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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
Endpoint summary
Administrative data
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Effects on fertility
Link to relevant study records
- 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).
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 10 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
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
described adverse effects in available studies occure in presence of maternal toxicity as well
and are rated rather unspecific.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- In-life phase: 07 April 2018 to 27 April 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Specific details on test material used for the study:
- Lot/Batch no.: 111617TBSSV-2
Purity: 96.4% - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- Age at first dose: 8-9 weeks
Weight range at mating (GD 0): 180-210 g
Weight range at first dose: 197.9-245.9 g
Animals were acclimated to laboratory conditions for a minimum of 1 day 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.
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. Animals were individually housed.
Temperature: 20 to 26°C
Humidity: 30 to 70%
Light/Dark cycle:12-hour light/12-hour dark
Air changes: Minimum of 10 air changes per hour
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. - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on exposure:
- The formulations were placed at room temperature prior to dosing. The animals were dosed daily on GD 5 to 20 (day of confirmation of mating = GD 0) via oral gavage at a volume of 2.0 mL/kg. Dose volumes were based on the most recent body weights.
- 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. Test substance formulations were solutions; therefore, homogeneity sampling and analysis was not required. Samples from dose formulations prepared for week 1 and last week were analyzed for concentration verification using a validated method.
- Details on mating procedure:
- Time-mated female Sprague Dawley rats were received by the test facility.
- Duration of treatment / exposure:
- The animals were dosed daily on GD 5 to 20 (day of confirmation of mating = GD 0).
- Frequency of treatment:
- Daily once
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25 per dose group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Animals were initially accepted into the randomization pool based upon GD 0 body weights provided by the vendor. The suitability of the randomized animals was confirmed by physical examinations upon arrival. They were assigned to study groups using computer-generated random numbers such that the mean body weight for each group was not statistically different (p ≤ 0.05) from the control mean. Following randomization each study animal was assigned a unique number and identified by an ear tag.
- Maternal examinations:
- Cageside observations included observation for mortality, morbundity, general health, and signs of toxicity (only abnormal findings were recorded during the cageside observations). Physical examinations included evaluation of skin and fur characteristics, eye and mucous membranes, respiratory, circulatory, autonomic, and central nervous systems, and somatomotor and behavior patterns.
- Ovaries and uterine content:
- The abdominal cavity was opened, the uterus was excised, and the gravid uterine weight was recorded. Beginning at the distal end of the left uterine horn, the location of viable and nonviable fetuses, early and late resorptions for each uterine horn, and the number of total implantations were recorded. The number of corpora lutea on each ovary was also recorded. The embryonic membrane of each fetus was gently removed. The fetuses were removed from the uterus and the placentae were grossly examined. Each implant was categorized as viable, nonviable, late resorption, or early resorption. Uteri from females that appeared to be nongravid were opened and placed in 10% ammonium sulfide solution for detection of implantation sites. The foci, if detected, were considered early resorptions, and data from these females were not included in mean calculations and statistics. If no foci were seen, the female was considered to be non-pregnant and data from these females were also not included in mean calculations or statistics.
- Fetal examinations:
- All live fetuses were individually weighed, identified, sexed, and examined for external malformations and variations. Following completion of the external examination of all fetuses in the litter, each fetus was euthanized. Approximately one-half of the fetuses in each litter were examined viscerally by fresh tissue dissection. The sex of the fetus was recorded. The heads were examined by Wilson’s sectioning. The remaining fetuses had the internal sex recorded and then were eviscerated, preserved, stained with Alizarin Red S and Alcian Blue, and examined for skeletal abnormalities. Fetal findings were classified as malformations or developmental variations. All fetal malformations were photographed, digitally saved and archived with the study file.
Intact fetuses from dams that died within 24 h of scheduled euthanasia were evaluated to the extent possible for external malformations and variations and sexed. All other intact fetuses from females not surviving to scheduled euthanasia were examined externally to the fullest possible extent and discarded. - 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:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant reduction in gravid uetrine weight which corresponded to reduced body weights.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not specified
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- mortality
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: general systemic toxicity
- Fetal body weight changes:
- effects observed, treatment-related
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- not specified
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 20 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: Reduced body weight and reduction in body weight gain
- Description (incidence and severity):
- observed at all dose levels
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 20 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects in the absence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
- Conclusions:
- Under the study conditions, the NOAEL for maternal systemic toxicity was determined to be 20 mg/kg bw/day. No NOAEL for fetal developmental effects could be determined due to effects at all doses and therefore, the LOAEL for fetal developmental toxicity was considered to be 20 mg/kg bw/day.
- Executive summary:
A prenatal developmental toxicity study was conducted in Sprague Dawley rats according to OECD Guideline 414, in compliance with GLP. The test substance was administered to groups of 25 time-mated Sprague Dawley female rats at 0, 20, 60 or 100 mg/kg bw/day through oral gavage from Gestation Day 5 to 20 (GD 5 to GD 20). Dams were subjected to a full gross necropsy and uterine and fetal examinations on GD 21. Parameters evaluated during the study included mortality, physical examinations, cageside observations, body weights, body weight changes, food consumption, gross pathology examinations, uterine data, and fetal examination data (external, visceral, skeletal, and head exams). Dose concentration analysis of samples from formulations prepared for Week 1 and the last week of dosing confirmed that the test substance was properly formulated. Administration of the test substance resulted in maternal mortality at 100 mg/kg bw/day due to body weight loss, decreased food consumption and associated clinical signs of rough haircoat and thin appearance. At 60 mg/kg bw/day, the adverse effects included reduced food consumption and body weight in the dams. There were no effects on pregnancy and uterine parameters including the number of live fetuses as a percentage of post-implantation sites. There was an increase in the incidence of fetal defects (malformations and variations) in all the treated groups. These skeletal variations included incomplete ossification and unossification of the sternebrae and cervical and thoracic centrum and were attributed to the increase in the incidence of unossified or incomplete ossification. These skeletal variations were considered secondary to the reduction in fetal body weight and associated with delayed ossification. Due to their reversible nature, these variations were considered non-adverse, as the offspring would continue to grow and the ossification process would continue until complete with no expected structural alterations. Under the study conditions, the NOAEL for maternal systemic toxicity was determined to be 20 mg/kg bw/day. No NOAEL for fetal developmental effects could be determined due to effects at all doses and therefore, the LOAEL for fetal developmental toxicity was considered to be 20 mg/kg bw/day (Murphy, 2019c).
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 10 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
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
Reproductive toxicity
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. 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).
Developmental toxicity
A prenatal developmental toxicity study was conducted in Sprague Dawley rats according to OECD Guideline 414, in compliance with GLP. The test substance was administered to groups of 25 time-mated Sprague Dawley female rats at 0, 20, 60 or 100 mg/kg bw/day through oral gavage from Gestation Day 5 to 20 (GD 5 to GD 20). Dams were subjected to a full gross necropsy and uterine and fetal examinations on GD 21. Parameters evaluated during the study included mortality, physical examinations, cageside observations, body weights, body weight changes, food consumption, gross pathology examinations, uterine data, and fetal examination data (external, visceral, skeletal, and head exams). Dose concentration analysis of samples from formulations prepared for Week 1 and the last week of dosing confirmed that the test substance was properly formulated. Administration of the test substance resulted in maternal mortality at 100 mg/kg bw/day due to body weight loss, decreased food consumption and associated clinical signs of rough haircoat and thin appearance. At 60 mg/kg bw/day, the adverse effects included reduced food consumption and body weight in the dams. There were no effects on pregnancy and uterine parameters including the number of live fetuses as a percentage of post-implantation sites. There was an increase in the incidence of fetal defects (malformations and variations) in all the treated groups. These skeletal variations included incomplete ossification and unossification of the sternebrae and cervical and thoracic centrum and were attributed to the increase in the incidence of unossified or incomplete ossification. These skeletal variations were considered secondary to the reduction in fetal body weight and associated with delayed ossification. Due to their reversible nature, these variations were considered non-adverse, as the offspring would continue to grow and the ossification process would continue until complete with no expected structural alterations. Under the study conditions, the NOAEL for maternal systemic toxicity was determined to be 20 mg/kg bw/day. No NOAEL for fetal developmental effects could be determined due to effects at all doses and therefore, the LOAEL for fetal developmental toxicity was considered to be 20 mg/kg bw/day (Murphy, 2019c).
Mode of Action Analysis / Human Relevance Framework
Due to the findings in offspring, no specific Mode of Action could be identified.
The findings could be relevant for humans.
Justification for classification or non-classification
Based on the results of combined repeated dose toxicity with reproduction-developmental toxicity screening test, subchronic repeated dose toxicity testing and the pre-natal developmental toxicity studies in rats, the test substance warrants classification as Rep. Cat. 2 (H361f: May damage fertility) according to CLP (1272/2008/EC) criteria. The available information is not sufficient for classification as Rep. Cat. 1, as a partial reversal of effects were seen in the subchronic repeated dose toxicity testing and low to mid exposure within the tests did not result in severe effects.
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