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EC number: 202-945-6 | CAS number: 101-48-4
- 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
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- Auto flammability
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- pH
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- 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
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- Toxicological Summary
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- Acute Toxicity
- Irritation / corrosion
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- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
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- Additional toxicological data
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Oral (OECD 422), rat: NOAEL fertility ≥ 600 mg/kg bw/day
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 22 Sep 2016 - 26 Jan 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:
- 28 Jul 2015
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Remarks:
- SPF
- Details on species / strain selection:
- Sprague-Dawley rats are commonly used in both the general systemic toxicity and reproductive and developmental toxicity studies with a large historical control data base. In addition, the rat is a required species in the regulatory guidelines.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: (P) 11 weeks (males) and 12 weeks (females)
- Weight at study initiation: (P) Males: 375.8 - 443.3 g
- Housing: Acclimation, pre-mating and dosing period: 1 animal per cage; Mating: 1:1; Lactation: neonates were kept with the dam; animals were kept in stainless wire mesh cages (260W x 350D x 210H mm) and in polycarbonate cages (260W x 420D x 180H mm)
- Diet: Pelleted rodent chow (Teklad Certified Irradiated Global 18% Protein Rodent Diet 2918C; Envigo RMS, Inc., U.S.A.), ad libitum
- Water: public tap water filtered and irradiated by ultraviolet light, ad libitum
- Acclimation period: 7 or 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2 - 23.8
- Humidity (%): 45.3 - 64.7
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12 - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance was mixed with a small amount of vehicle to dissolve using a magnetic stirrer, and then the vehicle was gradually added to yield the desired concentrations. The dosing formulations were stored in a refrigerator (4.3–5.9°C). These dosing formulations were used within 7 days.
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 well dissolved in it.
- Amount of vehicle: 5 mL/kg bw
- Lot/batch no.: MKBV2080V, MKBW9504V - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: All females were examined for the presence of vaginal plug or sperm in the vaginal smear twice a day (AM and PM) for the confirmation of mating. The day of positive confirmation was defined as Gestation Day 0. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses of the dosing formulations were conducted using gas chromatography and samples were taken three times from the middle of each dosing formulation prior to dosing and analyzed for verification of dose level concentration. The results of dose concentration analyses were determined to be 98.75 - 102.10%. These results were within the acceptable limits (± 15% of nominal values). As a result of homogeneity and stability analyses conducted the 0.2 and 200 mg/mL dosing solutions were confirmed to be homogenous and stable for 4 h at room temperature and for 7 days under refrigeration.
- Duration of treatment / exposure:
- Main groups:
males: for 50 days, starting 2 weeks before mating, during 2 weeks of mating and 22 days after mating
females: for 2 weeks prior to mating, throughout gestation and for 13 days after delivery
Recovery groups:
Males and females of recovery groups were dosed once daily for 50 days. Animals were not mated and were assigned to 2 weeks of recovery period after the completion of administration. - Frequency of treatment:
- once daily, 7 days/week
- Details on study schedule:
- not applicable for an OECD 422 study
- Dose / conc.:
- 60 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 600 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 12 (main groups)
6 (recovery groups; for control and high dose groups) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: In previously conducted 2-week repeated oral dose range-finding study, salivation or soiled perineal region was observed in one male and/or one female at 800 mg/kg bw/day. And increases of the absolute and relative liver weights were noted in both sexes at 800 mg/kg bw/day. Therefore, the high dose level was selected at 600 mg/kg bw/day. Then, the mid and low dose levels were selected at 200 and 60 mg/kg bw/day, respectively.
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily mortality/viability
- Cage side observations included: All animals were observed for general condition and clinical signs at least once daily throughout the study. Females were also observed for signs of abortion and pre-mature birth.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed physical examinations for signs and symptoms of adverse effects, including central and autonomic nervous system effects, motor activity and behavior, were conducted on all animals once before the test and once a week throughout the dosing and recovery periods.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights of males of the main groups and animals of both sexes of the recovery groups were recorded just prior to dosing on Day 1, once a week throughout the dosing and recovery periods, the day prior to necropsy and on the day of necropsy (fasted body weights). Body weights of females of the main groups were recorded just prior to dosing on Day 1 (the first day of dosing), once a week throughout the dosing period, on Gestation Days 0, 7, 14 and 20, on Day 0, 4 and 13 postpartum and on the day of necropsy (fasted body weights). Fasted body weights recorded on the day of necropsy were presented, but were not included in the statistical analysis.
FOOD CONSUMPTION: Yes
- Food consumption of males of the main groups and animals of both sexes of the recovery groups was recorded just prior to dosing on Day 0 (one day before first dosing), once a week during the dosing and recovery periods (except during mating) and the day prior to necropsy. Food consumption of females of the main groups was recorded just prior to dosing on Day 0 (one day before first dosing), once a week throughout the dosing period (except during mating), on Days 0, 6, 13 and 19 of gestation, on Days 0, 3 and 12 postpartum and the day prior to necropsy. Residual feed was recorded on the next day. Food consumption was not recorded during mating.
WATER CONSUMPTION: No
OTHER:
- Thyroid hormone analysis: Serum samples for immunoassay analysation of total thyroxine (T4) were taken from all adult males of the main group at termination and on postnatal Day 13 from at least two pubs per litter analyzed for total thyroxine (T4). Animals were fasted for more than 18 hours before necropsy and anesthetized with isoflurane. Blood samples were collected from the abdominal aorta in a vacutainer.
Haematology, clinical chemistry, urinalysis, neurobehavioural examination (for details refer to IUCLID section 7.5.1 Repeated dose toxicity: oral) - Oestrous cyclicity (parental animals):
- Observations of the estrous cycle for females of the main groups were conducted from dosing initiation day to confirmed copulation day and necropsy day. Smears of vaginal mucosa were prepared in the morning daily. Prepared smears of the vaginal mucosa were stained with Diff Quick stain (Hemacolor® for microscopy, Merck, Germany). Stained vaginal mucosa smears were examined using light microscopy. The estrous cycle is divided into four stages; proestrus, estrus, metestrus and diestrus. One estrous cycle is defined as the period between the day of estrus and the day prior to next estrus. Estrous cycle was calculated from dosing initiation day to the day before mating initiation.
- Sperm parameters (parental animals):
- Parameters examined in male parental generations: testis weight, epididymis weight, histopathological examinations with focus on spermatogenesis
- Litter observations:
- STANDARDISATION OF LITTERS
Four male and four female pups were randomly selected from each litter on PND 4 for culling. Extra pups were euthanized by hypothermia method. Litters of 8 pups or less were not culled. When litters contained less than four pups of one sex, pups of the opposite sex were added to be a total of 8 pups.
PARAMETERS EXAMINED
The following parameters were examined in offspring: number and sex of pups, live births, postnatal mortality, presence of gross anomalies, weight gain, anogenital distance (AGD), presence of nipples in male pups
GROSS EXAMINATION OF DEAD PUPS: no - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: Animals of the main group were sacrificed on Day 51.
- Maternal animals: Animals of the main groups were sacrificed on Day 14 postpartum.
All animals of the recovery groups were sacrificed two weeks after final dosing.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations. All grossly visible abnormalities were recorded.
The uterine implantation sites were counted at necropsy.
HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weights
Paired organs were weighed together. Animals were fasted overnight prior to necropsy and body weights were recorded on the day of necropsy. Organs were weighed and organ-to-body weight ratios were calculated. The testes and epididymides of all adult males were weighed. 6 males and 6 females were randomly selected from the main study animals in addition to all recovery animals for necropsy. Following organs were weighed: brain, heart, liver, thymus, spleen, thyroid (weight after fixation), kidneys, adrenals, ovaries, uterus
Histopathology
Tissue preservation and slide preservation
6 males and 6 females were randomly selected from the main groups in addition to all recovery animals for tissue preparation. The testes, epididymides and eyes with optic nerves were fixed in Davidson´s fixative. All other tissues were preserved in 10% neutral buffered formalin.
For histopathological examination, the preparation of specimens of the following organs and tissues was carried out (remaining organs and tissues were preserved in 10% neutral buffered formalin): brain, pituitary, thymus, lung with bronchi, trachea, thyroid, esophagus, heart, liver, spleen, kidneys, adrenals, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, testes, epididymides, prostate, seminal vesicles with coagulatins glands, ovaries, uterus and cervix, vagina, submandibular lymph node, mesenteric lymph node, bone marrow (femur and sternum), spinal cord, sciatic nerve, eyes and optic nerves, urinary bladder, organs with gross lesions
Besides, from all animals except for six females and males in the main group, the following organs and tissues were harvested and preserved: brain, pituitary, heart, thymus, thyroid, liver, spleen, kidneys, adrenals, prostate, testes, epididymides, ovaries, uterus and cervix, vagina
Histopathological examinations were conducted as follows:
- 6 males and females from the control, low, mid and high dose group (especially, focused on spermatogenesis and interstitial testicular cell structure)
- All tissues from animals found dead or killed in a moribund condition
- All gross, macroscopic lesions
- Target organs noted at the high dose were examined for the recovery group (liver and stomach) - Postmortem examinations (offspring):
- GROSS NECROPSY
- Gross necropsy consisted of external examinations.
HISTOPATHOLOGY / ORGAN WEIGTHS
not performed - Statistics:
- The statistical analysis of this study was conducted using the SAS program (SAS® 9.3, SAS Institute Inc., U.S.A.). For the data including body weights, food consumption, estrous cycle, mating period, gestation period, post-implantation loss, body weights and birth and survival rates of pups, AGD index, nipple number, thyroid hormone value, urine volume, hematology and clinical chemistry parameters, organ weights, sensory function and motor activity, the Bartlett test was conducted to test for homogeneity of variance (significance level: 0.05). One-way analysis of variance (ANOVA) test was employed on homogeneous data, then if significant (significance level: 0.05), followed by Dunnett’s test for multiple comparisons (significance levels: 0.05 and 0.01, two-tailed). Kruskal-Wallis test was employed on heterogeneous data, then if significant (significance level: 0.05), Steel’s test was performed for multiple comparisons (significance levels: 0.05 and 0.01, two-tailed). The data of mating index, fertility index and other data associated with gestation were analyzed utilizing Fisher’s exact test (significance levels: 0.05 and 0.01). For the data of recovery groups, Folded-F test was employed to test homogeneity of variance (significance level: 0.05, two-tailed). Student t-test was employed for homogeneity, but if overruled, Aspin-Welch t-test was applied (significance levels: 0.05 and 0.01, two-tailed).
- Reproductive indices:
- Mating index (%) = (number of females with confirmed mating / number of females placed with males) x 100
Mating period = Day of confirmed mating - Day of initial mating (based on dosing day)
Gestation period = Day 0 post partum - Day 0 of gestation (based on dosing day)
Male fertility index (%) = (number of males impregnating a female / number of males with confirmed mating) x 100
Female fertility index (%) = (number of pregnant females / number of females with confirmed mating) x 100
Gestation index (%) = (number of females with live pups / number of pregnant females) x 100
Post-implantation loss (%) = [(number of implantations - number of live pups) / number of implantations] x 100 - Offspring viability indices:
- Live birth index (%) = (number of live pups on postnatal day 0 / number of implantations) x 100
Viability index on postnatal day 0 (%) = (number of pups born alive on postnatal day 0 / total number of pups born) x 100
Viability index on postnatal day 4 (%) = (number of pups surviving on postnatal day 4 / number of pups born alive on postnatal day 0) x 100 - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In animals of the main groups, salivation was observed in 3 males from Day 21 and in 2 females from Day 3 - 20 of gestation. However, salivation was considered to have little toxicological significance since it was caused by physicochemical characteristics.
In the main group, two dams of the 60 mg/kg/day group were found in a moribund state on Day 7 postpartum after soiled perineal region, reddish tear and inanimation were observed. However, these moribund dams were considered to be incidental because there was no dose-dependency.
At Week 6 (after parturition), one female showed a reduced grooming. This animal was found in a moribund state a few days after the examination.
In the recovery groups, no clinical signs were observed in males and females. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- A total of 2 females in the 60 mg/kg bw/day group were sacrificed in a moribund state on Day 7 postpartum. In the main and recovery groups, all other animals survived the duration of the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test substance-related effects on the body weight changes were noted in both sexes at 60, 200 and 600 mg/kg bw/day in the main and recovery groups.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- A statistically significant increase in food consumption was noted in females at 200 mg/kg bw/day in the main group on Day 13 postpartum. However, this statistical significance was not considered to be a test substance-related change since it was not related to the body weight changes.
Two moribund dams showed very low food consumption after parturition. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No adverse effects were observed in any animal in the main and recovery groups. Other statistical significances were considered not to be test substance-related changes because they were small magnitude and the values were within the range of historical reference data.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No adverse effects were observed in any animal in the main and recovery groups. Other statistical significances were considered not to be test substance-related changes because they were small magnitude and the values were within the range of historical reference data.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- In males of the main and recovery groups, no effects were noted in the test substance dose groups.
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- No test substance-related effects on auditory reflex, pinna reflex, pupillary reflex and corneal reflex were observed in animals of both sexes in the main and recovery groups when compared to the control group.
In the main groups, there were no test substance-related effects in the grip strength test on both sexes when compared to the control group. In spontaneous motor activity, a statistically significant decrease in vertical count was noted in males at 60 and 200 mg/kg bw/day. However, this statistical significance was not considered to be a test substance-related change because it was small magnitude and there was no dose dependency.
In the recovery groups, there were no test substance-related effects in the grip strength test on both sexes when compared to the control group. In spontaneous motor activity, a statistically significant decreased in ambulatory count was noted in males at 600 mg/kg bw/day. However, this change had little toxicological meaning because the total count did not show a significant change. - Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- In one moribund dam in the 60 mg/kg bw/day group, the irregular surface of the kidney corresponded to microscopically observed tubular degeneration at moderate severity. The dark-brown discoloration of the kidney in the other dam corresponded to orange-colored cast at moderate severity in the tubular lumen and tubular degeneration at severe severity. Small spleen and thymus were in concordance with atrophy at moderate/severe severity.
Orange-colored cast in the renal tubules is generally indicative of hemoglobin cast. This finding might imply hemolysis along with increased pigmentation in the spleen. The renal findings including tubular degeneration could affect the moribund state of the dams.
However, the administration of the test substance was not considered to contribute to the moribund condition since the renal findings were observed in the 60 mg/kg bw/day group only. As the dams showed poor condition/stress-related observations (correlated with microscopically observed adrenal cortical hypertrophy, lymphoid atrophy in the spleen, thymus and lymph nodes) after delivery, exacerbated condition with the renal findings in dams could be attributed to uncertain complications of labor/delivery. All microscopic findings seen in other organs and tissues were considered to be incidental and of no toxicological significance
In surviving animals the liver showed a centrilobular hypertrophy of hepatocytes in both sexes at 200 and 600 mg/kg/day. All animals of the 600 mg/kg bw/day group recovered at the end of the 2-week recovery period. Centrilobular hepatocellular hypertrophy was regarded as adaptive response to the test substance and it was considered not to be harmful to the animals since it was not accompanied with inflammation, degeneration or necrosis. All other microscopic findings seen in various organs and tissues were considered to be spontaneous or incidental, and to be unrelated to the test substance. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- Thyroid hormone analysis:
There were no adverse effects in total thyroxine (T4) level in F0 males at 60, 200 and 600 mg/kg bw/day. - Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- The estrus cycle lengths (day) of females in the 0, 60, 200 and 600 mg/kg bw/day dosing groups were 4.1, 4.0, 4.1 and 4.0 days, respectively. There was no statistically significant difference in any dose group.
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- In the control and 60, 200 and 600 mg/kg bw/day dose groups, the mating periods were 1.8, 2.9, 1.7 and 2.6 days, and the gestation periods were 22.3, 22.2, 22.3 and 22.4 days, respectively. The mating index was 100% and the fertility index of animals of both sexes was 100% in all groups. There was no statistically significant difference in any dose group. Post-implantation loss rates were 11.3, 3.2, 9.0 and 7.5% at 0, 60, 200 and 600 mg/kg bw/day, respectively. Gestation index was 100%.
- Dose descriptor:
- NOAEL
- Effect level:
- >= 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects on parental fertility up to and including the highest dose tested
- Clinical signs:
- not examined
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in body weights of pups at 60, 200 and 600 mg/kg bw/day.
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no test substance-related changes in external findings in pups at 60, 200 and 600 mg/kg bw/day.
- Histopathological findings:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - Anogenital distance (AGD) index: There were no test substance-related changes in AGD index of male pups and female pups at 60, 200 and 600 mg/kg bw/day.
- Nipple retention time: The nipple number was 0 in male pups at 60, 200 and 600 mg/kg bw/day on PND 12. There was no nipple retention in male pups at 60, 200 and 600 mg/kg bw/day on PND 12.
VIABILITY (F1):
Live birth indices at 0, 60, 200 and 600 mg/kg bw/day were 88.7, 96.8, 90.5 and 91.3%, respectively.
Mean litter sizes at 0, 60, 200 and 600 mg/kg bw/day were 12.9, 14.5, 13.4 and 12.3, respectively.
Viability indices at 0, 60, 200 and 600 mg/kg bw/day were 99.4, 99.0, 99.4 and 97.5% on postnatal Day 0 and 98.9, 82.1, 97.9 and 99.3% on postnatal Day 4, respectively.
Thyroid homone analysis:
There were no adverse effects in total thyroxine (T4) level in F1 pups of PND 13 at 60, 200 and 600 mg/kg bw/day.
Other statistical significance was considered not to be test substance-related change because of small magnitude and the values were within the range of historical reference data. - Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects on development of offspring up to and including the highest dose tested
- Critical effects observed:
- no
- Reproductive effects observed:
- no
- Conclusions:
- Based on the results of this study, the NOAEL for reproductive toxicity was ≥ 600 mg/kg bw/day, the highest dose tested. No adverse effects on development of offspring were observed up to and including 600 mg/kg bw/day, the highest dose tested.
- Executive summary:
The test substance was tested in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening study according to OECD Guideline 422 and in compliance with GLP (2017). Based on data of a range-finding study twelve Sprague Dawley rats per sex and dose were treated via gavage with test substance at doses of 60, 200 and 600 mg/kg bw/day, respectively. The control group received the vehicle corn oil. Additionally, a recovery group of 6 rats per sex was allocated to the control and high dose group. Males were treated for 50 days, starting 2 weeks before the mating period, during 2-week mating period and 22 days after mating. Females were treated for 2 weeks prior to mating, throughout gestation and for 13 days after delivery up to the day before the scheduled terminal necropsy.
In parental animals, no effects on reproductive function (spermatogenesis) or performance (mating period, mating index, gestation period, male and female fertility indexes, gestation index, pre- and post-implantation loss rates, live birth index, mean litter size) were observed, compared with the control group. No test substance-related findings were observed on reproductive organs in males and females at any dose group.
Therefore, a NOAEL for reproductive toxicity of≥600 mg/kg bw/day was derived for male and female parental rats.
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 600 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The test substance was tested in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening study according to OECD Guideline 422 and in compliance with GLP (2017). Based on data of a range-finding study twelve Sprague Dawley rats per sex and dose were treated via gavage with test substance at doses of 60, 200 and 600 mg/kg bw/day, respectively. The control group received the vehicle corn oil. Additionally, a recovery group of 6 rats per sex was allocated to the control and high dose group. Males were treated for 50 days, starting 2 weeks before the mating period, during 2-week mating period and 22 days after mating. Females were treated for 2 weeks prior to mating, throughout gestation and for 13 days after delivery up to the day before the scheduled terminal necropsy.
In parental animals, no effects on reproductive function (spermatogenesis) or performance (mating period, mating index, gestation period, male and female fertility indexes, gestation index, pre- and post-implantation loss rates, live birth index, mean litter size) were observed, compared with the control group. No test substance-related findings were observed on reproductive organs in males and females at any dose group.
Therefore, a NOAEL for reproductive toxicity of ≥ 600 mg/kg bw/day was derived for male and female parental rats.
Effects on developmental toxicity
Description of key information
Oral (OECD 422), rat: NOAEL developmental ≥ 600 mg/kg bw/day
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 600 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7, of Regulation (EC) No 1907/2006.
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 test substance was tested in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening study according to OECD Guideline 422 and in compliance with GLP (2017). Based on data of a range-finding study twelve Sprague Dawley rats per sex and dose were treated via gavage with test substance at concentrations of 60, 200 and 600 mg/kg bw/day, respectively. The control group received the vehicle corn oil. Additionally, a recovery group of 6 rats per sex was allocated to the control and high dose group. Males were treated for 50 days, starting 2 weeks before the mating period, during 2-week mating period and 22 days after mating. Females were treated for 2 weeks prior to mating, throughout gestation and for 13 days after delivery up to the day before the scheduled terminal necropsy.
There were no adverse effects on pup development (including the number of dead and living pups, postnatal loss, live birth index and sex ratio, body weight) with treatment up to 600 mg/kg bw/day. Furthermore, external macroscopic examination did not reveal treatment-related findings.
Therefore, a NOAEL for developmental toxicity of ≥ 600 mg/kg bw/day was derived.
Justification for classification or non-classification
The available data on toxicity to reproduction of the test substance do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for 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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