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EC number: 217-126-9 | CAS number: 1746-23-2
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- In-life phase: 07 June 2017 to 01 August 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- In-life phase: 07 June 2017 to 01 August 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)
- GLP compliance:
- yes (incl. QA statement)
- Specific details on test material used for the study:
- Lot/Batch no.: 122016TBSSV
Purity: 95.9% - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age at first dose: 11-12 weeks
Weight at first dose: Males-390-465 g and Females-239.1-292.6 g
Animals were acclimated to laboratory conditions for at least five days prior to the first dose and released from acclimation by a staff veterinarian. During that time, animals were identified by a temporary number that was recorded on each cage label.
Feed: Certified Global Teklad Laboratory Diet 2018 (pellets) was provided ad libitum.
Water: Filtered water was provided ad libitum via an automatic watering system supplemented with water bottles as needed.
Housing: Animals were housed in one room in polycarbonate cages suspended on stainless steel racks. Each cage was affixed with a cage card containing pertinent animal and study information.
Temperature: 20 to 26°C
Humidity: 30-70%
Light-dark cycle: 12-hour light/12-hour dark
Air changes: Minimum of 10 air changes per hour - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on exposure:
- The vehicle/control substance was considered 100% pure for formulation purposes. The test substance was used as received and formulated with no adjustments. The vehicle/control substance, peanut oil, was used as received; no formulations were necessary. Formulations for Groups 2 (5 mg/mL/10 mg/kg bw/day), 3, (15 mg/mL/30 mg/kg bw/day) 4 (30 mg/mL/60 mg/kg bw/day) and 5 (50 mg/mL/100 mg/kg bw/day) were prepared weekly by adding the appropriate amount of the control test substance to the required amount of vehicle/control substance and mixinged until visually uniform. Formulations were stored in a refrigerator (2-8 degree Celsius) until used for dosing.
- Details on mating procedure:
- Animals were individually housed prior to cohabitation and after confirmation of mating. During cohabitation, one male and one female from the same group were housed together. After at least 14 days of vaginal lavage and dosing, one female from each group was cohabited with one male from the corresponding group (1:1). Females assigned to 60 mg/kg bw/day were cohabitated with males assigned to 100 mg/kg bw/day group. The females were tested daily by vaginal lavage beginning on the day following cohabitation. The animals were separated when mating was confirmed, or after 14 days, and observed as indicated above. Day 0 of pregnancy (gestational day (GD) 0) was defined as the day on which mating evidence is was confirmed (vaginal plug or presence of sperm). The stage of estrus was determined in each female for at least 14 days prior to randomization, 14 days prior to cohabitation and during cohabitation until evidence of mating, or 14 days of cohabitation, whichever occurred first.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability analysis of the dose formulations was performed as part of the method validation. Samples were analyzed for test substance concentration using a validated method. Since all dose formulations were solutions; therefore, homogeneity analysis was not required.
- Duration of treatment / exposure:
- The animals were dosed via oral gavage at a volume of 2 mL/kg bw. Dosing volumes were based on the most recent body weights. F0 males were dosed for at least 28 days. The F0 females were dosed for two weeks prior to cohabitation, during cohabitation, through gestation, and to at least Postnatal Day (PND) 12. The first day of dosing was designated as Day 1 for each animal.
- Frequency of treatment:
- Once daily
- Details on study schedule:
- F0 males were dosed for at least 28 days. The F0 Females were dosed for two weeks prior to cohabitation, during cohabitation, through gestation, and to at least postnatal day (PND) 12. The first day of dosing was designated as SD1 for each animal.
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Remarks:
- for females only
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- for males only
- Parental animals: Observations and examinations:
- Post dosing, F0 males and females were examined regularly for mortality, moribundity, general health, body weight, food consumption and signs of toxicity. Physical examinations included evaluations of skin and fur characteristics, eye and mucous membranes, respiratory, circulatory, autonomic, and central nervous systems, and somatomotor and behavior patterns. Prior to scheduled necropsy, routine hematological, clinical chemistry and hormonal analysis were done.
- Oestrous cyclicity (parental animals):
- The stage of estrus was determined in each female for at least 14 days prior to randomization, 14 days prior to cohabitation and during cohabitation until evidence of mating, or 14 days of cohabitation, whichever occurred first.
- Litter observations:
- Following delivery, the F1 generation pups were observed for litter size, sex, weight, anogenital distance and nipple retention (in male pups) and clinical signs. On PND 4 and 13 9before scheduled necropsy), blood samples were collected, pooled and analysed for hormone levels.
- Postmortem examinations (parental animals):
- Gross necropsy of F0 animals included examination of the external surface of the body, all orifices, and the cranial, thoracic, and abdominal cavities and their contents. For all F0 females, the number of implantation sites was recorded. All reproductive organs (testes, epididymides, prostate, seminal vesicles with coagulating glands, ovaries, uterus with cervix; sex appropriate) and thyroids from all F0 animals were collected and weighed as soon as possible after dissection; paired organs were weighed together.
Histopathological examination of tissues from the selected animals in the control and high dose group revealed test substance-related changes in the bone marrow (femur) of females only, the pancreas, thyroid and thymus in males only, and the kidney and liver in both sexes. Therefore, the following tissues from selected animals in 10 mg/kg bw/day and 30 mg/kg bw/day were processed to slides and examined microscopically: bone marrow (femur, females only, 5/group); pancreas, thyroid, and thymus (males only, 5/group); kidney and liver (both sexes, 5/sex/group). - Postmortem examinations (offspring):
- All pups, except those assigned to blood collection, were examined externally for gross abnormalities.
- Statistics:
- See under "any other information on materials and methods incl. tables"
- Clinical signs:
- effects observed, treatment-related
- Dermal irritation (if dermal study):
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Reproductive performance:
- effects observed, treatment-related
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- gross pathology
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- clinical biochemistry
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reproductive function (sperm measures)
- reproductive performance
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw/day (nominal)
- System:
- male reproductive system
- Organ:
- seminal vesicle
- testes
- Treatment related:
- yes
- Dose response relationship:
- yes
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw/day (nominal)
- Organ:
- kidney
- liver
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- 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:
- no effects observed
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Anogenital distance (AGD):
- no effects observed
- Nipple retention in male pups:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- not specified
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- body weight and weight gain
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw/day (nominal)
- System:
- other: general systemic toxicity
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 10 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:
- yes
- Conclusions:
- Under the study conditions, the LOAEL for systemic toxicity in parental male ratss was determined to be 10 mg/kg bw/day (due to microscopic findings in thyroid). The NOAEL for systemic toxicity in female rats was considered to be 10 mg/kg bw/day due to adverse body weight changes, clinical chemistry, organ weight and microscopic findings. The NOAEL for reproductive toxicity in both male and female rats was determined to be 10 mg/kg bw/day dose. The NOAEL for fetal developmental toxicity was determined to be 10 mg/kg bw/day.
- Executive summary:
A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed in rats according to OECD Guideline 422, in compiance with GLP. Male rats were administered the test substance at doses of 0, 10, 30 or 100 mg/kg bw/day for 14 d prior to cohabitation and during cohabitation for at least a total of 28 d. Female rats were dosed with the test substance at doses of 0, 10, 30 or 60 mg/kg bw/day prior to cohabitation, during cohabitation, through pregnancy, and throughout lactation to Postnatal Day 13 (PND 13). Treatment-related effects in male rats included a significant effect on the body weight, body weight changes, organ weights, and microscopic findings. For female rats, repeat dose toxicity was observed at doses of 30 and 60 mg/kg bw/day primarily due to reduced body weight and microscopic findings in liver, kidney and thyroid. Important microscopic findings consisted of cytoplasmic alteration in hepatocytes at doses greater than 30 mg/kg bw/day in both sexes, thyroid follicular cell hypertrophy in males from 10 mg/kg bw/day and vacuolation of distal tubules in the kidney in males and females at the respective high doses. The test substance induced reproductive toxicity at doses of 30, 60 (females only) and 100 (males only) mg/kg bw/day. Treatment-related degeneration/atrophy of seminiferous tubules in all high dose males resulted in complete loss of fertility at this dose. Although degeneration of spermatids was only identified in one animal administered 30 mg/kg bw/day, this change was associated with decreased fertility and fecundity; therefore, testicular changes were adverse at or above 30 mg/kg bw/day. Decreases in testes and epididymal weight correlated with these changes in the high dose males. In females at 60 mg/kg bw/day, no viable pregnancy was observed and pups could not be evaluated. This was likely due to the effect on spermatogenesis, as there was evidence of copulation and normal estrus cyclicity at the time of cohabitation. The copulation index, fertility index and pregnancy rate are significantly and dose-dependently reduced due to the treatment-related effects in males. The test substance also induced developmental toxicity at 30 mg/kg bw/day evidenced by growth inhibition and reduced litter size without any indication of induced specific malformations. Therefore, the reduced pup growth and litter size could potentially be due to maternal and/or paternal toxicity rather than direct impairment of development in utero, but the potential for association between the treatment and direct impairment of in utero development cannot be ruled out based upon the results of this study. The dose group of 60 mg/kg bw/day could not be evaluated for developmental toxicity due to dams not producing any litters. Under the study conditions, the LOAEL for systemic toxicity in parental male rats was determined to be 10 mg/kg bw/day (due to microscopic findings in thyroid). The NOAEL for systemic toxicity in female rats was considered to be 10 mg/kg bw/day due to adverse body weight changes, clinical chemistry, organ weight and microscopic findings. The NOAEL for reproductive toxicity in both male and female rats was determined to be 10 mg/kg bw/day dose. The NOAEL for fetal developmental toxicity was determined to be 10 mg/kg bw/day (Murphy, 2019b).
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- p-tert-butylstyrene
- EC Number:
- 217-126-9
- EC Name:
- p-tert-butylstyrene
- Cas Number:
- 1746-23-2
- Molecular formula:
- C12H16
- IUPAC Name:
- p-tert-butylstyrene
- Test material form:
- liquid: volatile
1
- Specific details on test material used for the study:
- Lot/Batch no.: 122016TBSSV
Purity: 95.9%
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age at first dose: 11-12 weeks
Weight at first dose: Males-390-465 g and Females-239.1-292.6 g
Animals were acclimated to laboratory conditions for at least five days prior to the first dose and released from acclimation by a staff veterinarian. During that time, animals were identified by a temp
orary number that was recorded on each cage label.
Feed: Certified Global Teklad Laboratory Diet 2018 (pellets) was provided ad libitum.
Water: Filtered water was provided ad libitum via an automatic watering system supplemented with water bottles as needed.
Housing: Animals were housed in one room in polycarbonate cages suspended on stainless steel racks. Each cage was affixed with a cage card containing pertinent animal and study information.
Temperature: 20 to 26°C
Humidity: 30-70%
Light-dark cycle: 12-hour light/12-hour dark
Air changes: Minimum of 10 air changes per hour
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- The vehicle/control substance was considered 100% pure for formulation purposes. The test substance was used as received and formulated with no adjustments. The vehicle/control substance,
peanut oil, was used as received; no formulations were necessary. Formulations for Groups 2 (5 mg/mL/10 mg/kg bw/day), 3, (15 mg/mL/30 mg/kg bw/day) 4 (30 mg/mL/60 mg/kg bw/day) and 5 (50 mg/mL/100 mg/kg bw/day) were prepared weekly by adding the appropriate amount of the control test substance to the required amount of vehicle/control substance and mixinged until visually uniform. Formulations were stored in a refrigerator (2-8 degree Celsius) until used for dosing. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Stability analysis of the dose formulations was performed as part of the method validation. Samples were analyzed for test substance concentration using a validated method. Since all dose formulations were solutions; therefore, homogeneity analysis was not required.
- Duration of treatment / exposure:
- The animals were dosed via oral gavage at a volume of 2 mL/kg bw. Dosing volumes were based on the most recent body weights. F0 males were dosed for at least 28 days. The F0 females were dosed for two weeks prior to cohabitation, during cohabitation, through gestation, and to at least Postnatal Day (PND) 12. The first day of dosing was designated as Day 1 for each animal.
- Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Remarks:
- for females only
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- for males only
- No. of animals per sex per dose:
- 12 rats per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- F0 males were dosed for at least 28 days. The F0 Females were dosed for two weeks prior to cohabitation, during cohabitation, through gestation, and to at least postnatal day (PND) 12. The first
day of dosing was designated as SD1 for each animal.
Examinations
- Observations and examinations performed and frequency:
- Post dosing, F0 males and females were examined regularly for mortality, moribundity, general health, body weight, food consumption and signs of toxicity. Physical examinations included evaluations of skin and fur characteristics, eye and mucous membranes, respiratory, circulatory, autonomic, and central nervous systems, and somatomotor and behavior patterns. Prior to scheduled necropsy, routine hematological, clinical chemistry and hormonal analysis were done.
- Sacrifice and pathology:
- Gross necropsy of F0 animals included examination of the external surface of the body, all orifices, and the cranial, thoracic, and abdominal cavities and their contents. For all F0 females, the number of implantation sites was recorded. All reproductive organs (testes, epididymides, prostate, seminal vesicles with coagulating glands, ovaries, uterus with cervix; sex appropriate) and thyroids from all F0 animals were collected and weighed as soon as possible after dissection; paired organs were weighed together.
Histopathological examination of tissues from the selected animals in the control and high dose group revealed test substance-related changes in the bone marrow (femur) of females only, the pancreas, thyroid and thymus in males only, and the kidney and liver in both sexes. Therefore, the following tissues from selected animals in 10 mg/kg bw/day and 30 mg/kg bw/day were processed to slides and examined microscopically: bone marrow (femur, females only, 5/group); pancreas, thyroid, and thymus (males only, 5/group); kidney and liver (both sexes, 5/sex/group). - Statistics:
- See under "any other information on materials and methods incl. tables"
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- gross pathology
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- gross pathology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 10 mg/kg bw/day (nominal)
- System:
- male reproductive system
- Organ:
- kidney
- liver
- seminal vesicle
- seminiferous tubules
- testes
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
Applicant's summary and conclusion
- Conclusions:
- Under the study conditions, no NOAEL could be determined and the LOAEL for systemic toxicity in parental male rats was determined to be 10 mg/kg bw/day (due to lesions in thyroid at this dose). The NOAEL for systemic toxicity in parental female rats was considered to be 10 mg/kg bw/day due to adverse body weight changes, clinical chemistry, organ weight and microscopic findings in liver, kidney and thyroid.
- Executive summary:
A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed in rats according to OECD Guideline 422, in compliance with GLP. Male rats were administered the test substance at doses of 0, 10, 30 or 100 mg/kg bw/day for 14 d prior to cohabitation and during cohabitation for at least a total of 28 d. Female rats were dosed with the test substance at doses of 0, 10, 30 or 60 mg/kg bw/day prior to cohabitation, during cohabitation, through pregnancy, and throughout lactation to Postnatal Day 13 (PND 13). Treatment-related effects in male rats included a significant effect on the body weight, body weight changes, organ weights, and microscopic findings. In female rats, repeat dose toxicity was observed at doses of 30 and 60 mg/kg bw/day primarily due to reduced body weight and microscopic findings in liver, kidney and thyroid. Important microscopic findings consisted of cytoplasmic alteration in hepatocytes at doses greater than 30 mg/kg bw/day in both sexes, thyroid follicular cell hypertrophy in males from 10 mg/kg bw/day and vacuolation of distal tubules in the kidney in males and females at the respective high doses. The test substance induced reproductive toxicity at doses of 30, 60 (females only) and 100 (males only) mg/kg bw/day. Treatment-related degeneration/atrophy of seminiferous tubules in all high dose males resulted in complete loss of fertility at this dose. Although degeneration of spermatids was only identified in one animal administered 30 mg/kg bw/day, this change was associated with decreased fertility and fecundity; therefore, testicular changes were considered adverse at or above 30 mg/kg bw/day. Decreases in testes and epididymal weight correlated with these changes in the high dose males. Under the study conditions, no NOAEL could be determined and the LOAEL for systemic toxicity in parental male rats was determined to be 10 mg/kg bw/day (due to lesions in thyroid at this dose). The NOAEL for systemic toxicity in parental female rats was considered to be 10 mg/kg bw/day due to adverse body weight changes, clinical chemistry, organ weight and microscopic findings in liver, kidney and thyroid (Murphy, 2019b).
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.