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EC number: 208-534-8 | CAS number: 532-32-1
- 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
Description of key information
Oral:
The studies available are feeding studies in rat and mice (one drinking water study in mice). Mice seem to be less susceptible to the effects of the test substance than rats. Effects are severe decrease of body weight with effects in the liver. The no effect level is 2% in the diet of rats. In the reports available different conversion methods are used to calculate the actual test substance intake. This may have been done by actual measurement of food intake, but is not clearly described in the publications. Therefore a calculation was done based on the factors as described in the WHO report (EHS Environmental Health Criteria 240). This leads to a NOAEL of 1000 mg/kg bw based on the 2% dietary level in rats.
In a chronic toxicity/carcinogenicity study in rats (Sodemoto, 1979) no signs of toxicity were reported at 2% the test substance in feed (stated to be equivalent to 1000 mg/kg bw). In mice (Toth, 1984) no effects were reported at 2% the test substance in drinking water (119-124 mg/animal/day).
Dermal: An repeated dermal toxicity study with rabbit (Marroquin, 1981) which run on analog substance Benzoic acid (65-85-0) is available which is key study.The NOAEL was > 2500 mg/kg bodyweight.
Inhalation: A study is available with a NOAEL of the key study of 250 mg/m3 (Benson, 1981). These findings were primarily attributed to the physico-chemical properties of these fine low-solubility particles.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Limited study summary. Study predates approved guidelines, minimal data provided on study design and results, no GLP.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Study predates approved guidelines.
The chronic toxicity study of the test substance was examined in Fischer 344 rats. The test substance was administered in the diet for 18 to 24 months at two dose levels. - GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Provided by Japan CLEA Co. Ltd.
- Age at study initiation: 4-5 weeks old
- Weight at study initiation: 110-150 g
- Housing: Five in each cage
- Diet (e.g. ad libitum): CE-2 pellets, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-23℃
- Humidity (%): 55%
No additional data - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- None stated
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 18-24 months
- Frequency of treatment:
- Daily
- Remarks:
- Doses / Concentrations:
1 or 2%
Basis:
nominal in diet - No. of animals per sex per dose:
- Test group: 50 males and 52 females per dose
Control group: 25 males and 43 females - Control animals:
- yes, plain diet
- Details on study design:
- Both male and female rats were divided into three groups and maintained on the diet containing 2 or 1% of the test substance or basal diet for 18 to 24 months. The animals were maintained on a free choice diet, but amount of diet was adequately controlled to avoid excess. Tap water was freely offered to all animals. The rats were weighed weekly, and food intake was measured daily.
- Positive control:
- None stated
- Observations and examinations performed and frequency:
- Mortality, growth, food intake, behavior and general status were observed in the experimental period.
- Sacrifice and pathology:
- In the middle of the experimental period, several animals from each groups selected at random were sacrificed for morphologic examination. All surviving animals were killed between 18 to 25 months. For morphologic examination, autopsy was carried out in all animals and paraffin sections of various organs were prepared and stained (hematoxylin and eosin).
- Other examinations:
- None stated
- Statistics:
- T-test
- Clinical signs:
- no effects observed
- 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 specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Clinical signs and mortality:
During the first 16 months of the experimental period, the average mortality rate of all animals was 14.5%. Except for myeloproliferative disorder developed in one female control rat, all the dead animals showed pneumonia with abscess. Around 100 rats including those of the control groups died after 16 months of hemorrhagic pneumonia with edema which was probably induced by mixed infection of sialodacryoadenitis and mycoplasma. However, no differences in mortality rates between treated and control groups were observed throughout the experimental course.
Body weight gain and food intake:
Nor were there any significant differences in growth and food intake between groups of rats.
Histopathology:
Most developed tumours were benign, such as interstitial cell tumour of the testes and endometrial polyp of the uterus. However, a small number of malignant neoplasms including leukemia was also observed. Differences in numbers of tumor-bearing animals and time-to-tumor development between control and treated gorups were not significant (t-test). No specific toxic effect induced by the test substance was observed. - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No findings of toxicological significance at 20000 mg/kg diet (equivalent to 1000 mg/kg bw)..
- Critical effects observed:
- not specified
- Conclusions:
- From the results of this study, it may be concluded that the test substance was not toxic for male and female Fischer 344 rats after 18 to 24-month dietary exposure.
- Executive summary:
The chronic toxicity study of the test substance was examined in Fischer 344 rats. The test substance was administered in the diet for 18 to 24 months at two dose levels.
No adverse clinical signs directly attributable to the compound were observed in treated animals. Differences in the average body weight, and mortality rates between treated and control groups were negligible. The results of the statistical test for dose-related trends were significant (p<0.05). Although a variety of tumors occurred among test and control rats of each sex, tumors appearing in treated rats were similar in type and number to those in controls. It was concluded that no evidence of carcinogenicity in rats from the test substance was demonstrated.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- 2 (reliable with restrictions)
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- From 14 March to 11 April 1980
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study run to a method comparable with current guidelines and GLP.
- Justification for type of information:
- See Read Across Justification document in Section 13.2 of IUCLID
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- Principles of method if other than guideline:
- This study consisted of four groups, each containing ten male and ten female albino rats. One group served as an air exposed control while the other three were exposed to one of three different dust concentrations of the test substance. Exposures were for 6 hours per day five days per week for four consecutive weeks. At various times during the study body weights and observations for pharmacotoxic signs were recorded. After four weeks of exposure various serum biochemical, hematologic, organ weight and histopathologic evaluations were conducted.
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: At the time of receipt the rats were 42 days of age.
- Weight at study initiation: males 194-201 g, females 148-163 g
- Housing: caged individually
- Diet: ad libitum for non-exposure hours
- Water: tap water, ad libitum for non-exposure hours
- Acclimation period: yes
ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71.6-74.7°F
- Humidity (%): 41.0-51.0%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hour photoperiod
IN-LIFE DATES: From: 14 March 1980 To: 11 April 1980 - Route of administration:
- inhalation: dust
- Type of inhalation exposure:
- whole body
- Vehicle:
- air
- Remarks on MMAD:
- MMAD / GSD: A mean equivalent aerodynamic diameter of 4.7 µm was defined.
Group 2, EAD of 4.6 µm, ag of 3.1
Group 3, EAD of 4.4 µm, ag of 2.1
Group 4, EAD of 5.2 µm, ag of 2.1 - Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposures were conducted in 1 cubic meter glass and stainless steel exposure chambers.
- Method of holding animals in test chamber:
- Source and rate of air: Air for chamber ventilation was supplied from an HVAC system separate from general laboratory systems.
- Method of conditioning air:
- System of generating particulates/aerosols: The test material was ground in an Oster@ blender in order to produce a more respirable particle. The blender jar was filled approximately one third full with the test substance and run at high speed for one to two minutes. The ground compound was separated from the remaining flakes by using a flour sifter. The flakes were returned to the blender jar and reground. The procedure was continued until enough material for two exposure days had been prepared.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: Chamber air flow rate varied between one 145 and 310 liters per minute depending on desired exposure concentrations.
- Air change rate:
- Method of particle size determination: The particle size distribution of the test material in a sample of the chamber atmosphere was determined using an Andersen 8 stage cascade impactor.
- Treatment of exhaust air:
TEST ATMOSPHERE
- Brief description of analytical method used: Nominal concentrations were determined by weighing the amount of test material placed in the generator reservoir prior to exposure and then again after exposure. The difference in weight was the nominal concentration. Actual exposure concentrations were determined by standard gravimetric techniques. Exposure atmospheres were drawn through pre-weighed glass fiber filters at a known flowrate for a known time. The filters were reweighed, and the difference was divided by the total air volume to yield the actual concentrations.
- Samples taken from breathing zone: yes/no
VEHICLE (if applicable)
- Justification for use and choice of vehicle:
- Composition of vehicle:
- Type and concentration of dispersant aid (if powder):
- Concentration of test material in vehicle:
- Lot/batch no. of vehicle (if required):
- Purity of vehicle: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Both nominal and analytical exposure concentrations were determined for this study. Nominal concentrations were determined by weighing the amount of test material placed in the generator reservoir prior to exposure and then again after exposure. The difference in weight was divided by the total air passed through the chamber during the exposure period resulting in the nominal concentration.
Actual exposure concentrations were determined by standard gravimetric techniques. Exposure atmospheres were drawn through pre-weighed glass fiber filters at a known flowrate for a known time. The filters were reweighed and the difference was divided by the total air volume to yield the actual concentrations.
Group 2, desired concentration 0.02 mg/L, nominal concentration 0.31 mg/L, actual concentration 0.025 mg/L
Group 3, desired concentration 0.2 mg/L, nominal concentration 2.2 mg/L, actual concentration 0.25 mg/L
Group 4, desired concentration 2.0 mg/L, nominal concentration 16.5 mg/L, actual concentration 1.2 mg/L - Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- Animals were exposed for 6 hours per day, 5 days per week for 4 weeks.
- Remarks:
- Doses / Concentrations:
25, 250, 1200 mg/m3
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
310, 2200, 16500 mg/m3
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
20, 200, 2000 mg/m3
Basis:
other: Desired concentration - No. of animals per sex per dose:
- 10 male and 10 female per dose
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): The animals were randomized into the four groups based on body weight.
- Rationale for selecting satellite groups:
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random): - Positive control:
- None stated
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once each week
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice each day prior to exposure and again after each exposure
BODY WEIGHT: Yes
- Time schedule for examinations: prior to exposure and after 1, 2, 3 and 4 weeks of exposure
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: after four weeks of exposure
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all survivors
- Parameters: Hematocrit, Hemoglobin Concentration, Erythrocyte count, Leucocyte Count (total and differential), Platelet Count, MCV, MCH, MCHC
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after four weeks of exposure
- Animals fasted: No data
- How many animals: all survivors
- Parameters: Blood Urea Nitrogen, Serum Alkaline Phosphatase, Serum Glutamic Pyruvic Transaminase, Serum Glutamic Oxaloacetic Transaminase, Blood Glucose
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, heart, kidney, lungs/trachea, brain, liver, spleen
HISTOPATHOLOGY: Yes, adrenal, nasal turbinate, brain, pancreas, colon, pituitary, esophagus, prostate/uterus, eye with optic nerve, submaxillary salivary gland, testis (both), ovary, jejunum, Harderian glands, spleen, heart, sternum (bone marrow), kidney, stomach, liver, thymus, lungs (5 lobes), thyroid/parathyroid, bronchial lymph node, urinary bladder, mammary gland - Other examinations:
- None stated
- Statistics:
- Body weight data, clinical chemistry data, hematology data and organ weight data are presented on both an individual animal basis and as a group mean and standard deviation summary. Not all parameters were statistically evaluated at all intervals. Some parameters at some intervals were evaluated statistically after a review of the data indicated that a possible exposure related effect may have been present. All statistical analyses compared the treatment groups with the control group by sex.
Body weights (weeks 1, 2, 3 and 4), hematological parameters (week 4) and absolute and relative organ weights (terminal sacrifice) were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie using Dunnett's multiple comparison tables to judge significance of differences. - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
Reddisch discharge around the nares was seen in the mid and high dose groups. Two high dose animals died during the study.
BODY WEIGHT AND WEIGHT GAIN
High dose males and females showed a decreased body weight gain.
HAEMATOLOGY
A statistically significant decrease in platelets was seen in high dose males and females
CLINICAL CHEMISTRY
Random statistical differences were observed in the biochemical data. These differences were not considered to be exposure related nor of toxicological significance.
ORGAN WEIGHTS
Changes in absolute and relative weights of liver, kidneys and lungs were noted in high dose males or females.
GROSS PATHOLOGY
No changes in gross pathology were noted.
HISTOPATHOLOGY: NON-NEOPLASTIC
Compound related microscopic lesions were confined to the lung. An increased incidence and intensity of interstitial inflammatory cell infiltrate interstitial fibrosis was noted in low, mid and high dose animals. - Dose descriptor:
- NOAEC
- Effect level:
- <= 25 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Pulmonary fibrosis and inflammatory cell infiltrate at lowest dose level
- Dose descriptor:
- NOAEL
- Remarks:
- systemic
- Effect level:
- 250 mg/m³ air
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Only very slight organ weight and body weight decreases noted.
- Critical effects observed:
- not specified
- Conclusions:
- All test concentrations induced local effects: nasal redness and discharge and pulmonary fibrosis and inflammatory cell infiltrates in the lungs that can be related to the ittitant properties of the test substance. No systemic effects were noted at 25 mg/m3. At 250 mg/m3 a very slight decrease in absolute kidney weighth was seen in females only. At the highest dose level mortality, decresed body weights as well as decreased liver kidney and lung weights were reported. No histopathological findings except in the lungs were reported . No systemic effects were noted at this dose level. At 250 mg/m3 a very slight decrease in absolute kidney weighth was seen in females only. At the highest dose level mortality, decresed body weights as well as decreased liver kidney and lung weights were reported. No histopathological findings except in the lungs were reported .
- Executive summary:
This study consisted of four groups, each containing ten male and ten female albino rats. One group served as an air exposed control while the other three were exposed to one of three different dust concentrations of the test substance. Exposures were for 6 hours per day five days per week for four consecutive weeks. At various times during the study body weights and observations for pharmacotoxic signs were recorded. After four weeks of exposure various serum biochemical, hematologic, organ weight and histopathologic evaluations were conducted.
All test concentrations induced local effects: nasal redness and discharge and pulmonary fibrosis and inflammatory cell infiltrates in the lungs that can be related to the irritant properties of the test substance. No systemic effects were noted at 25 mg/m3. At 250 mg/m3 a very slight decrease in absolute kidney weighth was seen in females only (body weight was also slightly lower (not significantly) than in control females). At the highest dose level mortality, decreased body weights as well as decreased liver kidney and lung weights were reported. No histopathological findings except in the lungs were reported . The NOAEL for local effects is < 25 mg/m3; The NOAEL for systemic effects is 250 mg/m3.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 250 mg/m³
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- 1 (reliable without restriction)
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 14 November to 5 December 1979
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study run to a reliable method and to GLP.
- Justification for type of information:
- See Read Across Justification document in Section 13.2 of IUCLID
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Langshaw Farms, Augusta, Michigan
- Age at study initiation:
- Weight at study initiation: 2127 to 2891 grams
- Fasting period before study:
- Housing: Individually housed in hanging wire-mesh cages.
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°F): 70-76 °F
- Humidity (%): 44-57%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark
IN-LIFE DATES: From: 14 November 1979 To: 5 December 1979 - Type of coverage:
- semiocclusive
- Vehicle:
- physiological saline
- Remarks:
- 0.9%
- Details on exposure:
- TEST SITE
- Area of exposure: 100 cm2
- % coverage: 23%, 35% and 100%
- Type of wrap if used: Each site was covered with a 10 x 10-centimeter gauze pad with adhesive tape borders. The entire area was then wrapped with gauze bandaging and Elastoplast tape.
- Time intervals for shavings or clipplings: twice each week prior to test article administration during the three week study period
REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test areas were washed with tepid IRDC tap water and dried with disposable paper towels.
- Time after start of exposure: 6 hours
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100, 500 and 2500 mg/kg bw
- For solids, paste formed: no
VEHICLE
not applicable
USE OF RESTRAINERS FOR PREVENTING INGESTION: no - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 6 hours, test substance moistened with physiological saline
- Frequency of treatment:
- Once a day, 5 days per week, for 3 consecutive weeks
- Remarks:
- Doses / Concentrations:
100, 500, 2500 mg/kg
Basis:
nominal per unit body weight - No. of animals per sex per dose:
- 4 males and 4 females per dose
- Control animals:
- yes
- Details on study design:
- None stated
- Positive control:
- None stated
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily during the 21-day study period
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were obtained during the pretest period, prior to study initiation and at weekly intervals during the 21-day study period
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: once during the pretest period and at 21 days of study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters: hematocrit, hemoglobin, erythrocyte count, total leucocyte count, differential leucocyte count, platelets, MCH, MCV and MCHC
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Once during the pretest period and at 21 days of study.
- Animals fasted: Yes / No / No data
- How many animals: all animals
- Parameters:glucose, blood urea nitrogen, lkaline phosphatase, serum glutamic pyruvic transaminase, and serum glutamic oxalacetic transaminase
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
masses and lesions, untreated skin, treated skin, kidney, lungs, pituitary, sciatic nerve, muscle, spleen, urinary bladder, thymus, lumbar spinal cord, pancreas, stomach, duodenum, testes, thyroid, femur, colon, mesenteric lymph nodes, mediastinal lymph nodes, ovaries, parathyroid, liver, gall bladder, adrenals, heart, brain
HISTOPATHOLOGY: Yes
spleen, pancreas, stomach, duodenum, colon, lymph nodes, urinary bladder, heart, lung, brain (3 sections), treated skin (3 sections), untreated skin (3 sections), liver, kidney, gall bladder, adrenals, spinal cord, gonads, nerve (with muscle), bone marrow, thyroid (parathyroid), pituitary, thymus - Other examinations:
- None stated
- Statistics:
- All statistical analyses compared the treatment groups with the control group, by sex.
Body weights (day 21), hematological and biochemical parameters (pretest and day 21) and absolute and relative organ weights (terminal sacrifice) were compared by analysis of variance (one-way classification), Bartlett’s test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie using Dunnett’s multiple comparison tables to judge significance of differences. - Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
In the control group, a few rabbits exhibited signs of anorexia and purulent nasal discharge. One rabbit also exhibited diarrhea.
In the test groups, a few rabbits exhibited signs of anorexia, purulent nasal discharge, clear nasal discharge, soft stool, diarrhea and ocular discharge.
None of the rabbits died during the 21-day study period.
DERMAL IRRITATION
Very slight dermal irritation was noted for one rabbit at the 2500 mg/kg dosage level.
BODY WEIGHT AND WEIGHT GAIN
There were no statistical differences found between the control and test groups.
HAEMATOLOGY
There were no treatment-related differences noted in the hematology data in this study.
CLINICAL CHEMISTRY
Although there was one statistically significant difference noted, this was not considered physiologically meaningful or treatment-related. The mid-dose female SGOT mean was significantly lower than the control mean, however, there were only four females in each group and the difference was only 5 IU/1. Therefore the statistically significant difference observed does not have any biological significance.
ORGAN WEIGHTS
The comparison of the control and treated group means for body and organ weights did not show any important differences.
GROSS PATHOLOGY
The skin from the application site was described as erythematous in one, two and seven animals of groups I, III and IV, respectively. The lungs presented foci or areas of congestion that were considered unrelated to the application of the test compound.
HISTOPATHOLOGY: NON-NEOPLASTIC
The skin from the application site presented mainly infiltration of inflammatory cells in the dermis with slight severity in both control and treated groups. Slight hyperkeratosis was observed in three males and four females in group IV. These lesions were very slight and represent a minimal reaction to the test compound.
The foci of myocarditis found in some treated animals were considered unrelated to the application of the test compound since they are observed from time to time in control animals. - Dose descriptor:
- NOAEL
- Effect level:
- > 2 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: One female in the 2500 mg/kg test group exhibited dermal irritation during the 21-day study period.
- Critical effects observed:
- not specified
- Conclusions:
- The NOAEL was considered to be > 2500 mg/kg. Very slight dermal irritation was noted for one rabbit at this dosage level. No compound related changes were seen in general behavior and appearance, body weight, clinical laboratory tests, organ weights or survival.
- Executive summary:
In a dermal study in New Zealand White rabbits, the test substance was applied 5 days a week for 3 weeks at dosage levels of 100, 500 and 2500 mg/kg. Four male and four female rabbits were used in each treated group and in a control group. 0.9% physiological saline was used as the control substane. The rabbits were observed daily for signs of dermal irritation and changes in general behavior and appearance. Individual body weights were recorded weekly Hematologic and biochemical studies were conducted once in the pretest period and at 21 days of study.
The NOAEL was considered to be > 2500 mg/kg. Very slight dermal irritation was noted for one rabbit at this dosage level. No compound related changes were seen in general behavior and appearance, body weight, clinical laboratory tests, organ weights or survival.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 500 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rabbit
- Quality of whole database:
- 1 (reliable without restriction)
Additional information
Oral:
A short-term dietary study (10 days) in rats and mice (Fujitani, 1993) showed a NOAEL of 905 mg/kg bw in rats and of 3571 mg/kg bw in mice. Effects included decreased body weight and increased (rel) liver weights with enlarged (glossy) hepatocytes and eosininophilic foci around the protal vein. In high dosed decreased kidney weights were reported without histopathological changes. In addition, in a 35 day study in rats (Sodemoto, 1979) animals at the highest dose groups died. Symptoms in decendents were severe decrease in body weight. Morpholical effects were limited to atrophy of the spleen and lymphnodes at 4 and 8% in diet. At the NOAEL 2% in diet no morphological changes were reported. In a limited reported 90-day study in rats (Weil, 1953) a NOAEL of 2620 mg/kg bw was established based on reduced body weight gain, increased relative liver and kidney weights and pathological changes in liver and kidneys at 6290 mg/kg bw/day.
The overall NOAEL for repeated dose toxicity is based on a chronic toxicity study and is set at 1000 mg/kg bw/day (Sodemoto, 1979).
Dermal:
A 21-day dermal toxicity study with rabbit (Marroquin, 1981) which run on analog substance Benzoic acid (65-85-0) is available. No effects were found at the highest dose level, thus the NOAEL was > 2500 mg/kg bodyweight.
Inhalation:
A repeated inhalation toxicity study with rat (Benson, 1981) which was run on an analog substance Benzoic acid (65-85-0) is available. All test concentrations induced local effects: nasal redness and discharge and pulmonary fibrosis and inflammatory cell infiltrates in the lungs that can be related to the irritant properties of the test substance. Hence these are not taken into account in relation to classification.
No systemic effects were noted at 25 mg/m3. At 250 mg/m3 a very slight decrease in absolute kidney weight was seen in females only (body weight was also slightly lower (not significantly) than in control females). At the highest dose level mortality, decreased body weights as well as decreased liver kidney and lung weights were reported. No histopathological findings except in the lungs were reported. The NOAEL for local effects is < 25 mg/m3; The NOAEL for systemic effects is 250 mg/m3. At 1,200 mg/m3 significant adverse toxicological effects were observed.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study was read-across from benzoic acid. It was carried out with rabbits according to a reliable method.
Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Only one read-across study from benzoic acid is available.
Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Only one read-across study from benzoic acid is available.
Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung
Justification for classification or non-classification
Oral: NOAEL > 1000 mg/kg bw in a chronic toxicity study > 90 days.
Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.9.2 and 3.9.3 the substance is not classified for the repeated oral toxicity endpoint.
Dermal: A dermal value of 833 mg/kg bw (which is above 200 mg/kg bw) does not lead to the substance being classified.
Inhalation: Classification of STOT RE comes from the consideration of the dose/concentration which has been shown to produce significant health effects. In Bensen 1981 significant systemic toxic effects were seen to occur at 400 mg/m3 (28 day result: 1200 mg/m3). Local effects are not taken into consideration as these are considered to be related to the irritant nature of the substance and not associated with substance toxicity itself. This then leads to the substance not being classified for inhalation (STOT RE effect >200 mg/m3).
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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