Registration Dossier
Registration Dossier
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EC number: 701-246-8 | 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
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
No formal study assessing fertility is available for the substance or required under REACH when considering the available data.
Results from the 28 and 90 day repeated dose studies indicated no effects on reproductive organs in males or females showing effects on fertility due to this would be unlikely. The NOAEL for fertility effects has been set as the
As a reliable PNDT study is also available the requirement for an OECD 421 study has been waived under REACH Annex VIII, Column 2.
As no findings related to reproductive organs or developmental effects were noted in the available studies, the requirement for an EOGRTS has been waived under Annex IX, Column 1.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- the study does not need to be conducted because a pre-natal developmental toxicity study is available
- Endpoint:
- extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Referenceopen allclose all
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Reliable OECD 407 and 408 studies available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Effects on developmental toxicity
Description of key information
A reliable OECD 414 study is available conducted in rats via the oral route of exposure. Based on the results of this study the NOAEL was set as 1000 mg/kg/day (limit dose) for all endpoints.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Deutschland, Sulzfeld, Germany
- Age at study initiation: 10 to 14 weeks old
- Weight at study initiation: 177 to 260g
- Fasting period before study: No
- Housing: On arrival and following randomization females were housed individually in Macrolon plastic cages (MIII type, height 18 cm) containing appropriate bedding equipped with water bottles.
- Diet (e.g. ad libitum): Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures.
- Water (e.g. ad libitum): Municipal tap water was freely available to each animal via water bottles.
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were prepared at least weekly as a solution, filled out in daily portions and stored in the refrigerator. The dosing formulations were removed from the refrigerator and stirred at room temperature for at least 30 minutes before dosing and dosed within 24 hours after removal from the refrigerator. Test item dosing formulations were kept at room temperature until dosing. If practically possible, the dosing formulations and vehicle were continuously stirred until and during dosing. A factor of 0.935 was used to correct for the specific gravity of the test item.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil is a standard vehicle for toxicity studies and was deemed to be suitable for the test substance based on trial formulation and analytical work.
- Concentration in vehicle: 0, 25, 75 and 250 mg/mL.
- Amount of vehicle (if gavage): 4 mL/Kg - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis was based on the analytical method validated for the test item in vehicle.
Accuracy and homogeneity were determined for formulations prepared for use in Week 1. The chemical analyses were conducted as specified below. Samples and remaining formulation were stored in normal glassware causing the samples stored at room temperature to be exposed to normal laboratory light conditions.
Duplicate samples (approximately 510 or 670 mg), which were taken from the formulations using a pipette, were accurately weighed into volumetric flasks of 50 mL. For determination of accuracy, samples were taken at middle position (50% height) or at top, middle and bottom position (90%, 50% and 10% height). The samples taken at 90%, 50% and 10% height were also used for the determination of the homogeneity of the formulations. The volumetric flasks were filled up to the mark with tetrahydrofuran. When necessary, the solutions were further diluted with 1% corn oil in tetrahydrofuran to obtain concentrations within the calibration range.
Results:
Accuracy: In the Group 1 formulation, no test item was detected. The concentrations analyzed in the formulations of Group 2, Group 3 and Group 4 were in
agreement with target concentrations (i.e. mean accuracies between 90% and 110%).
Homogeniety:
The formulations of Group 2 and Group 4 were homogeneous (i.e. coefficient of variation ≤ 10%). - Details on mating procedure:
- - Impregnation procedure: Purchased timed pregnant from reputable supplier.
- Duration of treatment / exposure:
- The test item and vehicle were administered to the appropriate animals by once daily oral gavage 7 days a week from Day 6 to Day 20 post-coitum, inclusive.
- Frequency of treatment:
- Daily
- Duration of test:
- Day 6 to Day 20 post-coitum
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 22 females per group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on the results of the dose range finder, and in an attempt to produce graded responses to the test item. At 1000 mg/kg/day, no clinical signs were observed, and body weight (gain) and (relative) food consumption were comparable between groups and within the range of available historical control data.
- Rationale for animal assignment (if not random): Randomly assigned
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations: Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from the cage during observation, unless necessary for identification or confirmation of possible findings.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were performed at least once daily, beginning on Day 2 post-coitum and lasting up to the day prior to necropsy.
- Clinical observations: The time of onset, grade and duration of any observed sign was recorded. Signs were graded for severity and the maximum grade was predefined at 1, 2, 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (grade 1) or absence (grade 0) was scored. Cage debris was examined to detect any premature birth.
BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually on Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption was quantitatively measured for Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18 21 post-coitum.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes (qualitatively)
- Time schedule for examinations: Water consumption was monitored on regular basis throughout the study by visual inspection of the water bottles/containers.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21 post-coitum
- Organs examined: All animals were subjected to an external, thoracic and abdominal examination, with special attention being paid to the reproductive organs. All macroscopic abnormalities were recorded, collected and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution). The uterus and the thyroid were weighed and organ to bodyweight values calculated.
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- The number and distribution of live and dead fetuses: Yes
- The number and distribution of embryo-fetal deaths: Yes - Fetal examinations:
- - External examinations: Litters of females surviving to scheduled necropsy, were subjected to detailed external, visceral and skeletal examinations, as described in the following sections. External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).
- Soft tissue examinations: The sex of all fetuses was confirmed by internal examination and approximately one-half of the fetuses (live and dead) in each litter (all groups) were examined for visceral anomalies by dissection in the fresh (non-fixed) state. The thoracic and abdominal cavities were opened and dissected. This examination included the heart and major vessels. Fetal kidneys were examined and graded for renal papillae development. The heads were removed from this one-half of the fetuses in each litter and placed in Bouin's solution for soft-tissue examination. After examination, the tissues without variation or malformations were discarded. Tissues with variations or malformations were stored in 10% formalin. All carcasses, including the carcasses without heads, were eviscerated, labeled and fixed in 96% aqueous ethanol for subsequent examination of skeletons.
- Skeletal examinations: All eviscerated fetuses, following fixation in 96% aqueous ethanol, were macerated in potassium hydroxide and stained with Alizarin Red S. Subsequently, skeletal examination was done for one-half of the fetuses (i.e. the fetuses with heads). All specimens were archived in glycerin with bronopol as preservative. A few bones were not available for skeletal examination because they were accidentally damaged or lost during processing. The missing bones were listed in the raw data; evaluation by the fetal pathologist and Study Director determined there was no influence on the outcome of the individual or overall skeletal examinations, or on the integrity of the study as a whole.
- Fetal sex: The anogenital distance (AGD) was measured for all viable fetuses. The AGD was normalized to the cube root of the fetal body weight. - Statistics:
- Statistical analysis:
All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% or 5% levels. Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible.
Parametric: Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test).
Non-parametric: Datasets with at least 3 groups were compared using a Steel-test (many-to-one rank test). Mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss, and sex distribution were compared using the Mann Whitney test. Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the compound-treated groups to the control group.
Incidence: An overall Fisher’s exact test was used to compare all groups at the 5% significance level. The above pairwise comparisons were conducted using a two-sided Fisher’s exact test at the 5% significance level if the overall test was significant. No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and postimplantation loss. - Indices:
- Maternal variables:
Bodyweight gains: Calculated against the body weight on Day 6 post-coitum.
Corrected bodyweight gains: Body weight on Day 21 post-coitum minus the body weight on Day 6 post-coitum and the weight of gravid uterus.
Relative food consumption: Calculated against the body weight for scheduled intervals.
Organ weight relative to body weight: Calculated against the body weight on Day 21 post-coitum.
Reproductive and developmental indices:
Pre-implantation loss (%): (number of corpora lutea - number of implantation sites)/(number of corpora lutea) x 100
Postimplantation loss (%): (number of implantation sites - number of live fetuses)/(number of implantation sites) x 100
The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a mean litter proportion on a total group basis, where:
Viable fetuses affected/litter (%): (number of viable fetuses affected/litter)/(number of viable fetuses/litter) x 100 - Historical control data:
- Where required HCD has been included in the relevant results sections.
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Piloerection was observed for 1/22 females treated at 100 mg/kg/day, for 9/22 females at 300 mg/kg/day, and for 8/22 females at 1000 mg/kg/day. The only other clinical sign observed during the treatment period was alopecia. It occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg/day, body weight gain corrected for gravid uterus was statistically significantly higher (23% higher compared to concurrent controls).
At 1000 mg/kg/day, a trend towards a slightly higher body weight gain was observed on Day 21 post-coitum (1.11x of control, not statistically significant), after correction for gravid uterus this change was more pronounced, with mean body weight reaching 1.23x of control (statistical significant). All mean values for (corrected) body weight and corrected body weight gain remained within the range of available historical control data and are therefore not considered adverse.
HCD for pregnant Wistar Han rats (period 2015-2019):
Bodyweight Day 21 post coitum (g): mean = 325; P5 - P95 = 278 - 373 (n = 1315)
Corrected body weight gain (g): mean = 29; P5 - P95 = 14.9 - 44.2 (n = 1311)
Corrected body weight gain (%): mean = 13; P5 - P95 = 6.9 - 20.5 (n=1311) - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg/day, food consumption before or after correction for body weight was statistically significantly higher on Days 15-21 post-coitum (up to 15% higher compared to controls). This was likely in part due to slightly lower control means in comparison with the historical control data. As all mean values remained within the historical control range , no toxicological relevance was attributed to the observed increases in food consumption.
Historical control data for pregnant Wistar Han rats (period 2015-2019):
Food consumption (gram/animal/day):
Days 15-18 post coitum: mean = 23; P5 – P95 = 17.7 – 28 (n=1328)
Days 18-21 post coitum: mean = 23; P5 – P95 = 18.0 – 28 (n=1319)
Relative food consumption (gram/kg body weightl/day):
Days 15-18 post coitum: mean = 79; P5 – P95 = 64.9 – 94.9 (n=1328)
Days 18-21 post coitum: mean = 71; P5 – P95 = 58.1 – 85.4 (n=1313) - 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Increased serum levels of thyroid stimulating hormone (TSH) were noted at 300 and 1000 mg/kg/day (1.53x and 1.57x of controls, respectively). Values remained within the available historical control range.
Serum levels of triiodothyronine (T3) and total thyroxine (T4) were statistically significantly lower at 1000 mg/kg/day (0.75x and 0.84x of controls, for T3 and T4, respectively) and remained within the available historical control data for T4 values. The remaining serum levels were comparable to the concurrent control.
At 100 mg/kg/day, one female was not gravid and was therefore excluded from the data tables. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Test item-related higher thyroid gland weights (absolute and relative to body weights) were noted in the 1000 mg/kg/day group females. However, mean values remained well within the available historical control data .
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment with the test item. Findings that were noted among control and/or treated animals were considered to be of no toxicological significance, as they are occasionally seen among rats used in these types of study and/or remained within the range of biological variation for rats of this age and strain.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Test item-related microscopic findings were noted in the thyroid gland. Follicular cell hypertrophy was present in the thyroid gland at increased incidence in females treated at 300 mg/kg/day, and at increased incidence and severity (up to moderate) at 1000 mg/kg/day.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- Abortions are not a common feature in rats.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The numbers of pregnant females and implantation sites, and pre- and postimplantation loss in the control and test groups were similar and in the range of normal biological variation.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- not examined
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- not examined
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The male:female ratio was unaffected by treatment up to 1000 mg/kg/day.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- There were no test item-related effects on litter size of any group. Fetal weights (male, female and combined) were comparable to the controls for all treated groups.
At 300 mg/kg/day, the mean fetal weight of males was just above the 95-percentile of the historical control data (5.6 gram versus P5-P95 HCD: 5.2-5.5 gram). However, as this occurred at the mid dose only and the magnitude of change was only minimal, this was considered to be unrelated to treatment with the test item. - Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no test item-related effects on external morphology following treatment up to 1000 mg/kg/day.
One control fetus was observed with omphalocele. This was the only external malformation that occurred, and external variations were not seen in any group. - Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- There were no test item-related effects on skeletal morphology following treatment up to 1000 mg/kg/day.
Three fetuses at 100 mg/kg/day and one at 300 mg/kg/day were observed with bent limb bones. As this malformation occurred without dose relationship and is among historical control data, it was considered to be unrelated to treatment with the test item.
At 100 and 300 mg/kg/day, statistically significantly higher incidences of the variation bent ribs were observed compared to concurrent controls (3.6x of controls). Mean litter incidences were 6.4%, 23.3%, 23.3% and 15.4% per litter in the control, 100, 300 and 1000 mg/kg/day groups. Nevertheless, the higher incidences at the low and mid dose level were considered not to be test item-related as there was no dose relationship and incidences were within the historical control data range (1.9% – 27.6% per litter).
The other variations occurred in the absence of a dose-related incidence trend, infrequently and/or at frequencies that were within the range of available historical control data. Therefore, they were considered to be unrelated to treatment with the test item. - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- There were no test item-related effects on visceral morphology following treatment up to 1000 mg/kg/day.
At 300 mg/kg/day, cephalic examination revealed internal hydrocephaly in one fetus. As this occurred singly at the mid dose level, it was considered a chance finding.
The two visceral variations that were noted (small supernumerary liver lobes and convoluted ureter) occurred at low incidences and at frequencies that were within the range of available historical control data. Therefore, they were considered to be unrelated to treatment with the test item. - Other effects:
- not examined
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- In conclusion, based on the results of this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for the test substance was established as being at least 1000 mg/kg/day for all endpoints.
Reference
Time-mated female Wistar Han rats were treated with the test substance from Day 6 to Day 20 post-coitum, inclusive, by daily oral gavage at dose levels of 100, 300 and 1000 mg/kg/day. The rats of the control group received the vehicle, corn oil,
alone.
Test formulations prepared were considered homogeneous at the concentrations tested, and analysis of the accuracy revealed acceptable levels.
Piloerection was observed for 1/22 females treated at 100 mg/kg/day, 9/22 females at 300 mg/kg/day and 8/22 females at 1000 mg/kg/day. In the absence of a clear dose-related response and supportive changes indicative of a reduced clinical condition, this was considered not to represent an adverse effect of the test item.
At 1000 mg/kg/day, a trend towards a slightly higher body weight gain was observed on Day 21 post-coitum (not statistically significant), which was more pronounced after correction for gravid uterus (statistically significant). Similarly, food consumption before or after correction for body weight was statistically significantly higher on Days 15-21 post-coitum. As all values remained within the historical control range, the changes observed in body weights and food consumption were considered not of toxicologically relevance.
At 300 and 1000 mg/kg/day, test item-related morphologic alterations in the thyroid gland were present. Follicular cell hypertrophy was recorded at 300 mg/kg/day at an increased incidence, but the severity did not exceed the severity of control females. In addition, there were no macroscopic findings or organ weight changes in the thyroid gland at 300 mg/kg/day. At 1000 mg/kg/day, the follicular cell hypertrophy was recorded at both an increased incidence and increased severity compared to concurrent controls. As a result, also thyroid organ weight (absolute and relative to body weight) was increased. Furthermore, serum levels
of total triiodothyronine (T3) and total thyroxine (T4) were decreased at this high dose level and TSH was increased at 300 and 1000 mg/kg/day. However, mean values of thyroid organ weight, total T4 and TSH remained within historical control data ranges. Therefore, the observed changes in thyroid gland morphology and organ weight were considered to be non-adverse. In the 90-day study performed with this test item liver enzyme induction was reported. The relation to the thyroid findings in the present study could not be evaluated as the relevant investigations are outside the remit of the study design.
No test item-related changes were noted in any of the remaining maternal parameters investigated in this study (i.e. mortality/moribundity, uterine contents, corpora lutea, implantation sites, and pre- and postimplantation loss).
No test item-related changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, anogenital distance, and external, visceral and skeletal malformations and developmental variations).
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Reliable OECD 414 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
Justification for classification or non-classification
The substance has been tested in 28 and 90 day repeated dose studies alongside a rat PNDT study.
The repeated dose studies showed no effects to reproductive organs and the PNDT study showed no adverse effects to any parameters assessed. The NOAEL was set as the limit dose of 1000 mg/kg/day for all studies.
Based on the lack of effects observed the substance does not warrant classification in accordance with the CLP Regulation (EC No. 1272/2008, as adapted).
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.
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.