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EC number: 202-723-9 | CAS number: 99-04-7
- 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

Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Remarks:
- haematology and clinical chemistry parameters only assessed in male rats
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
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)
- Version / remarks:
- 1996
- Deviations:
- yes
- Remarks:
- haematology and clinical chemistry parameters only assessed in male rats
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- m-toluic acid
- EC Number:
- 202-723-9
- EC Name:
- m-toluic acid
- Cas Number:
- 99-04-7
- Molecular formula:
- C8H8O2
- IUPAC Name:
- m-toluic acid
- Test material form:
- solid: particulate/powder
- Details on test material:
- -Appearance: colorless to pale yellow
-Molecular weight: 136.15
-Melting point: 11.7 °C
-Boiling point: 263 °C
- soluble in organic solvents, almost insoluble in vegetable oils, sparingly water soluble
Constituent 1
- Specific details on test material used for the study:
- STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: sealed at a cool (4 °C) and dark place
- Stability under test conditions: stable during use period
- Solubility and stability of the test substance in the solvent/vehicle: stable for at least 7 days
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: dissolved in 1 % methylcellulose in water
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Remarks:
- SPF
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Co., Ltd., Japan
- Females nulliparous and non-pregnant: yes
- Age at study initiation:
males: 9 weeks
females: 8 weeks
- Weight at study initiation:
males: mean weight 357 g (range: 342 - 372 g)
females: mean weight 222 g (range: 209 - 237 g)
- Fasting period before study:
- Housing:
-housed individually in stainless steel wire mesh cages
-after confirmation of mating, females were housed individually in polycarbonate cages, nest-making material (obtained from Charles River Co., Ltd., Lot No.: 9623) was provided
- Diet (ad libitum): diet was obtained from Japan Agricultural Association Company, national feed laboratory MR stock, Lot. No.: 71064 (assumed)
- Water (ad libitum): UV irradiated tap water
- Acclimation period: 5 days
DETAILS OF FOOD AND WATER QUALITY: quality of feed, water and nest-making materials was confirmed by analysis
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23 °C
- Humidity (%): 53 - 60 %
- Air changes (per hr): 10 times or more per hour
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1 % methylcellulose i(aqueous solution)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Rate of preparation of dosing solution (frequency): once or twice a week
- Storage temperature and stability of dosing solution: stored sealed in the dark at 4 °C, used within 7 days of preparation
VEHICLE
- Concentration in vehicle:
- 30 mg/kg bw/ day group: 0.6 % (w/v) m-toluic acid
- 100 mg/kg bw/day group: 2 % (w/v) m-toluic acid
- 300 mg/kg bw/day group: 6 % (w/v) m-toluic acid
- 1000 mg/kg bw/day group: 20 % (w/v) m-toluic acid
- Amount of vehicle (if gavage): 5 mL/ kg bw
- Lot/batch no.: methylcellulose was obtained from Wako Pure Chemical Industries, Ltd. (Lot No.: DLH 5715) (assumed) - Details on mating procedure:
- - M/F ratio per cage: one male/one female
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear, referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged individually in polycarbonate cages, nest-making material (obtained from Charles River Co., Ltd., Lot No.: 9623) was provided - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- Exposure period:
Males: 14 days before mating
Females: from 14 days before mating to day 3 of lactation
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: Males: 44 days from 14 days before mating
Females: 41 - 45 days from 14 days before mating to day 3 of lactation - Details on study schedule:
- once a day
Doses / concentrationsopen allclose all
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10 males/ 10 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
- a 14-day study was conducted at doses of 0, 80, 150, 300, 600 and 1000 mg/kg bw/day in groups of 4 male and 4 female rats. One male and one female rat were cohoused from day 7. In the 1000 mg/kg bw/day group effects were observed (males: decreased platelet coun; females: decreased platelet counts, tendency of decreased body weight gain, tendency of decreased food consumption), consequently this dose was selected as high dose for the present study. Acidification of urine was observed in males and females in the 600 and 1000 mg/kg bw/day groups. 30 mg/kg bw/day were selected as low dose, which is expected to display no treatment-related effects.
- Rationale for animal assignment: based on body weights
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Not specified
BODY WEIGHT: Yes
- Time schedule for examinations:
males: once before administration period, and weekly thereafter and at termination
females: once before administration, and weekly thereafter (covering pregnancy day 0, 7, 14 and 20), and on day 0 and day 4 postpartum
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
OPHTHALMOSCOPIC EXAMINATION: Not specified
HAEMATOLOGY: Yes, males only
- Time schedule for collection of blood: before termination (45 days after administration), from abdominal aorta
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all male rats
- The following parameters were examined: red blood cell count (RBC), hemoglobin (Hb), Hematocrit (Ht), mean red blood cell volume (MCV), mean, red blood cell hemoglobin content (MCH), mean red blood cell hemoglobin concentration (MCHC), white blood cell count (WBC), platelet count (Plat), reticulocyte count (Ret), differential keukocyte counts (basophiles, eosinophiles, neutrophiles, lymphocytes, monocytes, prothrombin time (PT), activated partial thromboplastin time (APTT)
CLINICAL CHEMISTRY: Yes, males only
- Time schedule for collection of blood: before termination (45 days after administration), from abdominal aorta
- Animals fasted: Yes
- How many animals: all male rats
- The following parameters were examined: total protein, albumin, A/G ratio, glucose, triglycerides, total cholesterol level, total bilirubin, urea nitrogen, creatinine, aspartate aminotransferase (AST or GOT), alanine aminotransferase (ALT or GPT), gamma-glutamyltransferase (gamma-GTP), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), cholinesterase, calcium, inorganic phosphorus, sodium, potassium, chloride
URINALYSIS: Yes, males only
- Time schedule for collection of urine: on day 39 or day 42 of administration
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Not specified
- The following parameters were examined: colour, cloudiness, specific gravity, pH, protein, glucose, ketones, blood, urobilinogen, bilirubin, erythrocytes, leukocytes, crystals (ammonium magnesium phosphate, calcium phosphate, amorphous), epithelial cells (squamous, round, spindle), casts (granule, hyaline, waxy), fat globules
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:daily (cage side observations)
- Dose groups that were examined: all rats
- Battery of functions tested: locomotor activity
IMMUNOLOGY: Not specified - Oestrous cyclicity (parental animals):
- Estrous cyclicity was examined daily during mating period of 14 days by analysis of vaginal smear
- Sperm parameters (parental animals):
- Parameters examined in male rats:
testis weight, epididymis weight - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- All pups/litter were examined
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups (including sex ratio), stillbirths, live births, postnatal mortality, presence of gross anomalies (external and visceral findings), weight gain; anogenital distance (AGD)
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: not specified
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: not specified - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals were sacrificed 45 days after first administration
- Maternal animals: All surviving animals were sacrificed at day 4 postpartum
GROSS PATHOLOGY: Yes
- Necropsy was conducted on all male and female rats.
- The whole body including all organs was examined for abnormalities. For females, corpora lutea and implantation sites were examined
- The following organs were weighed: brain, liver, kidney, spleen, heart, thymus, pituitary gland, adrenal gland, testes, epididymes
HISTOPATHOLOGY: Yes
- Histopathological examination was conducted on male and female rats of the control groups and of the high dose groups (1000 mg/kg bw/day). Male and female rats with unsuccessful mating and pregnancy were additionally examined.
-The following organs were prepared: all gross lesions, heart, tongue, lung, liver, pancreas, kidney, urinary bladder, testes, epididymes, prostate, thymus, spleen, uterus, adrenal gland, skin, eye, harder's gland, thyroid (including parathyroid) gland, salivary gland, trachea, esophagus, stomach, intestine, seminal vesicles, ovaries, aorta, spinal cord, sciatic nerve, bone/bone marrow, lymph nodes (cervical, mesenteric), skeletal muscle, mammary gland
-The following organs were histopathologically examined: all gross lesions, brain, pituitary gland, thymus, heart, liver, lung, kidney, spleen, urinary bladder, adrenal gland, bone marrow, testes epididymes, prostate, seminal vesicles, ovaries, uterus, skin - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring was sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the main organs in the chest and abdomen - Statistics:
- - Bartlett's variance test was performed on parametric data
- Dunnett method or Scheffe method was performed for one-way analysis of variance
- Kruskal-Wallis test was performed on non-parametric data - Reproductive indices:
- Copulation index = (No. of pairs with successful copulation/No. of pairs mated) x 100
Fertility index = (No. of pregnant females/No. of pairs with successful copulation) x 100
Implantation index =(No. of implantation sites/ No. of corpora lutea) x 100
Gestation index = (No. of females with live pups/No. of pregnant females) x 100 - Offspring viability indices:
- Delivery index = (No. of pups born/No. of implantation sites) x 100
Live birth index = (No. of live pups on day 0/No. of pups born) x 100
Viability index = (No. of live pups on day 4/No. of live pups on day 0) x 100
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Males: decreased locomotor activity was observed in 4 male rats after 16 days of administration in the high dose group (1000 mg/kg bw/day)
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Females:
- periportal hepatocellular vacuolar degeneration in liver was observed in 7 females at 1000 mg/kg bw/day
- periportal hepatocellular vacuolar degeneration in liver was observed in 3 females at 300 mg/kg bw/day - Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Details on results (F1)
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In the combined repeated dose/ reproductive and developmental toxicity test, rats were exposed to 30, 100, 300 and 1000 mg/kg bw/day m-toluic acid for 41 to 45 days. Reproductive parameters in parental animals were examined and no adverse effects were observed. Offspring parameters wer examined and no adverse effects were observed. Thus, the reproductive NOAEL was considered at 1000 mg/kg bw/day.
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