Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a study performed according to OECD 421 guideline, the substance was administered daily by oral administration (gavage) to male and female rats from before mating, through mating and gestation until Day 6 post-partum at dose levels of 100, 300 and 1000 mg/kg bw/day. The NOAEL for the substance was 1000 mg/kg/day (the limit dose) for reproductive performance and offspring growth and survival.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 26 March 2010 to 4 August 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: approximately 62 to 69 days of age
- Weight at study initiation: Males: 310-365 g; Females: 206-257 g
- Fasting period before study: no
- Housing: See table 7.8.1/1
- Diet: standard rodent diet (SDS VRF1 Certified) ad libitum
- Water: potable water taken from the public supply ad libitum
- Acclimation period: 6 days before dosing started

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 23°C
- Humidity: 40 to 70%
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 28 April 2010 To: 23 June 2010
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% w/v aqueous methylcellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Rate of preparation (frequency): weekly
- Storage conditions : stored refrigerated (approximately at 2-8°C)

VEHICLE
- Justification for use and choice of vehicle (if other than water): the test substance is poorly soluble in water
- Amount of vehicle (if gavage): 10 mL/kg bw
- Lot/batch no. (if required): no data
- Purity: no data
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to two weeks
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- After unsuccessful pairing replacement of first male by another male with proven fertility: not needed in this study
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged (how): see table 7.8.1/1
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity and stability of the dosage forms: homogeneity of the test substance in 1% methylcellulose formulations was assessed with respect to the level of concentration at nominal concentrations of 10 mg/mL and 100 mg/mL. Homogeneity was confirmed during distribution between the bottles, during magnetic stirring for 2 hours, and on re-suspension following storage at ambient temperature for 1 day and refrigeration for up to 15 days. At each time-point, the mean analysed concentration for the three samples remained within 6% of the initial time zero value and the coefficient of variation was less than 5%.

Test item concentrations: the test item concentrations in the administered dosage forms analyzed in the first and last weeks of treatment remained within an acceptable range of +10% to -15% when compared to the nominal values.
Duration of treatment / exposure:
In the males:
- 2 weeks before mating,
- during the mating period (up to 2 weeks),
- until sacrifice in week 6,

In the females:
- 2 weeks before mating,
- during the mating period (up to 2 weeks),
- during pregnancy,
- during lactation until day 6 post-partum inclusive

Frequency of treatment:
Daily
Details on study schedule:
- No F1 parents (only one generation mated)
- Age at mating of the mated animals in the study: approximately 10-12 weeks
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 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:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose-levels used in this study (0, 100, 300 and 1000 mg/kg/day) were selected on the basis of the results of a 7-day repeated- dose preliminary study in the CD rat. In that study, dose levels of 100, 300 and 1000 mg/kg/day were used. There were no test material-related mortalities and no signs observed, bodyweight performance and food intake were unaffected by administration of the test material and there was no clear effect on organ weights and no macroscopic abnormalities detected. The high dose of 1000 mg/kg/day is considered in most circumstances to be the limit dose for an OECD 421 study and this was selected as no toxicity had been detected in the preliminary study. The low dose of 100 mg/kg/day was chosen anticipated No Observed Adverse Effect Level and the intermediate dose of 300 mg/kg/day was set at a logarithmic interval between the low and high doses.
Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to dosing.
A detailed physical examination was performed on the first day of dosing and weekly thereafter for F0 males until termination, and weekly for F0 females prior to pairing and on Days 0, 7, 14 and 20 after mating and Days 1 and 7 of lactation to monitor general health.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily in relation to dose administration during the first week of dosing, twice weekly during the second to fourth weeks of dosing and weekly from Week 5 until termination for males. After mating, these observations were conducted for females on Days 0, 7, 14 and 20 after mating and on Day 4 lactation.

BODY WEIGHT: Yes
- Time schedule for examinations: F0 males were weighed before dosing commenced (Day -1), on the first day of dosing (Week 0) and weekly throughout dosing until termination. F0 females were weighed before dosing commenced (Day -1), on the first day of dosing (Week 0) and weekly until mating was detected. The females were weighed subsequently on Days 0, 6, 13 and 20 after mating and on Days 1, 4 and 7 of lactation.

FOOD CONSUMPTION: Yes
The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded on a weekly basis from the start of dosing until the animals were paired for mating. From these records the mean daily consumption per animal (g/animal/day) was calculated for each phase, for each cage.
For each F0 female, the weight of food supplied, that remaining and an estimate of any spilled was recorded for the periods Days 0-5, 6-12 and 13-19 after mating and Days 1-3 and 4-6 of lactation. From these records the mean daily consumption (g/animal/day) was calculated for each animal.

WATER CONSUMPTION AND COMPOUND INTAKE: No

PARTURITION OBSERVATIONS AND GESTATION LENGTH
From Day 20 after mating, F0 females were checked three times daily for evidence of parturition. The progress and completion of parturition was monitored.
The duration of gestation was calculated as the time elapsing between the detection of mating and commencement of parturition.
Oestrous cyclicity (parental animals):
For 15 days before pairing (including the day of pairing), daily vaginal smears were taken from all females, using cotton swabs moistened with saline. The smears were subsequently examined to establish the duration and regularity of the oestrous cycle. After pairing with the male, smearing was continued using pipette lavage, until evidence of mating was observed.
Sperm parameters (parental animals):
Not examined
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- Number and sex of pups, stillbirths, live births
- Clinical signs: Daily records were maintained for evidence of ill health or reaction to parental dosing; these were on an individual offspring basis or for the litter as a whole, as appropriate.
- Litter size: Daily records were maintained of mortality and consequent changes in litter size from Days 1-7 of age.
- Sex ratio: The sex ratio of each litter was recorded on Days 1, 4 and 7 of age.
- Bodyweight: Individual offspring bodyweights were recorded on Days 1, 4 and 7 of age.

GROSS EXAMINATION OF DEAD PUPS:
Missing offspring and those grossly autolysed or grossly cannibalised could not be examined. All other offspring killed or dying before Day 7 of age were examined. The necropsy also included an assessment for the presence of milk in the stomach, where this was possible.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals were terminated after Day 7 of lactation of the females.
- Maternal animals: All surviving animals were killed on Day 7 of lactation, after confirmation that a second mating was not required.

GROSS NECROPSY
After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. After ventral mid-line incision, the neck and associated tissues and the thoracic, abdominal and pelvic cavities and their viscera were exposed and examined in situ. Any abnormal position, morphology or interaction was recorded. External and cut surfaces of the organs and tissues were examined as appropriate. Any abnormality in the appearance or size of any organ and tissue was recorded and the required tissue samples preserved in appropriate fixative.
For F0 females, the numbers of corpora lutea on each ovary and the numbers of implantation sites in each uterine horn were counted.

ORGAN WEIGHTS
Epididymides (Left and Right)
Ovaries (Left and Right)
Testes (Left and Right)

HISTOPATHOLOGY
For Groups 1 (Control) and 4 (1000 mg/kg/day) the epididymides, ovaries, and testes were examined for parental animals sacrificed on completion of the scheduled dosing period and for the parental animals killed during the study.
Tissues reported at macroscopic examination as being grossly abnormal were examined for all parental animals in line with current practice.
Special emphasis was placed on the stage of spermatogenesis and interstitial testicular cell structure.

Postmortem examinations (offspring):
GROSS NECROPSY
All external features and orifices were examined visually. The cranial roof was removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral mid-line incision, the neck and associated tissues and the thoracic, abdominal and pelvic cavities and their viscera were exposed and examined in situ. Any abnormal position, morphology or interaction was recorded. Any abnormality in the appearance or size of any organ and tissue was recorded and the required tissue samples preserved in appropriate fixative.
Statistics:
Statistical analyses were performed on the majority of data presented and results of these tests, whether significant or non-significant, are presented on the relevant tables. For some parameters, including pre-coital interval and mating performance and fertility, the similarity of the data was such that analyses were not considered to be necessary.
All statistical analyses were carried out separately for males and females. For adult parameters, the analyses were carried out using the individual animal as the basic experimental unit. For litter/fetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population
Reproductive indices:
Percentage mating = Number animals mating / animals paired x 100
Conception rate (%) = Number animals achieving pregnancy / animals mated x 100
Fertility index (%) = Number animals achieving pregnancy / animals pairing x 100
Gestation index (%) = Number of live litters born / Number pregnant x 100
Offspring viability indices:
Post-implantation survival index (%) = Total number offspring born / Total number uterine implantation sites x 100
Live birth index (%) = Number live offspring on Day 1 after littering / Total number offspring born x 100
Viability index (%) = Number live offspring on Day 7 after littering /Number live offspring on Day 1 after littering x 100
Percentage males = Number males in litter / Total number offsprings in litter x 100
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Bodyweight gain amongst males receiving 300 mg/kg/day and females receiving 100 and 300 mg/kg/day was slightly high during the pre-pairing phase when compared with Controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Bodyweight gain amongst males receiving 300 mg/kg/day and females receiving 100 and 300 mg/kg/day was slightly high during the pre-pairing phase when compared with Controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
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):
Epididymal weight was slightly low for males receiving 300 mg/kg/day; however, in the absence of a similar effect in the high dose group, no toxicological significance is attached to this finding.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
One female, assigned to the group receiving 100 mg/kg/day was killed for welfare reasons on Day 4 of dosing due to trauma to the eye which may have arisen from interaction with cage mates or the cage environment. The finding was considered incidental to administration of the test substance and the cause of the trauma is unclear.
There were no signs of adverse reaction to administration of the test substance during the pre-pairing,

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Administration of the test substance had no clear effect on bodyweight during the pre-pairing, gestation and lactation phases.
Bodyweight gain amongst males receiving 300 mg/kg/day and females receiving 100 and 300 mg/kg/day was slightly high during the pre-pairing phase when compared with Controls. However, in the absence of a clear dose response and a consistent effect between the sexes the significance of this is unclear.
There was no clear effect of administration of the test substance on mean food consumption during the pre-pairing period or for females during the gestation or lactation phases.

REPRODUCTIVE FUNCTION (PARENTAL ANIMALS)
Oestrous cycle activity, pre-coital interval, mating performance and fertility were considered to be unaffected by administration of the test substance. A number of animals across all three dose groups receiving the test material showed slightly extended cycles (classified as irregular cycles) or prolonged acyclic periods (presumed pseudopregnancy) from early in the dosing period but there was no indication that this was associated with dosing and the incidences were considered fortuitous.
There was no evidence of dystocia, and all females successfully gave birth to live young. There was no clear effect of administration of the test substance on gestation length, all being within the expected range of 22 to 23 days. The gestation index for all groups was 100%.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Reproductive organ weights were unaffected by administration of the test substance.
Epididymal weight was slightly low for males receiving 300 mg/kg/day; however, in the absence of a similar effect in the high dose group, no toxicological significance is attached to this finding.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Amongst adult animals surviving to scheduled termination there were no test material related findings.

HISTOPATHOLOGY (PARENTAL ANIMALS)
There were no histopathological findings considered to be related to administration of the test substance.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
At 1000 mg/kg/day, bodyweight gain to Day 7 was marginally lower than Controls for both males and females (92% and 88% of control respectively). Much of this difference could be attributed to the lower bodyweight gain of offspring in the larger litters.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
VIABILITY (OFFSPRING)
Parental dosing with the test substance had no effect on mean litter size or offspring survival to Day 7 of age at any dose level investigated.
There was no clear effect on sex ratio. The percentage of males in the group receiving 100 mg/kg/day was slightly high, however, sex ratio varied widely from 3M:12F to 12M:2F within the study and apparent intergroup differences in mean values are not uncommon in small studies. In the absence of a similar finding in the other dose groups no toxicological significance is attached to this finding.

CLINICAL SIGNS (OFFSPRING)
There were no test material-related clinical signs recorded amongst the offspring.

BODY WEIGHT (OFFSPRING)
Mean offspring birth weights were unaffected by parental dosing with the test substance. At 1000 mg/kg/day, bodyweight gain to Day 7 was marginally lower than Controls for both males and females (92% and 88% of control respectively). Much of this difference could be attributed to the lower bodyweight gain of offspring in the larger litters at the high dose level and was considered to be unrelated to dosage withthe test substance.

GROSS PATHOLOGY (OFFSPRING)
Of the few offspring that died during the early post-natal period, most showed an absence of milk in the stomach as the predominant necropsy finding. This finding is common among offspring that die at an early age, and there were no findings observed which indicated a specific reason why these pups failed to thrive.
The type and distribution of findings at necropsy of the offspring that survived to scheduled termination on Day 7 of age did not suggest any adverse effect of dosing of the parental animals with the test substance.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
It was concluded that the No-Observed-Adverse-Effect-Level (NOAEL) for the substance was 1000 mg/kg/day (the limit dose) for reproductive performance and offspring growth and survival in the CD rat following oral gavage administration in a standard screening test.
Executive summary:

A reproduction/developmental toxicity screening test was conducted with the test substance according to the OECD test guideline No. 421 and in compliance with Good Laboratory Practice.

Crl:CD®(SD) rats (10/sex/dose level) were dosed once daily by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day (dose volume of 10 mL/kg bw in 1% methylcellulose) for 15 days prior to pairing through to Day 6 after birth of the F1 generation.

During the study, data was recorded on clinical condition, bodyweight, food consumption, oestrous cycles, mating performance and fertility and gestation length. Organ weight, macroscopic and microscopic pathology investigations were undertaken on the adult animals. The clinical condition, litter size and survival, sex ratio and bodyweight of all offspring were assessed before macroscopic pathology investigations were undertaken at necropsy.

There were no test material-related mortalities and no signs considered to be related to administration of the test substance

There was no clear effect on bodyweight during the pre-pairing, gestation and lactation phases. Amongst males receiving 300 mg/kg bw/day and females receiving 100 and 300 mg/kg bw/day bodyweight gain was slightly high during the pre-pairing phase, and to termination for males, when compared with Controls. However, in the absence of a clear dose response and a consistent effect between the sexes the significance of this is unclear. Food consumption was unaffected during the pre-pairing period for both sexes and for females during the gestation and lactation phases. 

Oestrous cycle length, mating performance, fertility, parturition, reproductive capacity and gestation length were unaffected by administration of the test substance at all dose levels investigated. Bodyweight gain, survival and development of the offspring to Day 7 of age were also unaffected.

There was no test material related effect on the weights of the testes and epididymides or ovaries, and no test material related macroscopic or microscopic abnormalities were detected in the reproductive organs.

Based on the results of this reproduction/developmental toxicity screening study, it was concluded that for the test substance a dose level of 1000 mg/kg bw/day represented the No Observed Adverse Effect Level (NOAEL) for reproduction/developmental toxicity in the CD rat.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Quality of whole database:
Screening reprotoxicity study complete and sufficient to fulfill the REACh annex VIII requirements
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 reproduction/developmental toxicity screening test was conducted with the test substance according to the OECD test guideline No. 421 and in compliance with Good Laboratory Practice.

Crl:CD®(SD) rats (10/sex/dose level) were dosed once daily by gavage at dose levels of 0, 100, 300, or 1000 mg/kg bw/day (dose volume of 10 mL/kg bw in 1% methylcellulose) for 15 days prior to pairing through to Day 6 after birth of the F1 generation.

There were no test material-related mortalities and no signs considered to be related to administration of the test substance.

There was no clear effect on bodyweight during the pre-pairing, gestation and lactation phases. Amongst males receiving 300 mg/kg bw/day and females receiving 100 and 300 mg/kg bw/day bodyweight gain was slightly high during the pre-pairing phase, and to termination for males, when compared with Controls. However, in the absence of a clear dose response and a consistent effect between the sexes the significance of this is unclear. Food consumption was unaffected during the pre-pairing period for both sexes and for females during the gestation and lactation phases. 

Oestrous cycle length, mating performance, fertility, parturition, reproductive capacity and gestation length were unaffected by administration of the test substance at all dose levels investigated. Bodyweight gain, survival and development of the offspring to Day 7 of age were also unaffected.

There was no test material related effect on the weights of the testes and epididymides or ovaries, and no test material related macroscopic or microscopic abnormalities were detected in the reproductive organs.

 Based on the results of this reproduction/developmental toxicity screening study, it was concluded that for the test substance a dose level of 1000 mg/kg bw/day represented the No Observed Adverse Effect Level (NOAEL) for reproduction/developmental toxicity in the CD rat.


Effects on developmental toxicity

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study planned
Study period:
to be agreed by ECHA
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
99422018

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION

- available GLP studies: None

- available non-GLP studies: None

- historical human data: None

- (Q)SAR: According to ECHA guidance, QSAR approaches are currently not well fitted-for-purpose for reproductive toxicity and not all necessary aspects can be covered by a QSAR prediction. (ECHA guidance R.7a, October 2015, page 382).

- in vitro methods:
In vitro studies are not available on the test substance.
Some in vitro test methods have been developped, however, according to Chapter R 7a Version 4.1, the regulatory acceptance of these in vitro methods has not been achieved as they do not provide equivalent information (ECHA guidance R.7a, October 2015, page 381).

- weight of evidence: No data is available which allow a weight of evidence approach

- grouping and read-across: not found

- substance-tailored exposure driven testing : Not applicable
- approaches in addition to above: Not applicable
- other reasons: None


CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Test proposal is fully compliant with ECHA guidance R 7.a (july 2017, version 6). No specific adaptation possibilities of Annexes VI to X (and column 2 thereof) are applicable.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Developmental toxicity study in rat according to OECD guideline


Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Species:
rat
Route of administration:
oral: gavage
Abnormalities:
not specified
Developmental effects observed:
not specified
Endpoint:
developmental toxicity
Type of information:
experimental study planned
Study period:
After submission of the first developmental toxicity study results on rat to ECHA and in parallel with the Extended-One Generation Reproductive Toxicity Study
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
99422018

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION

- available GLP studies: None

- available non-GLP studies: None

- historical human data: None

- (Q)SAR: According to ECHA guidance, QSAR approaches are currently not well fitted-for-purpose for reproductive toxicity and not all necessary aspects can be covered by a QSAR prediction. (ECHA guidance R.7a, October 2015, page 382).

- in vitro methods:
In vitro studies are not available on the test substance.
Some in vitro test methods have been developped, however, according to Chapter R 7a Version 4.1, the regulatory acceptance of these in vitro methods has not been achieved as they do not provide equivalent information (ECHA guidance R.7a, October 2015, page 381).

- weight of evidence: No data is available which allow a weight of evidence approach

- grouping and read-across: not found

- substance-tailored exposure driven testing : Not applicable
- approaches in addition to above: Not applicable
- other reasons: None


CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Test proposal is fully compliant with ECHA guidance R 7.a (july 2017, version 6). No specific adaptation possibilities of Annexes VI to X (and column 2 thereof) are applicable.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Developmental toxicity study in rabbit according to OECD guideline


Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Route of administration:
oral: gavage

Justification for classification or non-classification

No effects on reproductive performance and offspring growth and survival were observed at the limit dose of 1000 mg/kg bw/day in a screening study for reproductive /developmental effects performed in rats.

On the basis of this results and according to regulation (EC) No. 1272/2008 and its subsequent amendments on classification, labeling and packaging (CLP) of substances and mixtures, no classification is warranted with respect to reproductive toxicity.