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EC number: 251-311-5 | CAS number: 32961-44-7
- 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
Carcinogenicity
Administrative data
- Endpoint:
- carcinogenicity: dermal
- Remarks:
- subcutan
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- Until June 1974
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- study sufficiently documented to support information from genetic toxicity studies
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 974
- Report date:
- 1974
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test: In an orienting carcinogenesis study, rats were dosed with the test item.
- Short description of test conditions: Rats were injected doses of the test item of 500 - 1000 mg/kg in intervals of 1 - 5 weeks subcutaneously.
- Parameters analysed / observed: Body weight gains, behaviour, appearance, survival time, localisation and amount of tumours. - GLP compliance:
- no
- Remarks:
- conducted prior to GLP implementation
Test material
- Reference substance name:
- Isobutyl 4-chloro-3,5-diaminobenzoate
- EC Number:
- 251-311-5
- EC Name:
- Isobutyl 4-chloro-3,5-diaminobenzoate
- Cas Number:
- 32961-44-7
- Molecular formula:
- C11H15ClN2O2
- IUPAC Name:
- 2-methylpropyl 3,5-diamino-4-chlorobenzoate
- Test material form:
- solid
Constituent 1
- Specific details on test material used for the study:
- OTHER SPECIFICS: LD50 of the aqueous suspension with single subcutaneous application was >5000 mg/kg in female Wistar-W.64 rats weighing 120-140 g (Breeder Winkelmann, Borchen)
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- SPF-bred Wistar-W.64 rats
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Breeder Winkelmann, Borchen
- Age at study initiation: 100 days
- Housing: conventionally, in groups of 3 in Macrolon cages
- Diet (e.g. ad libitum): Altromin-Standardfutter ad libitum
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±2°C
Administration / exposure
- Route of administration:
- subcutaneous
- Details on exposure:
- The test item was milled and, as suspension in physiological saline, injected subcutaneously in the middle of the back. Dependent of the state of the animals, the test item was injected in doses of 500 or 1000 mg/kg bw in intervals of 1 - 5 weeks. After 371 days the test item was applied a last time, a total dose of 25 g/kg was reached.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 371 days
- Frequency of treatment:
- intervals of 1 - 5 weeks
- Post exposure period:
- until death
Doses / concentrations
- Dose / conc.:
- 25 other: g/kg
- Remarks:
- total dose, single doses of 500 or 1000 mg/kg
- No. of animals per sex per dose:
- 18 (test item)
25 (control) - Control animals:
- yes, concurrent vehicle
- Positive control:
- not required
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
BODY WEIGHT: Yes
OTHER: survival time - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- see below
- 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
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- see below
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- see below
- Details on results:
- Details can be derived from attached figures.
The average survival time of the male rats treated with isobutyl 4-chloro-3,5-diaminobenzoate was 824 ± 194 days of the study (As testing started at an age of 100 days, 100 days need to be added to the days of study to calculate total lifetime of the rats, which applies also to the following information on lifetime). Of the 18 male rats, 6 died with each a malignant tumour and 2 rats with each 3 benign tumours.
The average survival time of the female rats treated with isobutyl 4-chloro-3,5-diaminobenzoate was 737 ± 236 days of the study. Of these 18 female rats, 4 died with in total 5 malignant tumours. Further, in 8 animals in total 14 benign tumours were observed.
So of the 36 isobutyl 4-chloro-3,5-diaminobenzoate-treated rats 10 died with malignant tumours (28%). Total amount of malignant tumours were 11 (referring to the total animal number 31%), the benign 17 (47%).
The average survival time of the male control rats treated with physiological saline was 834 ± 229 days of the study, the one of the females 888 ± 177 days. Of the 25 male control rats 4 died with each one malignant tumour. Of the 25 female control rats 9 died with malignant tumours, 3 of them with a double tumour. Further, in 9 animals 14 benign tumours were observed. Of the 50 control rats hence 13 (26%) died with malignant tumours. The total number of benign tumours were 15 (30%).
For the used rat strain it is characteristic that the animals (especially females) develop when aging a high percentage of tumours of the hypophysis of questionable malignancy. In this case such tumours were formed in 19% of the treated animals and 40% in the control animals.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 25 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- gross pathology
- histopathology: neoplastic
- mortality
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- compared to control
Applicant's summary and conclusion
- Conclusions:
- The available study was conducted scientifically reasonably. The study and the report do not provide equivalent information to serve as a standalone carcinogenicity study, but the given information suffices to support information from the available genotoxicity studies and to clearly indicate that isobutyl 4-chloro-3,5-diaminobenzoate does not induce tumours over background in Wistar-W.64 rats. So, isobutyl 4-chloro-3,5-diaminobenzoate does not need to be regarded as carcinogen.
- Executive summary:
In an orienting carcinogenesis study, 100 d old Wistar-W.64 rats were injected doses of isobutyl 4-chloro-3,5-diaminobenzoate of 500 or 1000 mg/kg as suspension in physiological saline in intervals of 1 - 5 weeks subcutaneously in the middle of the back. After 371 days the test item was applied a last time, a total dose of 25 g/kg was reached, and the animals were observed until death. Examined parameters were Body weight gains, behaviour, appearance, survival time, localisation and amount of tumours. All dead animals were carefully dissected and tumours / suspected tumours histologically examined.
The average survival time of the male rats treated with isobutyl 4-chloro-3,5-diaminobenzoate was 824 ± 194 days of the study. Of the 18 male rats, 6 died with each a malignant tumour and 2 rats with each 3 benign tumours. The average survival time of the female rats treated with isobutyl 4-chloro-3,5-diaminobenzoate was 737 ± 236 days of the study. Of these 18 female rats, 4 died with in total 5 malignant tumours. Further, in 8 animals in total 14 benign tumours were observed. So of the 36 isobutyl 4-chloro-3,5-diaminobenzoate-treated rats 10 died with malignant tumours (28%). Total amount of malignant tumours were 11 (referring to the total animal number 31%), the benign 17 (47%)
The average survival time of the male control rats treated with physiological saline was 834 ± 229 days of the study, the one of the females 888 ± 177 days. Of the 25 male control rats 4 died with each one malignant tumour. Of the 25 female control rats 9 died with malignant tumours, 3 of them with a double tumour. Further, in 9 animals 14 benign tumours were observed. Of the 50 control rats hence 13 (26%) died with malignant tumours. The total number of benign tumours were 15 (30%).
Despite a total dose of 25 g/kg there were neither an elevated number of malignant tumours with a specific localisation nor tumours at the injections site which is more susceptible towards carcinogenic noxa. Weight gains, behaviour, appearance and survival times do also not indicate any impairment by the substance.
So, isobutyl 4-chloro-3,5-diaminobenzoate does not need to be regarded as carcinogen.
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