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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
read across substance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD 421 screening
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Reference substance 002
EC Number:
603-331-4

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF breeding, VELAZ s.r.o., Kolec u Kladna, Czech Republic, RCH CZ 21760152
- Age at study initiation: 10 weeks
- Weight at study initiation: males 307.89 - 309.22g, females: 224.33 - 226.55g
- Housing: exept from mating period, two rats of the same sex per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: males from: 19.01.2011 To: 22.02.2011 females: 19.01.2011 - 13.03.2011

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
suspension
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): daily just before administration
- Storage temperature of food: test item was administered by gavage

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
According to the information from Sponsor the main component of the test substance is insoluble in the used vehicle (water for injection).
Mixture of sample and deionised water results in yellow non-transparent suspension but undissolved particles of the test substance were easily visible in the application form and homogeneity could be checked by eye. Stability of the test substance in the application form cannot be verified analytically. The application form was prepared just before the application and there was no indication that test substance would have been unstable in the suspension in deionised water for that short time period.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 to 1
- Length of cohabitation: one week
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
males and females - 2 weeks prior to the mating period and during the mating period,
pregnant females - during pregnancy and till the 3rd day oflactation,
males - after mating period - totally for 28 days,
nonpregnant females (mated females without parturition) - for 25 days after the confirmed mating
Frequency of treatment:
daily, 7d/week
Doses / concentrationsopen allclose all
Dose / conc.:
160 mg/kg bw/day (actual dose received)
Dose / conc.:
400 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on data of 14d range finder

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly in premating and mating period,
during pregnancy: day 0, 7th , 14th, 20th day, during lactation: 0. or 1st and 4th day;
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- weight of ovaries and pituitary gland
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: No
- Head examinations: No data

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, presence of gross anomalies, physical or behavioural abnormalities

Dead pups were sexed and externally examined; the stomach was examined for the presence of milk. Pups killed on the 4th day of lactation were sexed and subjected to external examination of the cranium, and to macroscopic examination of the thoracic and abdominal tissues and organs.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Statistics:
The ANOVA test - Analysis of Variance (QC.Expert 2.5) at significance level 0.05 was used for the statistical analysis. This statistical analysis was used for the results of body weight, biometry of organs and number of pups. Control group with vehicle was compared with three treated groups. The results statistically significant on probability level 0.05 are indicated by figures with asterisk in the summary tables.
Indices:
Male mating index
number of males with confirmed mating x 100 / number ofmales cohabited

Female mating index
number of sperm-positive females x l00 / number of females cohabited

Male fertility index
number of males impregnating a females x 100 / number ofmales cohabited

Female fertility index
number ofpregnant females x 100 / number of sperm-positive females

Gestation index
number of females with live born pups x l00 / number of pregnant females

Survival index
number of live pups on day 4 post partum* x l00 / number of pups born alive+

Note: * WIthout shll born pups (dead pups WIth anaenallungs)
+ with dead pups with aerial lungs

Pre-implantation loss: Number of corpora lutea - number of implantations
Post-implantation loss: Number of implantations - number of live births
Post-natal loss: Number of live births - number of alive at postuatal day 4
Historical control data:
yes, 13 control groups from Reproduction / Developmental Toxicity Screening tests

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
yellow discolored feces at 400 and 1000 mg/kg bw/day dose levels.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Statistically significant differences were not detected.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Pregnant animals: The mean food consumption was slightly decreased at all dose levels for the whole time of pregnancy.
Lactating animals: Mean food consumption of treated females was slightly lower than in control females.
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
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Relative and absolute weights of ovaries, uterus and pituitary gland were similar in the control females and females of the dose levels 160 and 400 mg/kglday.
In females of the dose level 1000 mg/kglday absolute weights of evaluated organs were slightly lower whilst relative weights of ovaries and pituitary gland were quite balanced. In uterus of females at the dose level 1000 mg/kglday relative weight was decreased against the control.
No statistically significant differences were detected.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Macroscopic changes of genital organs were recorded in both control and treated females:
dilatation of uterine horns in 3-1-0-4 females, atrophy of one uterine horn and absence of one oviduct in 0-0-0-1 female.
In all females of the middle and the highest dose level and one female of the lowest dose level the content of intestine and stomach was test substance-colored.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Microscopic changes were found in uterus and vagina, however, in treated animals as well as in control animals. Other microscopical changes were recorded only sporadically.
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
One female in the control and lowest dose group each and two females in the 400 and 1000 mg/kg bw/day group each had an abortion.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
Pre-implantation losses were slightly increased at 1000 mg/kg bw/day. Slightly increased post-implantation losse at 160 mg/kg bw/day. No significant differences were detected in post-natal losses
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
The number of corpora lutea and implantations was insignificantly decreased at the dose level 1000 mg/kg/day compared to control.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no effects observed
Remarks on result:
other: no effects observed

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

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
Description (incidence and severity):
Balanced weights of the litters except for the mean weight of litter at the lowest dose level on the 4th day of lactation.
Changes in postnatal survival:
effects observed, non-treatment-related
Description (incidence and severity):
One male pup died during lactation period (400 mg/kg bw/day)
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
One stillborn pup at the highest dose level. No pathological findings.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion