Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no studies available on reproductive toxicity/fertility of the substance. In rodents histopathological examinations in repeated dose toxicity studies of reproductive tissues are of high value and high sensitivity for evaluation of reproductive toxicity in males and females, as confirmed by literature*. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. With this respect repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

For the substance there is no evidence for treatment-related findings on reproductive organs or tissues on the basis of gross and histopathological investigations of reproductive organs performed in a subacute toxicity (28-day) study according to OECD 407 and thus classification on reproductive toxicity/fertility is not warranted.

(*BAuA Forschungsbericht 984, 2003, Mangelsdorf. et al., Reg. Tox. and Pharm.37, 2003, 356-369; Ulbrich & Palmer, J. Am. Coll. Toxicol. 14, 1995, 293-327; Janer et al., Reproductive Tox. 24, 2007, 103-113; Dent, Reg. Tox. and Pharm. 48, 2007, 241-258; Sanbuissho et al., J Tox. Sci. 34, 2009, Special Issue SP1-SP22)

Effects on developmental toxicity

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)
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
Stability in vehicle analytically confirmed.
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Hsd Cpb:WU (SPF-bred)
- Source: Harlan-Netherlands B.V., Horst 5961 NM, Netherlands
- Age at study initiation: at least 12 weeks
- Weight at study initiation: 205 - 276 g (females)
- Housing: From gestation day 0 (= day 0 p.c.) animals were individually accommodated in Type IIIh Makrolon cages on low-dust wood shavings.
- Diet and water: ad libitum
- Acclimation period: at least seven days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.8 – 22.7
- Humidity (%): 54 - 67
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
paraffin oil
Details on exposure:
Administration volume: 2 mL/kg bw

PREPARATION OF DOSING SOLUTIONS: The formulations were prepared as needed taking into account the analytically determined stability.

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item in the vehicle gave a liquid formulation/ oily solution, for which stability for at least 8 days was given.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For content check the concentrations of samples of control and each test item dosage form prepared were determined twice during the study.
For analysis a portion of the dosage form was filled into a sodium chloride cell. A high resolution FTIR spectrum was scanned and evaluated. Quantification is based upon the concentration-dependent absorption bands due to the oscillation of ester function bond which occurs near 1750/cm.
Details on mating procedure:
The animals were mated by placing one female overnight into a Type IIIh cage together with one male rat. If sperm 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:
Day 6 - 20 p. c.
Frequency of treatment:
once daily (between 06:00 and 12:00 CET)
Duration of test:
From study initiation date to end of in-life-phase 55 days.
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In an orientating embryotoxicity study in rats with the test substance 5 female rats received the limit dose of 1000 mg/kg bw orally once daily from day 6 to day 20 of gestation. Corn oil was used in this study as vehicle. In this orientating study no indications for maternotoxicity or fetotoxicity occurred. A further orientating study was conducted in 3 male and 3 female rats each which were treated once daily orally over a period of 2 weeks with 1000 mg/kg bw by using paraffin oil as vehicle (pilot study for oral repeated dose toxicity study). Again the limit dose was tolerated without obvious findings of toxicity.
Maternal examinations:
CLINICAL EXAMINATIONS: Yes
- Time schedule: From day 0 to 21 p.c. all animals were inspected once daily, and all findings were recorded.
Attention was paid to disturbances in the general condition of the rats (appearance, behavior), and any alterations concerning their excretory products.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weights of the animals were determined on day 0 p.c. and daily from days 6 to 21 p.c.
Additionally, corrected body weight was calculated by subtracting the weight of the uterus on day 21 p.c. from the body weight on day 21 p.c. Furthermore, corrected body weight change was calculated by subtracting the body weight of day 6 p.c. from the corrected body weight.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day.

WATER CONSUMPTION: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Necropsies/cesarean sections were performed on gestation day 21.
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of dead and live fetuses: Yes
- Other: individual weight and appearance of the placentas
Fetal examinations:
- sex of live fetuses
- individual weights of live fetuses
- External examinations: Yes, findings in alive and dead fetuses are included
- Soft tissue and head examinations: Yes, evaluation of about half of alive fetuses per litter, fetuses of one dam could not be evaluated due to fixation problems
- Skeletal and cartilage abnormalities: Yes, evaluation in about half of alive fetuses per litter
Statistics:
Differences between the control and test item treated groups were considered to be significant when p < 0.05. Statistical evaluation was done by Dr. J. Fry, P.N. Lee Statistics and Computing Ltd., Sutton, Great Britain.
The following standard statistical tests were applied to the data in order to compare dose group values with the respective control group values: For the endpoints where Gaussian distribution was assumed, mean values and standard deviations were calculated and Dunnett-test was applied to the data in order to compare dose group values with the respective control group values. For the endpoints where binomial distribution was assumed, Bonferroni-Holm procedure with pairwise Fisher's Exact tests was used to compare dose group values with the respective control group values. For the endpoints for which no assumption about the distribution was made, group medians and quartiles were calculated and pairwise Wilcoxon Man Whitney tests were used to compare dose group values with the respective control group values.
Indices:
gestation rate
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No substance related finding was noted in maternal animals up to and including the high dose level of 1000 mg/kg bw.
The gestation rate, number of corpora lutea, postimplantation loss, litter size, number of fetuses, fetal sex distribution, placental weights and placental appearance were not affected by treatment up to and including 1000 mg/kg bw.
Dose descriptor:
NOAEL
Remarks:
Maternal toxicity
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: No substance-related findings noted in maternal animals up to and including 1000 mg/kg (highest dose tested)
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No compound-related fetal structural findings classified as malformations or variations were observed in this study at levels up to and including 1000 mg/kg bw.
Dose descriptor:
NOAEL
Remarks:
Developmental toxicity
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No substance-related structural findings noted in fetuses up to and including 1000 mg/kg (highest dose tested)
Abnormalities:
no effects observed
Developmental effects observed:
no
Executive summary:

A developmental toxicity/teratogenicity study according to OECD TG 414 was conducted with twenty-five inseminated female Wistar rats each treated daily orally by gavage with the test substance using paraffin oil as vehicle. Females were treated from day 6 to day 20 of gestation with dosages of 0 (vehicle control), 100, 300 and 1000 mg/kg bw. The fetuses were delivered by cesarean section on day 21 of gestation.

No substance related findings were noted in maternal animals up to and including the high dose level of 1000 mg/kg bw. The gestation rate, number of corpora lutea, postimplantation loss, litter size, number of fetuses, fetal sex distribution, placental weights and placental appearance were not affected by treatment up to and including 1000 mg/kg bw test substance. No compound-related fetal structural findings classified as malformations or variations were observed in this study at levels up to and including 1000 mg/kg bw.

The no-observed-adverse-effect levels (NOAELs) were determined both for maternal and developmental toxicity to be 1000 mg/kg bw.

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
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

REACH establishes that for substances manufactured or imported in quantities of 100 tonnes and more a screening for reproductive/developmental toxicity (OECD 421 or 422) and a developmental toxicity study (OECD 414) is the standard information requirement. In January 2009 the substance was allocated to the tonnage band >100 t/y and thus, a developmental toxicity study (OECD 414) was initiated. At that time the REACH requirements were interpreted such that for a substance in the >100 t/y band it would be an option to perform the definitive study (OECD 414) instead of the screening (OECD 421 or 422) together with a testing proposal for the definitive study (OECD 414). Because of the known limitations of the screening study (mainly as it will not lead to a final conclusion as needed under REACH in a vast majority of cases and therefore would lead to additional in vivo testing) and for reasons of animal welfare (to reduce the overall number of animals) as well as to cover potential regulatory needs outside Europe no such screening study was initiated, but the definitive developmental toxicity study (OECD 414). Only later, in September 2009 the ECHA fact sheet (ECHA-09-FS-05-EN) was published, which clarified that registration dossiers for substances >100 t/y were considered as technically complete if they would contain a testing proposal for a prenatal developmental toxicity study only. Therefore a developmental toxicity study was already available in 2010.

This developmental toxicity/ teratogenicity study according to OECD TG 414 was conducted with twenty-five inseminated female Wistar rats treated once daily with the test substance in paraffin oil administered by gavage. Females were treated from day 6 to day 20 of gestation with dosages of 0 (vehicle control), 100, 300 and 1000 mg/kg bw. The fetuses were delivered by cesarean section on day 21 of gestation.

No substance related findings were noted in maternal animals up to and including the highest dose of 1000 mg/kg bw. The gestation rate, number of corpora lutea, postimplantation loss, litter size, number of fetuses, fetal sex distribution, placental weights and placental appearance were not affected by the treatment. No compound-related fetal structural findings classified as malformations or variations were observed in this study up to and including 1000 mg/kg bw.

The no-observed-adverse-effect levels (NOAELs) were determined both for maternal and developmental toxicity to be 1000 mg/kg bw.

Justification for classification or non-classification

No classification required for toxicity to reproduction according to Regulation (EC) No 1272/2008, Annex I.