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EC number: 202-112-7 | CAS number: 91-97-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1997-10-17 to 1998-02-23
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 998
- Report date:
- 1998
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 1995
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- 1996
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 3,3'-dimethylbiphenyl-4,4'-diyl diisocyanate
- EC Number:
- 202-112-7
- EC Name:
- 3,3'-dimethylbiphenyl-4,4'-diyl diisocyanate
- Cas Number:
- 91-97-4
- Molecular formula:
- C16H12N2O2
- IUPAC Name:
- 3,3'-dimethylbiphenyl-4,4'-diyl diisocyanate
- Test material form:
- solid
1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 178 - 213 g (males); 154 - 190 g (females)
- Housing: housed in groups of five by sex in polypropylene grid-floor cages suspended over trays lined with adsorbent paper
- Diet: ad libitum (pelleted diet (Rat and Mouse SQC Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK))
- Water: free access to food and water (supplied from polycarbonate bottles attached ot the cage).
- Acclimation period: 14 days
DETAILS OF FOOD AND WATER QUALITY: The diet and drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- For oral exposure by gavage a stainless steel cannula attached to a disposable plastic syringe was used.
- Vehicle:
- arachis oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test material was prepared at the appropriate cocentrations as a suspension in dried Arachis oil BP.
VEHICLE
- Justification for use and choice of vehicle: arachis oil was used due to high instability of test material in aqueous media and in the presence of methanol
- Concentration in vehicle: 3.75 mg/mL; 37.5 mg/mL; 250 mg/mL
- Treatment volume: 4 mL/kg
- Lot/batch no.: GD-076
- Purity: 99.9 % - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test material was shown to be highly unstable in aqueous media and also in the presence of methanol. The instability was such that degradation occured rapidly producing a relatively stable degradation product. The test material concentrations were, therefore, determined by monitoring the test material degradation peak produced in the presence of methanol.
The test material formulations were diluted with methanol to give a final, theoretical test material concentration of approximately 0.1 mg/mL. The formulations were stable for at least eleven days. - Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 15 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 150 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:
- five
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: 14 day range-finding study
- Positive control:
- Not applicable
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: clinical observations (immediately before dosing and one and five hours after dosing furing the working week; immediately before dosing and 1 hour after dosing at weekends)
- Cage side observations checked: signs of toxicity, ill-health or behavioural change
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the start of treatment and on days 7, 14, 21 and 27
- Following parameters were observed: gait, tremors, twitches, convulsions, bizarre/abnormal/stereotypic behaviour, salivation, pilo-erection, exophthalmia, lachrymation, hyper/hypothermia, skin colour, respiration, palpebral closure, urination, defaecation, transfer arousal, tail elevation
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 7, 14, 21, 28; at terminal kill
FOOD CONSUMPTION: Yes
- Time schedule: weekly (each cage group)
- calculated as g/rat/week
FOOD EFFICIENCY: Yes
- Time schedule: weekly (each cage group)
- calculated as followed: Group mean bodyweigh gain (g/rat/week)/ Group mean food consumption (g/rat/week)
WATER CONSUMPTION: Yes
- Time schedule: daily (each cage group)
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 28 (repeat samples on Day 29 prior to necropsy, where necessary)
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: All animals from each test and control group
- Parameters examined: Haemoglobin (Hb); Erythrocyte count (RBC); Haemoatocrit (Hct); Erythrocyte indices (mean corpuscular haemoglobin (MCH); mean corpuscular volume (MCV); mean corpuscular haemoglobing concentration (MCHC)); Total leucocyte count (WBC); Differential leucocyte count (neutrophils (Neut); lymphocytes (Lymph); monocytes (Mono); eosinophils (Eos); basophils (Bas)); Platelet cout (PLT); Reticulocyte count (Retic)
BLOOD CHEMISTRY: Yes
- Time schedule for collection of blood: Day 28 (repeat samples on Day 29 prior to necropsy, where necessary)
- Animals fasted: No
- Parameters checked: urea, glucose, total protein, albumin, albumin/globulin (A/G) ratio by calculation, sodium, potassium, chloride, calcium, inorganic phosphorus, aspartate, aminotransferase, alkaline phosphatase, creatinine, total cholesterol, total bilirubin
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to the start of treatment and on days 7, 14, 21 and 27; on day 27 sensory reactivity was assessed
- Dose groups that were examined: each animal of each dose group
- Battery of functions tested: sensory activity, grip strength (forelimb and hindlimb), motor activity - Sacrifice and pathology:
- On completion of the dosing period all animals were killed by intravenious overdose of sodium pentobarbitone (Sagatal, 60 mg/ml; May and Baker Limited, Dagenham, Essex, UK) followed by exsanguination.
GROSS PATHOLOGY: Yes
All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
Organ Weights: adrenals, kidneys, testes, brain, liver, thymus, epididymides, ovaries, heart, spleen
HISTOPATHOLOGY: Yes
Samples of the following tissues were removed from all animals and preserved in buffered 10% formalin:
Adrenals, aorta (thoracic), bone & bone marrow (femur including stifle joint), bone & bone marrow (sternum), brain (including cerebrum, cerebellum and pons), caecum, colon, duodenum, epididymides, eyes, gross lesions, heart, ileum, jejunum, kidneys, liver, lungs (with bronchi), lymph nodes (cervical and mesenteric), muscle (skeletal), oesophagus, ovaries, pancreas, pituitary, prostate, rectum, salivary glands (submaxillary) sciatic nerve, seminal vesicles, skin (hind limb), spinal cord (cervical), spleen, stomach, testes, thymus, thyroid/parathyroid, trachea, urinary bladder, uterus - Statistics:
- Data were processed to give group mean values and standarf deviations where appropriate..
Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight), weekly bodyweight gain and quantitative functional performance data were assessed for dose response relationships by linear regression analysis followed by one way analysis of variance (ANOVA) incorporating Levene's test for homogeneity of variance. Where variances were shown to be homogenous pairwise comparisons were conducted using Dunnetts's test. Where Levene's test showed unequal variances the data were analysed using non-parametic methods: Kruskal-Wallis ANOVA and Mann-Whitney "U" test.
The haematology variable basophils was not analysed since consistently greater than 30 % of the data were recorded as the same value.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Animals of either sex treated with 1000 mg/kg/day showed increased salivation approximately two minutes after dosing from Day 6 onwards. From Day 14 increased salivation was occasionally observed prior to or up to one hour after dosing together with sporadic incidents of red/brown staining around the mouth. The incidence of these observations increased as the study progressed and by Day 27 one male showed further clinical signs, which continued throughout Day 28. These included hunched posture, pilo-erection, noisy respiration, dehydration and red/brown staining around the mouth and snout. Another male from this treatment group developed hunched posture five hours after dosing on Day 27 and by the end of Day 28 red/brown staining around the snout was also apparent.
No clinically observable signs were detected in animals treated with 150 or 15 mg/kg/day throughout the study period. - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Males treated with 1000 mg/kg/day showed a reduction in bodyweight gain during Weeks 2 and 4 of the study when compared with controls. The reduction resulted in statistical significance being attained during Week 2 (p < 0.05) and one male showed static bodyweight during this time. A further two males showed bodyweight losses during Week 4. A reduction in bodyweight gain was also detected for 1000 mg/kg/day females during Weeks 1 and 3 but this did not achieve statistical significance at any time.
No adverse effect on bodyweight development was detected for animals of either sex treated with 150 or 15 mg/kg/day. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Males treated with 1000 mg/kg/day showed a reduction in dietary intake and food efficiency during Weeks 2 and 4.
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- Males treated with 1000 mg/kg/day showed a reduction in dietary intake and food efficiency during Weeks 2 and 4. A slight reduction in food efficiency was also detected for females treated with 1000 mg/kg/day during Weeks 1 and 3 when compared with that of controls.
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A statistically significant reduction in plasma glucose was detected for males treated with 1000 mg/kg/day when compared with controls, with three of the individual values outside the normal range for rats of the strain and age used.
There were no treatment-related effects detected for females treated with 1000 mg/kg/day or for animals of either sex dosed at 150 or 15 mg/kg/day.
The remaining statistically significant intergroup differences were either isolated, minimal (p < 0.05) changes or changes where the dose relationship was unconvincing. In all instances, the individual values were within the respective normal ranges and, as such, all were regarded as fortuitous. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in the functional performance parameters measured. Statistical analysis of data revealed no intergroup differences.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no toxicologically significant changes in the organ weights measured.
A statistically significant reduction in absolute kidney and thymus weight was detected for males treated with 1000 mg/kg/day when compared with controls. In the absence of any such changes detected in the respective relative weights or any evidence of adverse histopathological kidney or thymus changes, the intergroup differences were considered to be without toxicological importance. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Macroscopic examination of 1000 mg/kg/day animals revealed treatment-related gastric changes. The stomach contents of three males and two females contained residual test material and one of the affected males also showed gaseous distension of the gastro-intestinal tract.
No treatment-related macroscopic abnormalities were detected for animals of either sex treated with 150 or 15 mg/kg/day. The remaining incidental findings recorded for two males from either dose group, identified as dark areas on various lobes of the lungs, whilst showing no dose-related response, were consistent with normally expected, low incidence findings in laboratory maintained rats and were, therefore, of no toxicological importance. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment-related gastric changes were observed. Hyperkeratosis and occasionally acanthosis were observed in the forestomach of animals of either sex treated with 1000 mg/kg/day. Animals from the remaining dose groups were not similarly affected.
A residue of test material was also observed to overlie the forestomach epithelium for the majority of animals treated with 1000 mg/kg/day and one male and one female dosed at 150 mg/kg/day. The presence of test material in the absence of histopathological changes should not be employed in establishing a no observed effect level since it is not intrinsically an adverse effect.
Although an increased severity of hepatocyte vacuolation was observed in the liver of animals dosed at 1000 mg/kg/day, this was considered to be unrelated to treatment. The vacuolation was of the glycogen storage type, which is very variable amongst control rats at this facility, and the appearance of somewhat higher grades amongst 1000 mg/kg/day treated rats was considered to be purely fortuitous.
All remaining morphological changes were those commonly observed in laboratory maintained rats of the age and strain employed, and there were no differences in incidence or severity between control and treatment groups that were considered to be of toxicological significance. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Behavioural assessment revealed isolated observations for individual males treated with 1000 mg/kg/day during Weeks 3 and 4. One male showed pilo-erection during Week 3 followed by another male showing hunched posture, pilo-erection, laboured and noisy respiration and decreased respiratory rate during Week 4. A further two males were reported as having hunched posture or noisy respiration respectively during this time. These observations were consistent with the changes seen clinically at 1000 mg/kg/day during the study period.
No such observations were detected for animals of either sex treated with 150 or 15 mg/kg/day. - Details on results:
- 1. Mortality
There were no deaths during the study.
2. Clinical Observations
Animals treated with 1000 mg/kg/day showed increased salivation approximately two minutes after dosing from Day 6 onwards followed by sporadic incidents of increased salivation prior to and up to one hour after dosing and red/brown staining around the mouth during the final two weeks of treatment. One male from this dose group developed observations including hunched posture, piloerection, noisy respiration and dehydration on Days 27 and 28 whilst a further male showed hunched posture five hours after dosing on Day 27 followed by increased salivation and red/brown staining around the snout on Day 28.
No clinically observable sign were detected in animals treated with 150 or 15 mg/kg/day.
3. Functional Observations
3.1 Behavioural Assessments
Behavioural assessment revealed isolated observations for one male treated with 1000 mg/kg/day during Week 3 and three males from this dose level during Week 4, supporting the observations seen clinically during the study period.
No such observations were detected for animals of either sex treated with 150 or 15 mg/kg/day during the study period.
3.2 Functional Performance Tests
No intergroup differences were detected.
3.3 Sensory Reactivity Assessments
No intergroup differences were detected.
4. Bodyweight
Males treated with 1000 mg/kg/day showed a reduction in bodyweight gain during Weeks 2 and 4 with individual bodyweight losses/static gain seen on both occasions. Females from this dose level also showed a slight reduction in bodyweight development during the first and third week of treatment.
No adverse effect on bodyweight development was detected at 150 or 15 mg/kg/day.
5. Food Consumption
Males treated with 1000 mg/kg/day showed a reduction in dietary intake and food efficiency during Weeks 2 and 4. A slight reduction in food efficiency was also detected for females treated with 1000 mg/kg/day during Weeks 1 and 3 when compared with that of controls.
No adverse effect on dietary intake was detected for animals of either sex treated with 150 or 15 mg/kg/day.
6. Water Consumption
No intergroup differences were detected.
7. Haematology
No treatment-related effects were detected.
8. Blood Chemistry
Males treated with 1000 mg/kg/day showed a reduction in plasma glucose when compared with controls.
Females from the 1000 mg/kg/day dose group and animals of either sex treated with 150 or 15 mg/kg/day showed no such change.
9. Organ Weights
No treatment-related effects were detected.
10. Necropsy
The stomach contents of three males and two females treated with 1000 mg/kg/day contained residual test material and one male showed gaseous distension of the gastro-intestinal tract.
No treatment-related macroscopic abnormalities were detected for animals treated with 150 or 15 mg/kg/day.
11. Histopathology
Microscopic examination of stomach sections revealed changes identified as hyperkeratosis and occasionally acanthosis in the forestomach of animals of either sex treated with 1000 mg/kg/day.
No such changes were detected for animals of either sex treated with 150 or 15 mg/kg/day.
A residue of test material was also observed to overlie the forestomach epithelium for the majority of animals treated with 1000 mg/kg/day and one male and one female from the 150 mg/kg/day dose group, but this is not intrinsically an adverse effect and was, therefore, considered not to be toxicologically important.
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- gross pathology
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- stomach
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The subacute toxicity oral of TODI was assessed in a study performed according to OECD Guideline 407 in rats. The "No Observed Effect Level" (NOEL) was determined to be 150 mg/kg/day.
- Executive summary:
The study was designed to investigate the systemic toxicity of the test material according to EU Method B7 and OECD Guidelines No. 407 "Repeated Dose 28 Day Oral Toxicity Study in Rodents".
The test material was administered by gavage to three groups, each of five male and five female Sprague-Dawley Crl:CD(R)BR strain rats, for twenty-eight consecutive days, at dose levels of 15, 150 and 1000 mg/kg/day. A control group of five males and five females was dosed with vehicle alone (dried Arachis oil BP). Chemical analysis showed that the test material decomposed rapidly and, as such, the systemic toxicity identified was probably attributable to the degradation product(s) of TODI.
Clinical signs, functional observations, bodyweight development and food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study.
All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.
The results are summarised as follows:
Mortality
There were no deaths during the study.
Clinical Observations
Animals treated with 1000 mg/kg/day showed increased salivation approximately two minutes after dosing from Day 6 onwards followed by sporadic incidents of increased salivation prior to and up to one hour after dosing and red/brown staining around the mouth during the final two weeks of treatment. One male from this dose group developed observations including hunched posture, piloerection, noisy respiration and dehydration on Days 27 and 28 whilst a further male showed hunched posture five hours after dosing on Day 27 followed by increased salivation and red/brown staining around the snout on Day 28.
No clinically observable sign were detected in animals treated with 150 or 15 mg/kg/day.
Functional Observations
Behavioural Assessments
Behavioural assessment revealed isolated observations for one male treated with 1000 mg/kg/day during Week 3 and three males from this dose level during Week 4, supporting the observations seen clinically during the study period.
No such observations were detected for animals of either sex treated with 150 or 15 mg/kg/day during the study period.
Functional Performance Tests
No intergroup differences were detected.
Sensory Reactivity Assessments
No intergroup differences were detected.
Bodyweight
Males treated with 1000 mg/kg/day showed a reduction in bodyweight gain during Weeks 2 and 4 with individual bodyweight losses/static gain seen on both occasions. Females from this dose level also showed a slight reduction in bodyweight development during the first and third week of treatment.
No adverse effect on bodyweight development was detected at 150 or 15 mg/kg/day.
Food Consumption
Males treated with 1000 mg/kg/day showed a reduction in dietary intake and food efficiency during Weeks 2 and 4. A slight reduction in food efficiency was also detected for females treated with 1000 mg/kg/day during Weeks 1 and 3 when compared with that of controls.
No adverse effect on dietary intake was detected for animals of either sex treated with 150 or 15 mg/kg/day.
Haematology
No treatment-related effects were detected.
Blood Chemistry
Males treated with 1000 mg/kg/day showed a reduction in plasma glucose when compared with controls.
Females from the 1000 mg/kg/day dose group and animals of either sex treated with 150 or 15 mg/kg/day showed no such change.
Organ Weights
No treatment-related effects were detected.
Necropsy
The stomach contents of three males and two females treated with 1000 mg/kg/day contained residual test material and one male showed gaseous distension of the gastro-intestinal tract.
No treatment-related macroscopic abnormalities were detected for animals treated with 150 or 15 mg/kg/day.
Histopathology
Microscopic examination of stomach sections revealed changes identified as hyperkeratosis and occasionally acanthosis in the forestomach of animals of either sex treated with 1000 mg/kg/day.
No such changes were detected for animals of either sex treated with 150 or 15 mg/kg/day.
A residue of test material was also observed to overlie the forestomach epithelium for the majority of animals treated with 1000 mg/kg/day and one male and one female from the 150 mg/kg/day dose group, but this is not intrinsically an adverse effect and was, therefore, considered not to be toxicologically important.
Conclusion
Oral administration of the test material, TODI, to rats for a period of twenty-eight consecutive days, at dose levels of up to 1000 mg/kg/day resulted in toxicologically significant effects at 1000 mg/kg/day. No such effects were demonstrated in animals treated with 150 or 15 mg/kg/day and the "No Observed Effect Level" (NOEL) was, therefore, considered to be 150 mg/kg/day.
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