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EC number: 948-071-5 | 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
The objectives of the study were to evaluate the potential toxic effects of the test material when administered to rats for at least 28 days and to evaluate the potential of the test substance to affect male and female reproductive performance such as gonadal function, mating behavior, and conception through day 13 of postnatal life. The study was performed to the standardized guideline OECD 422, under GLP conditions.
The NOAEL for neonatal toxicity was 75 mg/kg/day based on the lower live litter size, lower postnatal survival, and lower pup body weights and body weight gains in the 250 mg/kg/day group.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16 February 2017 to 02 November 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- -Purity: > 98%
-Physical description: Yellow semi-solid - Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Following receipt and until pairing, all F0 animals were housed 2–3 rats/cage by sex in clean, solid-bottom cages with bedding material (Bed-O'Cobs®; The Andersons, Cob Products Division, Maumee, OH).
The basal diet used in this study, PMI Nutrition International, LLC Certified Rodent LabDiet® 5002, was a certified feed with appropriate analyses performed by the manufacturer and provided to Charles River.
Actual mean daily temperature ranged from 72.5°F to 73.0°F (22.5°C to 22.8°C) and mean daily relative humidity ranged from 38.4% to 56.7% during the study. Fluorescent lighting provided illumination for a 12-hour light (0600 hours to 1800 hours)/12-hour dark photoperiod.corn
Air handling units were set to provide a minimum of 10 fresh air changes per hour. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on mating procedure:
- The animals were paired on a 1:1 basis within each treatment group following 14 days of treatment for the males and females.Positive evidence
of mating was confirmed by the presence of a vaginal copulatory plug or the presence of sperm following a vaginal lavage and verified by a second biologist. Each mating pair was examined daily. The day when evidence of mating was identified was termed Gestation Day 0 and the
animals were separated. If evidence of copulation was not detected after 14 days of pairing, the animals were separated without further opportunity for mating. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples for concentration analysis were collected from the middle stratum of first, middle, and last dosing formulations (including the vehicle control group) prepared that included all dose groups. One set of samples from each collection was analyzed using a validated high performance liquid chromatography method with charged aerosol detection. The retention time of the test substance was approximately 1.5 to 2.1 minutes.
- Duration of treatment / exposure:
- Males and females were approximately 10 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through Lactation Day 13 for a total of 49–54 doses; females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (Postcohabitation Day 25 or Postmating Day 25, respectively) for a total of 40–52 doses.
- Frequency of treatment:
- Once daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dose selection was based upon a range-finding study (please see RSS section 7.5.1 Supporting study, Charles river, 2017).
- Parental animals: Observations and examinations:
- All rats were observed twice daily, once in the morning and once in the afternoon, for moribundity and mortality.
Clinical observations, body weights, and food consumption recorded at appropriate intervals.
Motor activity was assessed for 5 animals/sex/group during the last week of dose administration (Study Day 25, males) or on Lactation Day 13 (females).
Blood samples for clinical pathology evaluations (hematology, coagulation, and serum chemistry) were collected from 5 animals/sex/group at the scheduled necropsies (Study Day 28 for males and Lactation Day 14 for females). - Oestrous cyclicity (parental animals):
- Vaginal lavages were performed daily and the slides were evaluated microscopically to determine the stage of the estrous cycle of each female for 14 days prior to randomization and continuing until evidence of copulation was observed or until termination of the mating period for females with no evidence of mating.
- Sperm parameters (parental animals):
- Sperm morphology and concentrations were measured. In addition, testes with epididymides and vas deferens were collected for macroscopic examination.
- Litter observations:
- Each litter was examined daily for survival, and all deaths were recorded. Each pup received a clinical examination on PND 1, 4, 7, 10, and 13. Pups were individually weighed on PND 1, 4, 7, 10, and 13. Pups were individually sexed on PND 0, 4, and 13. On PND 13, all F1 male offspring were evaluated for the presence of thoracic nipples/areolae.
- Postmortem examinations (parental animals):
- A complete necropsy was conducted on all F0 parental animals found dead or at the scheduled termination.
All F0 adults were euthanized by carbon dioxide inhalation. Males were euthanized following completion of the mating period; blood samples were collected for thyroid hormone analysis immediately prior to euthanasia. - Postmortem examinations (offspring):
- On PND 13, surviving F1 rats were euthanized via an intraperitoneal injection of sodium pentobarbital. Blood samples were collected for thyroid hormone analysis immediately prior to euthanasia.
- Statistics:
- Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals (N) used to calculate the mean. Statistical analyses were not conducted if the number of animals was 2 or less.
- Reproductive indices:
- Mating, fertility, and copulation/conception indices were calculated as follows:
Male (Female) Mating Index (%) = No. of Males (Females) with Evidence of Mating (or Confirmed Pregnant)/Total No. of Males (Females) Used for Mating X 100
Male Fertility Index (%) = No. of Males Siring a Litter/Total No. of Males Used for Mating x 100
Male Copulation Index (%) = No. of Males Siring a Litter/ No. of Males with Evidence of Mating(or Females with Confirmed Pregnancy) X 100
Female Fertility Index (%) = No. of Females with Confirmed Pregnancy/Total No. of Females Used for Mating X 100
Female Conception Index (%) = No. of Females with Confirmed Pregnancy/No. of Females with Evidence of Mating (or Confirmed Pregnancy) x 100 - Offspring viability indices:
- Litter parameters were defined as follows:
Mean Live Litter Size = Total No. of Viable Pups on PND 0/No. of Litters with Viable Pups PND 0
Postnatal Survival Between Birth and PND 0 or PND 4 (% Per Litter) = Sum of (Viable Pups Per Litter on PND 0 or PND 4/No. of Pups Born Per Litter)/ No. of Litters Per Group x 100
Postnatal Survival for All Other Intervals (% Per Litter) = Sum of (Viable Pups Per Litter at End of Interval N/Viable Pups Per Litter at Start of Interval N)/No. of Litters Per Group x 100
Where N = PND 0–1, 1–4 (pre-selection), 4 (post-selection)–7, 7–10, 10–13, and 4 (post-selection)–13 - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Females and males in the 250 mg/kg/day group had clinical observations of tremors, clonic convulsions, rales, and/or dilated pupils noted primarily at approximately 1.5 hours following dose administration; the observations of tremors, clonic convulsions, and dilated pupils were noted generally 1–4 days prior to the day of death while rales was observed throughout.
Other remarkable clinical observations noted occasionally throughout the dosing period for females that were found dead at 250 mg/kg/day included yellow material on various body surfaces (hindlimbs, urogenital area, anogenital area, and/or ventral trunk) noted at the detailed physical and/or daily examinations, and salivation, clear and/or red material around the mouth and/or nose, and clear nasal discharge noted at approximately 1.5 hours following dose administration. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 5 females were found dead at 250 mg/kg/day. Histologic findings indicate acute inflammation in the non-glandular stomach.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related, significantly (p < 0.05 or p < 0.01) lower mean body weight gains were noted in the 250 mg/kg/day group F0 males during Study Days 0–7 and 13–21 compared to the vehicle control group; mean body weight gains in this group were similar to the vehicle control group during Study Days 7–13 and 21–27.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related lower mean food consumption was noted in the 250 mg/kg/day group F0 males during Study Days 0–7 and 7–13 compared to the vehicle control group; the difference was significant (p < 0.05) during Study Days 0–7.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A significantly (p < 0.05) lower activated partial thromboplastin time (APTT) value was noted in the 250 mg/kg/day group F0 males compared to the vehicle control group; this difference was of minimal magnitude and was considered to be the result of normal biological variation and not test substance-related.
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related microscopic findings were noted in the kidneys and stomach (glandular and non-glandular), these alterations were not considered adverse.
- Histopathological findings: neoplastic:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 75 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- Significantly (p < 0.05) lower mean live litter size on PND 0 was noted in the 250 mg/kg/day group compared to the vehicle control group
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Male and female pup birth weights (PND 1) in the 250 mg/kg/day group were lower (29.7% and 29.6%, respectively) than the vehicle control group.
- 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:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Male and female F1 pup body weights at 250 mg/kg/day were lower (up to 38.2% and 40.7%, respectively) than the vehicle control group from PND 1 to 13.
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related effects on thyroid hormone values in the F1 males and females at any dosage level on PND 13.
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 75 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- The NOAEL for neonatal toxicity was 75 mg/kg/day based on the lower live litter size, lower postnatal survival, and lower pup body weights and body weight gains in the 250 mg/kg/day group.
- Executive summary:
The objectives of the study were to evaluate the potential toxic effects of the test material when administered to rats for at least 28 days and to evaluate the potential of the test substance to affect male and female reproductive performance such as gonadal function, mating behavior, and conception through day 13 of postnatal life. The study was performed to the standardized guideline OECD 422, under GLP conditions.
Under the conditions of this screening study, no test substance-related effects were observed on reproductive performance at any dosage level. Therefore, a dosage level of 250 mg/kg/day, the highest dosage level evaluated, was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of the test material when administered orally by gavage to Crl:CD(SD) rats.
Adverse lower mean body weights, body weight gains, and food consumption were noted for F0 males throughout the study and for F0 females at the beginning of the premating period and during gestation in the 250 mg/kg/day group.
Macroscopic findings consisted of raised and eroded areas in the stomach noted in the 250 mg/kg/day group females and histologic findings consisted of inflammation in the glandular and non-glandular stomach noted in the 250 mg/kg/day group males and females.
Based on these results, the NOAEL for parental systemic toxicity was considered to be 75 mg/kg/day.
The NOAEL for neonatal toxicity was 75 mg/kg/day based on the lower live litter size, lower postnatal survival, and lower pup body weights and body weight gains in the 250 mg/kg/day group.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 75 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Justification for classification or non-classification
Additional information
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.
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