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Hsd Cpb:WU (SPF-bred)
- Source: Harlan-Winkelmann GmbH, 33178 Borchen, Germany
- Acclimation period: at least 7 days prior to mating
- Body weight of animals at the time of mating: 386-438 g for males, 216-254 g for females
- Age at the day of mating: 15-17 weeks
- Housing: individually in Makrolon cages (MIII type)
- Diet and water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): approximately 50
- Air changes (per hr): > 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 2002-01-21 to experimental completion date (fetal visceral evaluation) on 2003-10-21
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
400
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Fresh adminstration fromulations for each concentration were prepared daily.

VEHICLE
- vehicle: Polyethylene glycol 400
- Justification for use and choice of vehicle (if other than water): Based on trial formulations.
- Amount of vehicle (if gavage): 5 mL/kg bw

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity and stability for at least 4 hours at room temperature was confirmed over the concentration range 0.2 to 270 mg/mL.
Accuracy of formulations was proven at two days during inlife phase.
Details on mating procedure:
Animals were mated by placing two females overnight together with one male rat. If sperm count was detected in the vaginal smear taken on the morning following mating, this day was regarded as day 0 of gestation.
Duration of treatment / exposure:
Days 6 - 19 post-coitum, inclusive; fetuses were delivered by cesarean section on day 20 p.c.
Frequency of treatment:
Once daily
Duration of test:
from day 0 to necropsy at day 20 p.c.
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
160 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
27 pregnant females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In order to set the dose levels for the main teratology study, a dose range finding study was performed. Four groups of 8 pregnant females were exposed to 0, 10, 40 and 160 mg/kg bw/day for Days 6 to 19 post-coitum inclusive by oral gavage.

Based on the results of the dose range finding study, selected dose levels for the main study were 10, 40 and 160 mg/kg bw/day.
Maternal examinations:
CLINICAL EXAMINATIONS: Yes
- Time schedule: in general twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 pc and daily from day 6 to 20 pc

FOOD CONSUMPTION: Yes
- Days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-20 post-coitum.

WATER CONSUMPTION: Yes
- Once daily. Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.

POST-MORTEM EXAMINATIONS: Yes
- All animals surviving to the end of the observation period and the animal showing premature delivery were sacrificed using cardiotomy under deep carbon dioxide anestesia.
Ovaries and uterine content:
Each ovary and uterine horn of animals surviving to planned necropsy was dissected and examined as quickly as possible to determine:
- The number of corpora lutea.
- The weight of the (gravid) uterus.
- The number and distribution of live and dead fetuses.
- The number and distribution of embryo-fetal deaths (early and late resorptions).
- The weight of each fetus.
- The sex of each fetus from the ano-genital distance (during necropsy) and also from gonadal
inspections (during further fetal examination).
- Externally visible macroscopic fetal abnormalities.
Fetal examinations:
External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).
Statistics:
yes
Historical control data:
yes, historical data on fetal morphology are part of the report
Clinical signs:
no effects observed
Description (incidence and severity):
treatment resulted in increased incidences of salivation after administration at al dose levels, possibly a result of a bad taste or olfactory component of the test substance. For the reddish discolored salivation that was observed at 40 mg/kg bw and above a treatment related effect could not be excluded.
Mortality:
no mortality observed
Description (incidence):
two females in the control group and one female in the 160 mg group died/were sacrificed due to misapplication.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 160 mg/kg bw body weight gain from days 6-19 pc was distinctly reduced compared to control animals (54.8 g versus 76.4 g).
Also the corrected body weight gain from days 0-20 was lower in 160 mg/kg bw animals than in control animals (19.2 g versus 46.7 g).
Description (incidence and severity):
Food intake was reduced from start of treatment to the end of gestation at the 160 mg/kg bw dose level.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
necropsy revealed no treatment related findings.
Neuropathological findings:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
At 60 mg/kg bw/day, a significant increase in pre-implantation loss was observed (12.2 % compared to 6.0 % in the control group). Treatment was started on Day 6 post-coitum, after implantation has occurred, therefore this finding is considered not to be related to treatment. Moreover, no dose response relationship was noted.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: reddish discolored salivation after administration at >= 40 mg/kg bw and distinctly reduced body weight and food consumption at 160 mg/kg bw
Abnormalities:
effects observed, treatment-related
Localisation:
other: general maternal toxicity
Description (incidence and severity):
very slight severity at 40 and 160 mg/kg bw
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Dose descriptor:
NOAEL
Effect level:
160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects at this dose
Abnormalities:
no effects observed
Developmental effects observed:
no
Executive summary:

In a prenatal developmental toxicity study performed according to OECD TG 414 mated female Wistar rats were assigned to four dose groups, each containing twenty-seven animals. The test item was administered once daily by gavage from Day 6 to 19 post-coitum at doses of 10, 40 and 160 mg/kg bw/day. The animals were sacrificed on day 20 pc. The rats of the control group received the vehicle, Polyethylene glycol 400, alone.

With regard to maternal toxicity salivation occured in all treated animals. At 40 mg/kg bw and above reddish discolored salivation was observed that was considered as treatment related and adverse. At 160 mg/kg bw body weight development was distinctly impaired and food intake was reduced.

No further maternal toxicity or any developmental findings became obvious.

In conclusion and based on the results in this prenatal developmental toxicity study the maternal No Observed Adverse Effect Level (NOAEL) was established as being 10 mg/kg bw/day and the NOAEL for developmental toxicity was determined with 160 mg/kg bw.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
160 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP Guideline study
Additional information

In a prenatal developmental toxicity study performed according to OECD TG 414 mated female Wistar rats were assigned to four dose groups, each containing twenty-seven animals. The test item was administered once daily by gavage from Day 6 to 19 post-coitum at doses of 10, 40 and 160 mg/kg bw/day. The animals were sacrificed on day 20 pc. The rats of the control group received the vehicle, Polyethylene glycol 400, alone.

With regard to maternal toxicity salivation occurred in all treated animals. At 40 mg/kg bw and above reddish discoloured salivation was observed that was considered as treatment related. At 160 mg/kg bw body weight development was distinctly impaired and food intake was reduced.

No further maternal toxicity or any developmental findings became obvious.

In conclusion and based on the results in this prenatal developmental toxicity study the NOAEL for developmental toxicity was determined with 160 mg/kg bw/day.

Justification for classification or non-classification

Based on a one-generation reproduction toxicity study on rats following parameters of OECD 416 and a developmental toxicity study on rats following OECD 414 no classification if warranted for fertility or developmental toxicity.