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Diss Factsheets
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EC number: - | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Remarks:
- based on generations indicated in Effect levels (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Read-across from GLP-compliant guideline study performed with similar substance.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- of 1996
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Sprague Dawley rats, strain: Crl:CD(SD) with appropriate range of bodyweight at study start.
- Source: Charles River (UK) Ltd.
- Age at treatment start: 10 to 11 weeks.
- Weight at treatment start: Males: minimum 321 g, maximum 381 g,
Females: minimum 209 g, maximum 264 g.
- Housing Inside a barriered rodent facility:
all animals pre-mating + toxicity subgroup: In groups up to 5 by sex in solid floor polycarbonate cages.
during mating (1 male+1 female/cage): In RB3 modified propylene cages with stainless steel grid-floor over absorbent paper-lined trays.
males after mating: In groups up to 5 by sex in solid floor polycarbonate cages.
females during gestation and lactation: Females housed individually in solid floor polycarbonate cages.
- Bedding material (in solid floor cages): Wood based bedding, sterilised by autoclaving before use.
- Cage enrichment: Aspen chew block + plastic shelter (except during mating or post gestation day 20).
- Diet (ad libitum): Standard rodent diet (SDS VRF1 Certified) without antibiotic, chemotherapeutic or prophylactic agent.
- Fasting (diet withheld): Toxicity subgroup animals overnight before blood sampling for hematology/clinical blood chemistry.
- Water (ad libitum): Pottable drinking water from the public supply.
- Acclimation period: 13 days before treatment start, under laboratory conditions.
Routine analysis of the batch of diet used and water, chew blocks and wood bedding did not provide evidence of contamination that might have prejudiced the study.
IN-LIFE DATES:
- Duration of test, males & toxicity subgroup females: Five weeks
Duration of test, reproductive subgroup females: From 14 days prior to mating to day 7 of lactation.
Duration of test, offspring: From birth to day 7 of lactation.
ENVIRONMENTAL CONDITIONS
Air conditioned room kept at positve pressure without re-circulation of the filtered fresh air supplied to the room.
Controlled environment, environmental conditions were set at:
- Temperature (°C): 21 ± 2°C
- Relative Humidity (%): 40 to 70%
- Photoperiod (artificial lighting): 12 hrs day / 12 hrs night
Deviations from these target ranges were not evident.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Treatment of parental animals by oral gavage administration. Test substance was not directly administered to F1 animals.
- Concentration in vehicle: The concentration of the test material in vehicle varied between dose groups thus allowing constant dosage volume in terms of mL/kg bw/day.
- Amount (dose volume by gavage): 2 mL/kg bw/day.
Actual dose volumes were calculated at about weekly or shorter intervals accounting for the latest body weight. Litter animals were not dosed.
CONCENTRATION OF TEST MATERIAL IN VEHICLE
Group Concentration of Test Substance Treatment Volume Dose Level of Test Substance
(mg/mL) (mL/kg bw/day) (mg/kg bw/day)
Vehicle Control 0 2 0
Low Dose 50 2 100
Mid Dose 150 2 300
High Dose 500 2 1000 - Details on mating procedure:
- - Male/female ratio per cage: 1/1
- Length of cohabitation: At the most 14 days, until proof of pregnancy was confirmed.
- Proof of pregnancy: Formation of copulation plug or sperm in vaginal smear referred to as day 0 of gestation.
(During cohabitation, females were checked every morning for pregnancy). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Chemical analysis of test material formulations by high performance liquid chromatography (HPLC/UV) using an external standard technique.
- Concentrations (verified at first and last treatment week) of the test material formulations were confirmed at each dose level.
- Chemical analysis confirmed that the prepared formulations were 102% to 108% of the corresponding nominal concentration. - Duration of treatment / exposure:
- - Treatment period, males & toxicity subgroup females: Daily, for five consecutive weeks
- Treatment period, reproductive subgroup females: Ca. 6 to 8 weeks (from 14 days before mating to day 7 of lactation) - Frequency of treatment:
- Daily, 7 days/week (during parturition, dosing omitted as appropriate)
- Details on study schedule:
- - Age at mating of the mated animals in the study: 12 to 14 weeks
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0 (vehicle control), 100, 300, 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- Toxicity subgroups: 5 males* / 5 females
Reproductive subgroups: 5 males* / 10 females
* All males were killed at the same time (Week 6) after pairing with reproductive subgroup females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study
(OECD 422 test guideline). Therefore, animals initially entering the study were divided into toxicity subgroup animals and reproductive subgroup animals, whereby 5 of the 10 F0 males (used for pairing) per dose group formed the toxicity male subgroups.
Dose selection was based on the results of a 7-day preliminary oral toxicity study in the rat in which dose levels of 100, 300 or 1000 mg/kg/day did not have any overt treatment-related effects on young adult animals (females nulliparous and non-pregnant). The high dose level of 1000 mg/kg/day was considered to be the maximum practical dose level for the present OECD 422 study and was therefore chosen as the high dose level. - Positive control:
- Not included in the study.
Examinations
- Parental animals: Observations and examinations:
- Clinical observations performed and frequency:
- Clinical signs : At least twice a day (before and after administration)
- Detailed physical examination
and arena observations: Before treatment start and at least once a treatment week.
- Functional Observation Battery: During treatment week 5 (before dosing) on all toxicity subgroup animals (5 parental males/group inclusively)*.
- Body weight, all males: Weekly throughout the study.
Body weight, Toxicity Females: Weekly throughout the study.
Body weight, Repro. Subgr. Females: Weekly for pre-mating and mating period; on gestation days 0, 7, 14, 20; on lactation days 1, 4 & 7.
- Food consumption, all animals: Weekly for pre-mating period.
Food cons., Repro. Subgr. Females: During gestation for days 0-7, 7-14, 14-20, during lactation for days 1-4 & 4-7.
- Water consumption: Daily (based on visual observation inidicative of overt water intake).
- Hematology: During treatment week 5 after functional observation battery*
- Blood (plasma) chemistry: During treatment week 5 after functional observation battery*
* Examinations confined to toxicity subgroup animals are marked above with an asterisk*
and are detailed in the separate endpoint study record "7.5.1 Repeated dose toxicity: oral - Repeat dose tox combined, oral, rat read-across"
Explanatory note
This study was conducted to examine both repeated dose toxicity and reproductive/developmental toxicity as an OECD screening combined study
(OECD 422 test guideline). Therefore, animals initially entering the study were divided into toxicity subgroup animals and reproductive subgroup animals whereby 5 of the 10 F0 males (used for mating) per dose group formed the toxicity male subgroups. - Oestrous cyclicity (parental animals):
- Frequency of vaginal estrus was determined by examination of vaginal smears taken daily and checking for copulation plugs daily from all reproductive subgroup females from the beginning of the treatment period to the day of confirmed copulation.
- Regular: All observed cycles of 4 or 5 days
- Irregular: At least one cycle of 2, 3 or 6 to 10 days
- Acyclic: At least 10 days without oestrus - Sperm parameters (parental animals):
- Parameters examined in male parental animals:
- testis weight,
- epididymis weight
- detailed qualitative histopathology examination of the testes taking into account the tubular stages of the spermatogenic cycle. This was to identify treatment related effects such as missing germ cell layers or types, retained spermatids, multinucleate or apoptotic germ cells and sloughing of spermatogenic cells in the lumen. Any cell- or stage-specificity of testicular findings was noted. - Litter observations:
- STANDARDISATION OF LITTERS: Not performed. The study ended on lactation day 7.
LITTER PARAMETERS EXAMINED
- From Day 20 post copulation 3 times a day checks for evidence of parturition, any difficulties and numbers of live and dead offspring.
- Total litter size on day 1 of age and mortality/live litter size on each day until 7 days after littering.
- Sex ratio expressed as percentage males (Total No. of male pups in litter/Total No. of offspring in litter) x 100
- Gestation index (No. of live litters born on day 0/No. of living pregnant females) x 100
- Clinical signs, recorded daily
- Body weight of live pups (on days 1, 4 and 7 after littering) and weight change from days 1-4 and 1-7. - Postmortem examinations (parental animals):
- GROSS PATHOLOGY: Yes, see below
WEIGHING OF ORGANS: Yes, see below
HISTOPATHOLOGY: Yes, see below
Terminal sacrifice
- all males: Killed in Week 6, after completion of the Treatment Week 5 investigations.
- reproductive subgr. females: Killed on Day 7 post partum. 1 female without viable litter was killed on Day 25 after mating.
Gross pathology
- all rats: Full macroscopic examination with tissue collection.
- reproduction subgroup females: Recording of the number of uterine implatation sites.
Organs Weights:
- toxicity subgroup animals: Adrenals, brain, epididymides*, heart, kidneys, liver, ovaries*, pituitary, prostate*, seminal vesicles
& coagulation gland*, spleen, testes*, thymus, thyroid with parathyroids, uterus with cervix and oviducts*.
- reproductive subgroup animals: * These organs were also weighed for adult/parental reproductive subgroup animals.
Histopathology:
- reproductive subgroup animals: The following organs were microscopically examined for the control and 1000 mg/kg bw/day groups:
Epididymides, testes, ovaries, uterus (with cervix & oviducts), vagina, mammary area (caudal), seminal vesicle &
coagulation gland, prostate.
- toxicity subgroup animals: For the control and 1000 mg/kg bw/day groups (5 adult/parental males per group inclusive):
Brain, pituitary gland, thyroid with parathyroids, heart, thymus, liver, spleen, adrenals, kidneys, testes,
epididymides, ovaries, lung, trachea, esophagus, stomach, duodenum, jejunum, ileum, caecum, rectum,
colon, Peyer's patch, lymph node (left axillary, mesenteric), urinary bladder, uterus (with cervix & oviducts),
vagina, spinal cord, sciatic nerve, mammary area (caudal), sternum with marrow, seminal vesicle &
coagulation gland, prostate.
In addition, the kidneys were also examined for the 100 and 300 mg/kg bw/day toxicity subgroups.
- Postmortem examinations (offspring):
- Pup survivors were killed on Day 7 post partum.
Full macroscopic examination of decedent and surviving pups including assessment of the presence of milk in the stomach, where possible.
(Missing or grossly autolysed or cannibalised pups could not be examined). - Statistics:
- As detailed in Endpoint study record "7.5.1 Repeated dose toxicity: oral - Repeat dose tox combined, oral, rat read-across"
- Reproductive indices:
- - No. of animals mating (evidence of successful copulation, i.e. spermatozoa in vaginal smears and/or copulation plugs)
- Percentage mating (No. of animals mating/No. of animals paired) x 100
- Pre-coital interval (pairing days until detection of mating)
- No. of animals achieving pregnancy
- Conception rate (No. of animals achieving pregnancy/No. of animals mated) x 100
- Fertility index (No. of animals achieving pregnancy/ No. or animals pairing) x 100
- Gestation length (time elapsing between detection of mating and commencement of parturition
- No. of living pregnant females
- For further reproductive parameters, see also the above section "Litter observations" and section "Offspring viability indices" below. - Offspring viability indices:
- - Post-implantation survival index (Total no. of pups born/Total no. of uterine implantation sites) x 100
- Live birth index (No. of live pups on day 1 after littering/Total no. of pups born) x 100
- Viability index (No. of live pups on day 4 after littering /No. of live pups on day 1 after littering) x 100
- Lactation index (No. of live pups on day 7 after littering /No. of live pups on day 1 after littering) x 100
- For further parameters indicative of the viability of the offspring, see also the above section "Litter observations"
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- 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:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- in kidneys at 1000 mg/kg/day: Slight increase in incidence and/or severity of tubular casts in both sexes and in cortical tubular basophilia in females. Examination only in 5 toxicity subgroup females/group and 5 F0 males/group, not examined in F0 females
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- At 1000 mg/kg/day, 1 pair failed to produce a litter. Macroscopically no evidence of any implantation sites in the affected female, microscopically no changes in the reproductive tract in both F0 animals. This was not attributed to the test substance.
Details on results (P0)
- No deaths occurred in all F0 males or females during the study.
Water consumption:
- No overt effects, based on daily visual observation.
Histopathology:
Further details on renal histopathology findings in F0 animals of the present study are given in separate endpoint study record "7.5.1 Repeated dose toxicity: oral - Repeat dose tox combined, oral, rat read-across", e.g. in Table 1 and the commenting text underneath this table.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- on bodyweight gain to day 7, the day of scheduled sacrifice of the pups.
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
No abnormality in sex ratio.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: NOAEL = highest dose tested.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
As outlined in the „Validity Assessment Report“ for the read-across approach (see IUCLID Section 13) read-across from testing data obtained with the UVCB substance WS400128 is considered appropriate for the safety evaluation as well as classification and labelling of the UVCB substance WS400136 based on the close chemical similarity between the two substances.
Applicant's summary and conclusion
- Conclusions:
- As outlined in the „Validity Assessment Report“ for the read-across approach (see IUCLID Section 13) read-across from testing data obtained with the UVCB substance WS400128 is considered appropriate for the safety evaluation as well as classification and labelling of the UVCB substance WS400136 based on the close chemical similarity between the two substances.
The NOAEL for reproductive toxicity of 1000 mg/kg/day as derived with the read-across source substance WS400128 in this screening study also can be used for the read-across target substance WS400136 for the regulatory purposes of REACH.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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