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EC number: 252-043-1 | CAS number: 34454-97-2
- 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
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Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 February 2002 to 25 March 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study was conducted in compliance with OECD GLP regulations.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
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)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- T-7599.7
- IUPAC Name:
- T-7599.7
- Test material form:
- other: waxy solid
- Details on test material:
- - Name of test material (as cited in study report): T-7599.7
- Molecular formula (if other than submission substance):
- Molecular weight (if other than submission substance):
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: Mono constituent substance
- Physical state: Waxy solid
- Analytical purity: 95.55
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Isomers composition:
- Purity test date: 30 January 2002
- Lot/batch No.: Lot 6
- Expiration date of the lot/batch:
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling):
- Locations of the label (if radiolabelling):
- Expiration date of radiochemical substance (if radiolabelling):
- Stability under test conditions:
- Storage condition of test material: Stored at room temperature
- Other:
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleight, North Carolina
- Age at study initiation: Males: 71 days, Females: 65 days
- Weight at study initiation: Males: 282-333 g, Females: 185-226 g
- Fasting period before study: None
- Housing: F0 generation rats were individually housed in stainless steel wire-bottomed cages except during cohabitation period and postpartum periods. During cohabitation, each pair of male and female rats was housed in the male rat's cage. No later than DG 20, F0 generation female rats were individually housed in nesting boxes.
- Diet (e.g. ad libitum): Certified Rodent Diet #5002 (PMI Nutrition International, Inc., St. Louis, Missouri)
- Water (e.g. ad libitum): Reverse osmosis water ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 18 February 2002 To: 25 March 2002
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test article solubility
- Concentration in vehicle: 0, 1, 5, 25 mg test article/mL vehicle
- Amount of vehicle (if gavage): Dose volume was 10 mL/kg body weight
- Lot/batch no. (if required): Lot120K0252 - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 14 Days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as Day 0 of pregnancy
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- After successful mating each pregnant female was caged (how): individually in nesting boxes. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentration and homogeneity of the prepared formulations. Quadruplicate samples (2 mL) will be taken from the top, middle and bottom of each concentration on the first day of preparation. Two of those samples will be shipped for analysis.
- Duration of treatment / exposure:
- F0 Generation Rats: Male rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until sacrifice, after completion of the cohabitation period, after a minimum of 28 days of dosage. Female rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuting until DL 5.
- Frequency of treatment:
- Daily
- Details on study schedule:
- F0 Generation Rats: Male rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing until sacrifice, after completion of the cohabitation period, after a minimum of 28 days of dosage. Female rats were administered the test substance and/or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuting until DL 5.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 10, 50, 250 mg/kg
Basis:
actual ingested
- No. of animals per sex per dose:
- 15
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on previous studies with the test substance.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: None - Positive control:
- Not applicable
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily for viability
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Hourly on the first day of dosage and daily therafter an hour after dosing. Female rats were evaluated for adverse clinical signs observed during parturition, duration of gestation (DG 0 to the day the first pup was observed), litter sizes (all pups delivered) and pup viability at birth. The pups in each litter were counted once daily. Clinical observations were recorded once daily.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during acclimation and daily during dosing. Pup weights were recorded after all pups in a litter were delivered and groomed by the dam and again on DL 5.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Following sacrifice
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: 5/sex/dose
- Parameters checked: erythorocycte count, hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, total leukocyte count, differential leukocyte count, platelet count, mean platelet volume, cell morphology.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Following sacrifice
- Animals fasted: Yes
- How many animals: 5/sex/dose
- Parameters checked: total protein, triglycerides, albumin, globulin, albumin/globulin ratio, glucose, cholesterol, total bilirubin, urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, calcium, phosphorus, sodium, potassium, chloride.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: On one occasion during the study, shortly before scheduled sacrifice.
- Dose groups that were examined: A functional observational battery was conducted on five male and five female rats per group.
- Battery of functions tested: The following parameters were assessed in the functional observational battery: lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, urination, defecation, sensorimotor responses to visual, auditory tactile and paulful stimuli, reactions to handeling behavior in the open field, gait pattern in the open field, severity of gait abnormalities, air righting reaction, visual placing response and landing foot splay, forelimb and hindlimb grip strength. Each pup litter was evaluated for viability at least twice daily. - Oestrous cyclicity (parental animals):
- Estrous cycling was evaluated by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa were observed in a smear and/or a copulatory plug was observed during the cohabitation period.
- Sperm parameters (parental animals):
- Parameters examined in F0 male parental generations: testis weight, epididymis weight, seminal vesicles with coagulating gland and prostate.
- Litter observations:
- Pups were sacrificed on Day 5 of lactation.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: body weight (DL 1 and 5), clinical signs (once daily), gross necropsy, # liveborn, # stillborn, viability index
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after 36 days of dosage.
- Maternal animals: All surviving animals on DL 6.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues indicated were prepared for microscopic examination: brain, small and large intestines, lungs, lymph nodes, peripheral nerve, gross lesions, stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes, epididymides, seminal vesicles, prostate, spinal cord, liver, adrenals, heart, thyroid/parathyroid, uterus, bone marrow, ovaries, uterus, vagina, mammary gland.
The following tissues were weighed: liver, kidneys, adrenals, thymus, testes, epididymides, spleen, brain, heart, ovaries, uterus (with cervix). - Postmortem examinations (offspring):
- Pups were sacrificed on Day 5 of lactation.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: body weight (DL 1 and 5), clinical signs (once daily), gross necropsy, # liveborn, # stillborn, viability index
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead - Reproductive indices:
- Number of dams delivering litters, duration of gestation, averages for implantation sites per delivered litter, gestation index, numbers of dams with stillborn pups, and dams with all pups dying.
- Offspring viability indices:
- Number liveborn pups, number stillborn pups, viability index.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Terminal body weights of male rats was statistically significantly reduced in the 250 mg/kg/day group compared to controls. Female terminal body weights were also reduced in the 250 mg/kg/day group, but the reduction was not statistically significant.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): Not examined
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): All estrous, mating and fertility parameters were unaffected at all dose levels.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): Not examined
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There were no statistically significant differences among the groups in the values of the following parameters: number of dams delivering litters, duration of gestation, averages for implantation sites per delivered litter, gestation index, number of dams with stillborn pups, and dams with all pups dying.
ORGAN WEIGHTS (PARENTAL ANIMALS): Absolute liver weights were significantly increased in 250 mg/kg/day-treated males and females. Liver weights relative to terminal body weights were significantly increased in the 50 and 250 mg/kg/day treated males. The ratio of liver weight to brain weight was significantly increased in the 250 mg/kg/day-treated males and females. In both males and females, increased kidney weights were noted in the 250 mg/kg group and in males alone in the 50 mg/kg group.
GROSS PATHOLOGY (PARENTAL ANIMALS): No test substance related abnormalities were observed upon gross necropsy.
HISTOPATHOLOGY (PARENTAL ANIMALS): Microscopic examination revealed minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most males treated at 250 mg/kg/day and in 4/10 males treated at 50 mg/kg/day. Also in three 250 mg/kg/day-treated males, necrosis of individual enlarged hepatocytes was observed in the centrilobular areas. Minimal or mild hypertrophy of centrilobular hepatocytes was also observed in most females treated at 250 mg/kg/day. In both males and females, the hypertrophy was due to an increased amount of finely granular, dense eosinophilic cytoplasm. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of 2 males in the 250 mg/kg/day group. Minimal to mild edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 control group males, 2 males in the 50 mg/kg/day group, and 1 male in the 250 mg/kg/day group. Moderate edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 males in the 250 mg/kg/day group. Thus, the edema/inflammation was observed at a slightly higher incidence and severity in the 250 mg/kg/day dose group. No microscopic changes in the gastrointestinal tract of females were noted. Microscopic examination of the thymus revealed an increased incidence and severity of atrophy of the thymic lobules in female rats treated at 250 mg/kg/day. No toxicologically relevant findings in the organ weight and histopathology of the thymus in male rats. No microscopic changes were noted in the kidneys (male or female) upon histopathology.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 250 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
CLINICAL SIGNS (OFFSPRING): No abnormal clinical signs were observed.
BODY WEIGHT (OFFSPRING): Pup body weight was reduced in the 250 mg/kg dosage group on pospartum days 1 and 5.
SEXUAL MATURATION (OFFSPRING): Not examined.
ORGAN WEIGHTS (OFFSPRING): Not examined.
GROSS PATHOLOGY (OFFSPRING): No abnormal gross lesions were observed upon gross necropsy.
HISTOPATHOLOGY (OFFSPRING): Not examined.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- body weight and weight gain
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 250 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects as a secondary non-specific consequence of other toxic effects
- Dose response relationship:
- yes
Any other information on results incl. tables
All males and females survived. Significant increases in excess salivation, perioral substance and urine-stained abdominal fur was observed in the 250 mg/kg/day treated male rats. No abnormal clinical observations were noted in female rats. Body weight gains and absolute and relative food consumption were significantly reduced in the 50 and 250 mg/kg/day-treated males. Body weight gains of the females were significantly reduced during the precohabitation period in the 250 mg/kg/day dose group, but body weights and body weight gains were not significantly affected during gestation or lactation. Terminal body weights of the female rats were reduced in the 250 mg/kg/day dose group. No gross abnormalities were observed upon necropsy. Absolute liver weights were significantly increased in 250 mg/kg/day-treated males and females. Liver weights relative to terminal body weights were significantly increased in the 50 and 250 mg/kg/day treated males. The ratio of liver weight to brain weight was significantly increased in the 250 mg/kg/day-treated males and females. Microscopic examination revealed minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most males treated at 250 mg/kg/day and in 4/10 males treated at 50 mg/kg/day. Also in three 250 mg/kg/day-treated males, necrosis of individual enlarged hepatocytes was observed in the centrilobular areas. Minimal or mild hypertrophy of centrilobular hepatocytes was also observed in most females treated at 250 mg/kg/day. In both males and females, the hypertrophy was due to an increased amount of finely granular, dense eosinophilic cytoplasm. In both males and females, increased kidney weights were noted in the 250 mg/kg group and in males alone in the 50 mg/kg group. No microscopic changes were noted in the kidneys (male or female) upon histopathology. Microscopic examination of the thymus revealed an increased incidence and severity of atrophy of the thymic lobules in female rats treated at 250 mg/kg/day. No toxicologically relevant findings in the organ weight and histopathology of the thymus in male rats. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of 2 males in the 250 mg/kg/day group. Minimal to mild edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 control group males, 2 males in the 50 mg/kg/day group, and 1 male in the 250 mg/kg/day group. Moderate edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 males in the 250 mg/kg/day group. Thus, the edema/inflammation was observed at a slightly higher incidence and severity in the 250 mg/kg/day dose group. No microscopic changes in the gastrointestinal tract of females were noted. There were no abnormal clinical or necropsy observations in the F1 generation pups. The number of liveborn pups was significantly reduced and the number of stillborn pups was significantly increased in the 250 mg/kg dosage group. The viability index and number of pups surviving per liter on postpartum day 5 were significantly reduced in the 250 mg/kg dosage group. Pup body weight was also reduced in the 250 mg/kg dosage group on postpartum days 1 and 5. Based on the results of the study, the repeat dose toxicity No Observed Adverse Effect Level (NOAEL) for the test article is 50 mg/kg/day. The male and female reproductive NOAEL is 250 mg/kg/day and the developmental NOAEL is 50 mg/kg/day.
Applicant's summary and conclusion
- Conclusions:
- Based on the results of the study, the repeat dose toxicity No Observed Adverse Effect Level (NOAEL) for the test article is 50 mg/kg/day. The male and female reproductive NOAEL is 250 mg/kg/day and the developmental NOAEL is 50 mg/kg/day.
- Executive summary:
The subacute oral toxicity and potential for reproductive and developmental toxicity (screening level) of T-7599 (white powder, purity >99.9%, CASRN 34454-97-2, Lot 6) was evaluated in Sprague-Dawley rats following repeated oral doses. This study was performed in compliance with OECD GLP (1998), US FDA GLP 21 CFR 58, and Japanese MHW GLP (1997). The study method was based on OECD 422 (1996) and US EPA In Vivo Reproductive and Mutagenicity Tests (1982). T-7599 was prepared in 0.5% carboxymethylcellulose (CMC) for the first 4 days of the study and then was prepared in 1.0% CMC for the remainder of the study. Rats (15/sex/dose) received repeated doses of 0 (vehicle), 10, 50, or 250 mg/kg/day via oral gavage at a dose volume of 10 mL/kg. Male rats received their respective doses once daily beginning at 14 days before cohabitation and continuing after the cohabitation period for minimum total of 28 days. Female rats received their respective doses once daily beginning at 14 days before cohabitation and continuing until Day 5 of lactation (LD 5). Within each dosage group, one male rat was assigned per one female rat during the cohabitation period (maximum of 14 days). Mating was confirmed by examining female rats for spermatozoa in vaginal smears and/or absence of copulatory plug. After 36 days of dosage, all males were euthanized. On LD 5 and 6, all surviving pups and females were euthanized, respectively. Parameters evaluated: clinical observations (at least daily), body weight (daily during dosing), food consumption (at least weekly), estrous cycling, litter sizes, pup viability, clinical and necropsy observations of pups, maternal behavior, functional observational battery (5/sex/dose), and hematology and clinical biochemistry (5/sex/dose). Gross necropsy and histological evaluation of select organs were performed on males and females. All males and females survived. Significant increases in excess salivation, perioral substance and urine-stained abdominal fur was observed in the 250 mg/kg/day treated male rats. No abnormal clinical observations were noted in female rats. Body weight gains and absolute and relative food consumption were significantly reduced in the 50 and 250 mg/kg/day-treated males. Body weight gains of the females were significantly reduced during the precohabitation period in the 250 mg/kg/day dose group, but body weights and body weight gains were not significantly affected during gestation or lactation. Terminal body weights of the female rats were reduced in the 250 mg/kg/day dose group. No gross abnormalities were observed upon necropsy. Absolute liver weights were significantly increased in 250 mg/kg/day-treated males and females. Liver weights relative to terminal body weights were significantly increased in the 50 and 250 mg/kg/day treated males. The ratio of liver weight to brain weight was significantly increased in the 250 mg/kg/day-treated males and females. Microscopic examination revealed minimal or mild enlargement (hypertrophy) of centrilobular hepatocytes in most males treated at 250 mg/kg/day and in 4/10 males treated at 50 mg/kg/day. Also in three 250 mg/kg/day-treated males, necrosis of individual enlarged hepatocytes was observed in the centrilobular areas. Minimal or mild hypertrophy of centrilobular hepatocytes was also observed in most females treated at 250 mg/kg/day. In both males and females, the hypertrophy was due to an increased amount of finely granular, dense eosinophilic cytoplasm. In both males and females, increased kidney weights were noted in the 250 mg/kg group and in males alone in the 50 mg/kg group. No microscopic changes were noted in the kidneys (male or female) upon histopathology. Microscopic examination of the thymus revealed an increased incidence and severity of atrophy of the thymic lobules in female rats treated at 250 mg/kg/day. No toxicologically relevant findings in the organ weight and histopathology of the thymus in male rats. Microscopic examination of the stomach revealed focal erosions in the pyloric glandular mucosa of 2 males in the 250 mg/kg/day group. Minimal to mild edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 control group males, 2 males in the 50 mg/kg/day group, and 1 male in the 250 mg/kg/day group. Moderate edema/inflammation of the submucosa of the nonglandular and glandular areas was observed in 2 males in the 250 mg/kg/day group. Thus, the edema/inflammation was observed at a slightly higher incidence and severity in the 250 mg/kg/day dose group. No microscopic changes in the gastrointestinal tract of females were noted. There were no abnormal clinical or necropsy observations in the F1 generation pups. The number of liveborn pups was significantly reduced and the number of stillborn pups was significantly increased in the 250 mg/kg dosage group. The viability index and number of pups surviving per liter on postpartum day 5 were significantly reduced in the 250 mg/kg dosage group. Pup body weight was also reduced in the 250 mg/kg dosage group on postpartum days 1 and 5. Based on the results of the study, the repeat dose toxicity No Observed Adverse Effect Level (NOAEL) for the test article is 50 mg/kg/day. The male and female reproductive NOAEL is 250 mg/kg/day and the developmental NOAEL is 50 mg/kg/day.
The test article is classified as STOT RE 2 (for liver effects) and Repr. 2 according to CLP criteria. The thymus effects seen in the longer-dosed females do not lead to classification as the LOAEL is outside the guidance values for STOT RE 2. The dose at which the liver and thymus effects occurred is outside the guidance values for R48/22.
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.
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