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EC number: 291-768-8 | CAS number: 90480-35-6
- 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
For this endpoint a Combined Repeated Dose Toxicity 28-day / Reproduction/Developmental Toxicity Screening Test was performed. The study was performed in accordance to OECD TG 422 and in compliance to GLP.
The No-Observed-Adverse-Effect Level (NOAEL) for fertility when the test item is administered via oral gavage to Sprague-Dawley rats with dose levels of 0, 35, 150 and 600 mg/kg bw/day is considered to be 150 mg/kg/day for the animals of both sexes.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16.03.-29.09.2017
- 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)
- Version / remarks:
- July 29, 2016
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Sprague-Dawley/Crl:CD (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Number at receipt: 136 (Male 66, Female 70)
- Number on study: 120 (Male 60, Female 60)
- Age range at receipt: Approximately 7 weeks (Males) and 9 weeks (Females)
- Age range on study: Approximately 10 weeks (Males) and 12 weeks (Females)
- Body weight range: 338.7-404.8 g at the initiation of dosing (Males); 238.0-287.7 g at the initiation of dosing (Females)
- Method of identification: Color marking, Tail tattoo, Cage card
- Health status:Healthy animals were used in this study
- Acclimation: All animals were permitted an acclimation period of 6 days to the laboratory environment
- Animal assignment (Randomization): Animals were selected for use in the study on the basis of adequate body weight (recorded on the day of receipt and group assignment), estrus cycle and free from clinical signs of disease or injuries during the acclimation and pre-treatment periods. They were randomized and assigned to treatment groups to have a similar mean body weight distribution using the Pristima system based on the most recent body weight.
HOUSING AND ANIMAL CARE:
- Housing: stainless-steel cage (255W×465L×200H mm)
- Number of animals per cage: Acclimation 2 , Pre-treatment 2 , Treatment 2 or 1, Mating 1 (male):1 (female), Post-mating 2, Recovery 2 or 1, Gestation 1 mated female, Lactation 1 dam with her pups.
- Type of Cage: stainless-steel cage (255W×465L×200H mm) or poly sulfone cages (260W×420L×180 mm) during gestation and lactation.
- Temperature 21.1 - 24.1°C
- Humidity: 40.9 – 57.6%
- Light cycle: 12 hour light/12 hour dark cycle
- Light intensity: 150 - 300 Lux
- Air changes: 10 - 20 times/hour
- Cleaning: Animal room was cleaned daily. Stainless-steel cages were cleaned at least once per 2 weeks, and poly sulfone cages were cleaned at least once per week.
Food, Water and Bedding:
- A standard rat pellet diet was provided to the animals ad libitum. Microbial monitoring for diet was performed
- The animals have had ad libitum access to filtered, ultraviolet light-irradiated municipal tap water at all times. The drinking water was analyzed every 6 months for specified contaminants
- Aspen animal bedding material was sterilized and then provided to the animals in each cage. A certificate of analysis for the bedding was provided by the supplier.
There were no known contaminants in the food, water and bedding material at levels that would be expected to interfere with the results of the study and the data was maintained in the raw data. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dose was based on the most recently measured body weight. Animals were dosed at a volume of 2 mL/kg.
Dose formulation was continuously stirred by magnetic stirrer in the animal room (before and throughout the dosing procedure).
The control item or dose formulations were administered by oral gavage once a day at approximately the same time each day (08:30 - 12:30)
VEHICLE
Justification for use and choice of vehicle: Through the preliminary solubility test to determine the solubility and dispersion characteristics of the test substance, corn oil was selected as the vehicle because the test substance was dissolved in it. - Details on mating procedure:
- One male to one female mating was used, and males and females were paired for 2 weeks. Animals of the recovery group were not mated. Mating confirmation was checked every morning during the mating period. Mating was confirmed with vaginal plug(s) and/or sperm in the vaginal smear.
Day 0 of pregnancy was defined as the day of mating confirmation. Pregnancy was confirmed by implantation sites on the uterus at sacrifice or parturition. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability:
Dose formulations in the range 1-500 mg/mL have shown to be stable for 7 days when stored at room temperature
Homogeneity:
Dose formulations in the range 1-500 mg/mL have shown to be homogeneous. Homogeneity of dose formulations for dosing start date was determined prior to dosing.
Verification of dose level concentrations:
Analyses of the dosing formulations were conducted and samples for homogeneity analysis were also analyzed for verification of dose level concentration. Results of dose formulations were 107.21, 106.87 and 106.88% at each dose levels of 35, 150 and 600 mg/kg. They were acceptable as the mean concentration was within ±15% of the nominal concentration - Duration of treatment / exposure:
- Dosing of the males began 14 days prior to mating and continued throughout mating prior to sacrifice (at least 50 days).
Dosing of the females was beginning 14 days prior to mating and continued throughout lactation day (LD) 13.
Animals of the recovery group were not mated and assigned to 2 weeks of recovery period after the completion of administration. - Frequency of treatment:
- Frequency of treatment: 7 days/week.
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- vehicle control (VC)
- Dose / conc.:
- 35 mg/kg bw/day (actual dose received)
- Remarks:
- T1
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Remarks:
- T2
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- Remarks:
- T3
- No. of animals per sex per dose:
- 12 animals per sex per group
Additional recovery groups: 0 and 600 mg/kg (6 animals per sex per group) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- 120 animals (60 males and 60 females) were included in the study (at the start of administration).
All animals were examined for general health upon receipt. Animals were selected for use in the study on the basis of adequate body weight (recorded on the day of receipt and group assignment). They were randomized and assigned to treatment groups to have a similar mean body weight distribution using the Pristima system based on the most recent body weight.
All animals were permitted an acclimation period of 6 days to the laboratory environment. All assigned animals were permitted a pre-treatment period of 14 days before dosing start.
During the pre-treatment period, a vaginal smear was taken daily for each female and regularity and length of the estrus cycle was examined. Females that failed to exhibit normal estrus cycle were excluded from the study.
Cage card and animal room use record were attached on the cage and animal room, respectively.
- Dose selection rationale:
The dose level was selected based on the results of a two weeks dose range-finding study - Positive control:
- not applicable
- Parental animals: Observations and examinations:
- IN-LIFE OBSERVATIONS AND MEASUREMENTS
Mortality observation:
Mortality and morbidity observations were conducted twice daily except for the acclimation period. In addition, it was conducted once on necropsy day.
General clinical signs:
Clinical signs including mortality, moribundity, general appearance, behavior changes were recorded with date/time of finding, and duration. Animals judged to be abnormal were examined by a veterinarian or an experienced technician.
During the gestation period, dams were especially monitored for signs of abortion or premature delivery. In addition, nursing dams were carefully observed during the lactation period.
Detailed clinical signs:
Detailed clinical observations were made in all animals individually for abnormalities.
Signs noted were included (but are not limited to) evaluation of fur, skin, eyes, mucous membranes, occurrence of secretions and excretions, autonomic nervous system activity (lacrimation, piloerection, pupil size, and unusual respiratory pattern), changes in gait, posture, clonic and tonic movements, stereotypical and bizarre behavior, and difficult and prolonged parturition. General clinical signs after dosing were not additionally recorded in the day of detailed clinical signs observation.
Body weight (Period/Frequency):
- Acclimation: animal receipt day and day 6 of acclimation
- Pre-treatment: one time per week
- Treatment: first day of dosing and thereafter one time per week
- Mating: twice a day (before and after dosing)
- Post-mating: twice a day (before and after dosing)
- Gestation and Lactation: twice a day (before and after dosing). However, parturition completed females were observed additionally once more
- Recovery: one time per week
- Necropsy: the day prior to necropsy and on the day of necropsy
Food consumption (Period/Frequency):
- Treatment: one time per week
- Post-mating: one time per week
- Gestation: gestation day (GD) 0, 7, 14 and 20
- Lactation: lactation day (LD) 0, 4 and 13
- Recovery: one time per week
Amount of food given to each animal and amount of residual feed was measured. Individual food consumption was calculated by subtracting the amount of residual feed from the amount presented. The quantity of food consumption between intervals was presented as g/animal/day.
Functional observations:
Sensory function tests (approach and touch response, tail pinch, acoustic startle response and pupillary reflex), grip strength and motor activity were conducted in first six animals per sex in main group (if possible) and all animals in recovery group shortly before scheduled sacrifice.
CLINICAL PATHOLOGY
Blood collection:
Blood samples for clinical pathology were taken from all scheduled sacrifice animals in main and recovery groups. Blood samples were collected from abdominal vena cava.
Hematology:
Approximately 1.5 mL of blood samples was collected from all scheduled sacrifice animals in main and recovery groups.
Hematology Parameters:
Total leukocyte count (WBC), Mean corpuscular hemoglobin (MCH), Total red blood cell count (RBC), Mean corpuscular hemoglobin concentration (MCHC), Hemoglobin (HGB), Platelet count (PLT), Hematocrit (HCT), Reticulocyte count, Mean corpuscular volume (MCV), WBC differential count, Prothrombin time (PT), Activated partial thromboplastin time (APTT), Fibrinogen (FIB).
Clinical chemistry:
Approximately 1.5 mL of blood samples was collected from all scheduled sacrifice animals in main and recovery groups.
Clinical Chemistry Parameters:
Glucose (GLU), Alanine aminotransferase (ALT), Blood urea nitrogen (BUN), Total bilirubin (TBIL), Creatinine (CREA), Alkaline phosphatase (ALP), Total protein (TP), Gamma glutamyl transpeptidase (GGT), Albumin (ALB), Creatine phosphokinase (CK), Albumin/globulin ratio (A/G), Calcium (Ca),
Total cholesterol (TCHO), Inorganic phosphorus (IP), Triglyceride (TG), Sodium (Na), Phospholipid (PL), Potassium (K), Aspartate aminotransferase (AST), Chloride (Cl).
Thyroid Hormone (T4 and TSH) Analysis:
Blood samples (approximately 0.6 mL) for thyroid hormone (T4 and TSH) analysis were collected.
Pups blood was pooled in a tube by sex per litter. Thyroid hormone (T4 and TSH) concentration in the serum samples of pups on PND 13 were analyzed.
Parturition monitoring:
Mating-proven females were monitored twice daily for signs of parturition including abortion, premature delivery and difficult or prolonged parturition from GD 21.
Dams were allowed to litter. The duration of gestation, the number of dead and live pups, runts, sexing of live pups, individual body weight of live pups and external abnormalities were observed.
Females which were not observed to have parturition until GD 27 were sacrificed. - Oestrous cyclicity (parental animals):
- A vaginal smear was taken daily for each female from the beginning of the 14 days prior to mating with continued monitoring into the mating period until there was evidence of mating.
Furthermore, regularity and length of the estrus cycle was examined during the treatment period until mating.
In addition, vaginal smear of sacrificed females was taken at termination to examine the stage of the estrus cycle and allow correlation with histopathology of female reproductive organs. - Sperm parameters (parental animals):
- not specified
- Litter observations:
- Pups mortality:
All pups were monitored for mortality and morbidity once every day.
Pups general clinical signs:
All pups were monitored for general clinical signs once every day. Clinical signs including general appearance and behavior changes were recorded.
Pups body weight:
Body weight and sex were recorded on post-natal day (PND) 0, 4 (before culling), and 13, and it was reported as litter.
Anogenital distance and nipple retention:
Anogenital distance was measured in all pups on PND 4. Both, pup body weight and anogenital distance were collected on the same day and the anogenital distance was normalized based on the cube root of body weight. In addition, the number of nipples in all male pups was counted on PND 12.
Pups culling:
On LD 4, the size of each litter was adjusted by eliminating extra pups randomly to give 4 males and 4 females per litter, if possible. Litters with 8 or fewer pups were not culled. External examinations were conducted on all culled pups and subsequently humanly sacrificed by CO2 inhalation. Special attention was paid to the external reproductive genitals which should be examined for signs of altered development.
- Postmortem examinations (parental animals):
- Unscheduled Sacrifice:
Macroscopic findings:
Complete necropsy was performed under the direct supervision of a veterinarian pathologist. After blood sampling, the animals were sacrificed by exsanguination from the vena cava and aorta. The animals were examined carefully for external abnormalities. The abdominal, thoracic and cranial
cavities were examined for abnormalities and the organs were removed and examined.
Tissue preservation:
Tissues from each animal were preserved in 10% neutral buffered formalin, except the eyes (with optic nerve) which were fixed in Davidson’s fixative and the testes and epididymides which were fixed in Bouin’s fixative. The tissues were placed in the appropriate fixative for approximate 48 hours, an d then transferred to 70% ethanol. Formalin was infused into the lung via the trachea and into the urinary bladder. Tissues from unscheduled sacrificed animals were processed for microscopic evaluation.
Scheduled Sacrifice:
Method of termination
All surviving main group males were euthanized on the day after final dosing using isoflurane.
All surviving main group females on LD 14 were euthanized using isoflurane.
All surviving recovery group males and females were euthanized using isoflurane at least 14 days after the first scheduled sacrifice of males and females.
All animals were fasted more than 16 hours (overnight) prior to scheduled sacrifice.
Macroscopic findings:
Complete necropsy was performed under the direct supervision of a veterinary pathologist. After blood sampling, the animals were sacrificed by exsanguination from the vena cava and aorta.
The animals were examined carefully for external abnormalities. The abdominal, thoracic and cranial cavities were examined for abnormalities and the organs were removed and examined.
Organ weights:
Organs were weighed for all animals at terminal and recovery sacrifice groups, and organ/body weight ratios using the terminal body weight (TBW) obtained prior to necropsy were calculated. However, paired reproductive organs were weighed separately.
Tissue preservation:
Tissues from each animal were preserved in 10% neutral buffered formalin, except the eyes (with optic nerve) which were fixed in Davidson’s fixative and the testes and epididymides which were fixed in Bouin’s fixative.
The tissues were placed in the appropriate fixative for approximate 48 hours, and then transferred to 70% ethanol. Formalin was infused into the lung via the trachea and into the urinary bladder.
Microscopic findings:
Tissues except reproductive organs and thyroids (with parathyroids) collected from the first six animals per sex in the main group were further processed to slides, stained with hematoxylin and eosin, and examined microscopically. In addition, all reproductive organs (ovaries, prostate, testes,
epididymides, uterus with cervix and seminal vesicles with coagulation gland) and abnormal lesions collected from all animals in the main group were further processed to slides, stained with H&E, and examined microscopically. Thyroids (with parathyroids) for adult males were further processed to slides, stained with hematoxylin and eosin, and examined microscopically to clarify the change of thyroid hormone. Any target organs were additionally evaluated microscopically from recovery group animals. - Postmortem examinations (offspring):
- Dead pups:
External and visceral examinations were conducted in dead pups at parturition and dead or moribund pups from birth to day 4 of lactation, if possible.
Special attention was paid to the external reproductive genitals which should be examined for signs of altered development. - Statistics:
- Mean values and standard deviations were calculated in the final report. Statistical analyses for comparisons of the various dose groups with the vehicle control group were conducted using Pristima
System or Statistical Analysis Systems.
Data from non-pregnant females until mating will be included in the report. Data were considered to be significant when p<0.05 or p<0.01.
Multiple comparison tests for different dose groups were conducted. Variance of homogeneity was examined using the Bartlett’s Test.
Homogeneous data was analyzed using the Analysis of Variance (ANOVA) and the significance of inter-group differences were analyzed using Dunnett’s Test.
Heterogeneous data was analyzed using Kruskal-Wallis Test and the significance of inter-group differences between the control and treated groups were assessed using Dunn’s Rank Sum Test.
For comparing control group and recovery group, the data was analyzed for homogeneity for variance using F-test.
Homogeneous data was analyzed using T-test and the significant difference between control and recovery group was assessed using Dunnett’s Test.
Heterogeneous data was analyzed using Kruskal-Wallis Test and significant difference between control and recovery group was assessed using Dunn’s Rank Sum Test.
Data presented as frequencies was analyzed by χ2-test followed by the Fisher's exact test where necessary. - Reproductive indices:
- Based on the results, the following reproduction indices were calculated:
- Mating Index (%) = (No. of males with evidence of mating / No. of males paired) × 100
= (No. of females with evidence of mating / No. of females paired) × 100
- Fertility Index (%) = (No. of males impregnating a female / No. of males paired) × 100
= (No. of pregnant females / No. of females paired) × 100
- Fecundity Index and Pregnancy Index (%) = (No. of males impregnating a female / No. of males with evidence of mating) × 100
= (No. of pregnant females / No. of females with evidence of mating) × 100
- Precoital Time: No. of days taken to mate - Offspring viability indices:
- Based on the results, the followings were calculated:
On Day 0 of Lactation
- Delivery Index = (No. of dams with live pups / No. of pregnant dams) × 100
On Day 4 of Lactation
- Viability Index = (No. of live pups on Day 4 of lactation / No. of live pups at birth) × 100
On Day 13 of Lactation
- Weaning Index = (No. of live pups on Day 13 of lactation / No. of pups on Day 4 of lactation after culling) × 100
Dead pups:
External and visceral examinations were conducted in dead pups at parturition and dead or moribund pups from birth to day 4 of lactation, if possible.
Special attention was paid to the external reproductive genitals which should be examined for signs of altered development. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In both sexes at ≥ 150 mg/kg, salivation was observed.
Other clinical signs during the study were not considered test item-related since these findings were observed with low frequency, occurred sporadically, generally of low severity and/or did not have a dose-response. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One female (Animal No. 115) in the recovery group at 600 mg/kg was found dead on dosing day 47.
Macroscopic findings included minimal enlarged adrenal glands and partial irregular surface of the right kiney. Microscopic analysis revealed marked pyelonephritis in the kidneys, severe necrosis in the adrenal glands and slight hepatocyte hypertrophy in the liver.
Unscheduled sacrifice was performed on eight females (Animal No. 103, 105, 106, 108, 110, 112, 113 and 114) at 600 mg/kg .
In the results of microscopic findings, minimal to slight hepatocyte hypertrophy in the liver was observed in some unscheduled sacrificed animals, but there were no changes in reproductive organs. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In males at 600 mg/kg, decreased body weight gain in the main group (89% of control) and recovery group (79% of control) during the treatment period was observed.
In females at 600 mg/kg, decreased body weight gain in the main group (85% of control) and recovery group (58% of control) during the treatment period was observed.
Other statistically significant change in body weight was not considered test-item related since it was transient. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In females at 600 mg/kg, decreased food consumption in the main group (89% of control) during the treatment period was observed.
Other statistically significant changes in food consumption were not considered test-item related since it was minimal or transient. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Hematology:
In males at 600 mg/kg, decreased total red blood cell count (RBC, 92% of control), hemoglobin (HGB, 92% of control), and hematocrit (HCT, 91% of control) were observed.
Other statistically significant changes in hematology were not considered test item-related since it was minimal or only observed in the recovery group.
Coagulation:
In males at ≥ 150 mg/kg, increased prothrombin time (PT, up to 1.13-fold over control) and at 600 mg/kg decreased fibrinogen (FIB, 95% of control) were observed. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In males at 600 mg/kg, increased blood urea nitrogen (BUN, 1.17-fold over control), albumin/globulin ratio (A/G, 1.07-fold over control) and gamma glutamyl transpeptidase (GGT, 1.68-fold over control) and decreased triglyceride (TG, 41% of control) were observed.
In females at 600 mg/kg, increased GGT (2.21-fold over control) was observed.
Other statistically significant changes in clinical chemistry were not considered test item-related because there no dose-relationship, no correlated microscopic changes and/or observed only in recovery group. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- No test item-related changes in functional behavior examination were observed in both sexes during the study.
Motor activity examination:
No test item-related changes in motor activity examination were observed in both sexes during the study.
A statistically significant change in motor activity examination was not considered test item-related since it was transient and did not have a dose-response. - 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):
- In both sexes at 600 mg/kg, minimal to slight hepatocyte hypertrophy in liver was observed.
In males at 600 mg/kg, minimal to slight follicular epithelial hypertrophy in thyroid glands was observed.
In addition, minimal to slight tubular basophilia in kidney and minimal to slight ductal atrophy in epididymides were observed.
Other changes observed in microscopic findings were considered incidental or spontaneous changes since they were infrequent, generally of low severity, and similarly distributed among control and treated groups. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Thyroid Hormone (T4 and TSH) Analysis: In males at 600 mg/kg, decreased T4 (73% of control) was observed.
- Reproductive function: oestrous cycle:
- effects observed, treatment-related
- Description (incidence and severity):
- At 600 mg/kg, two females with irregular estrus cycle were observed.
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- - Precoital time:
No test item-related changes in precoital time were observed during the study.
- Fertility data:
At 600 mg/kg, decreased fertility index (33% of control), fecundity index (40% of control) and pregnancy index (40% of control) were observed. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- reproductive function (oestrous cycle)
- reproductive performance
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No test item-related changes in F1 pups clinical signs were observed in both sexes during the study.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 600 mg/kg, decreased F1 male and female pup body weight (up to 59% of control) were observed.
- 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
- Description (incidence and severity):
- F1 culled pups external examination:
No test item-related changes in F1 culled pups external examination were observed in both sexes during the study.
F1 pups external examinations:
No test item-related changes in F1 pups external examinations were observed in both sexes during the study - Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- - F1 pups anogenital distance:
No test item-related changes in F1 pups anogenital distance were observed in both sexes during the study.
- F1 male pups nipple retention:
No test item-related changes in F1 male pups nipple retention were observed during the study. - Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 150 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: general reproductive/developmental effects
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 600 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Conclusions:
- The No-Observed-Adverse-Effect Level (NOAEL) for reproductive/developmental effects when the test item is administered via oral gavage to Sprague-Dawley rats with dose levels of 0, 35, 150 and 600 mg/kg bw/day is considered to be 150 mg/kg/day for the animals of both sexes.
- Executive summary:
This study was conducted to evaluate the potential reproductive/developmental toxicities of the test item when administered via oral gavage to Sprague-Dawley rats. The assay was performed in accordance to OECD TG 422 and in compliance to GLP.
The test item was administered by oral gavage to Sprague-Dawley rats (12 animals per sex per group) at dose levels of 0, 35, 150 and 600 mg/kg with a dose volume of 2 mL/kg. Males and females were dosed for two weeks prior to mating and continued through the day before sacrifice in males (total 50 days), and continued through the lactation day (LD) 13 in females. Additional animals in the recovery groups 0 and 600 mg/kg (6 animals per sex per group) received the test item but were not mated. Afterwards, they were assigned to 2 weeks of recovery period after the completion of the test item administration.
Reproductive/developmental observations including estrus cycle, precoital time, fertility data, reproductive and littering findings, F1 pups clinical signs, body weight, anogenital distance, nipple retention and external examination were measured. Thyroid hormone (T4 and TSH) level in blood was also analyzed for pups at sacrifice.
Eight females at 600 mg/kg were sacrificed unscheduled due to non-parturiton and non-mated. This resulted in a decreased fertility, fecundity and pregnancy index. In addition, reproductive and littering finding changes including decreased number of implantation, pups born, live litter size from PND 0 to 13, viability index and weaning index. These findings were considered attributed to microscopic findings of mated males which revealed ductal atrophy in epdididymides since there were no test item-related changes in female reproductive organs. These findings were considered as test item-related adverse effects. Body weight gain was decreased during the treatment period in both sexes at 600 mg/kg. Decreased food consumption during the treatment period in females at 600 mg/kg was also found. These changes were considered to be accompanied by decreased F1 pups body weight. These findings were considered test item-related adverseeffects.
Two females with irregular estrus cycle were observed at 600 mg/kg. The relationship of test item and this finding was uncertain since the incidence was ambiguous. However, it was not considered to have toxicological relevance since no test item-related changes in microscopic findings of female reproductive organs as well as other females at 600 mg/kg.
Reproductive/development adverse effects including ductal atrophy in epdididymides, decreased fertility, fecundity and pregnancy index in both sexes, reproductive and littering finding changes including decreased number of implantation, pups born, live litter size from PND 0 to 13, viability index, weaning index, and decreased F1 pups body weight were observed at 600 mg/kg.
Therefore, the No-Observed-Adverse-Effect Level (NOAEL) for reproductive/developmental effects is considered to be 150 mg/kg/day.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 150 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- No issues with the quality of the study
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
This study was conducted to evaluate the potential reproductive/developmental toxicities of the test item when administered via oral gavage to Sprague-Dawley rats.
The test item was administered by oral gavage to Sprague-Dawley rats (12 animals per sex per group) at dose levels of 0, 35, 150 and 600 mg/kg with a dose volume of 2 mL/kg. Males and females were dosed for two weeks prior to mating and continued through the day before sacrifice in males (total 50 days), and continued through the lactation day (LD) 13 in females. Additional animals in the recovery groups 0 and 600 mg/kg (6 animals per sex per group) received the test item but were not mated. Afterwards, they were assigned to 2 weeks of recovery period after the completion of the test item administration.
Body weight gain was decreased during the treatment period in both sexes at 600 mg/kg. Decreased food consumption during the treatment period in females at 600 mg/kg was also found. These changes were considered to be accompanied by decreased F1 pups body weight. These findings were considered test item-related adverse effects.
Two females with irregular estrus cycle were observed at 600 mg/kg. The relationship of test item and this finding was uncertain since the incidence was ambiguous. However, it was not considered to have toxicological relevance since no test item-related changes in microscopic findings of female reproductive organs as well as other females at 600 mg/kg.
Reproductive/development adverse effects including ductal atrophy in epdididymides, decreased fertility, fecundity and pregnancy index in both sexes, reproductive and littering finding changes including decreased number of implantation, pups born, live litter size from PND 0 to 13, viability index, weaning index, and decreased F1 pups body weight were observed at 600 mg/kg.
Therefore, the No-Observed-Adverse-Effect Level (NOAEL) for reproductive/developmental effects is considered to be 150 mg/kg/day.
Effects on developmental toxicity
Description of key information
The F1 pups from the 600 mg/kg bw/d dose group showed a decreased body weight. There were no test item related gross and microscopic changes in both males and females during the gross examination of pups on lactation day 4.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
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
The F1 pups from the 600 mg/kg bw/d dose group in the OECD 422 Screening Test in rats showed a decreased body weight (up to 59% of control). There were no test item related gross and microscopic changes in both males and females during the gross examination of pups on lactation day 4.
Justification for classification or non-classification
Based on the findings of reduced fertility in the 600 mg/kg bw/d dose group in the OECD 422 screening test, a classification as Reprotox. Cat. 2 (H361f) is warranted in accordance with the criteria described in Regulation 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP).
Additional information
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