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EC number: 220-135-0 | CAS number: 2638-94-0
- 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:
- 12 December 2016 - 14 December 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2018
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:
- 2015
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 4,4'-azobis[4-cyanovaleric] acid
- EC Number:
- 220-135-0
- EC Name:
- 4,4'-azobis[4-cyanovaleric] acid
- Cas Number:
- 2638-94-0
- Molecular formula:
- C12H16N4O4
- IUPAC Name:
- 4,4'-azobis[4-cyanovaleric] acid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Batch No. of test material: 150726 (Test item No.: 16/0252-1)
- Expiration date of the lot/batch: 26 July 2018
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Refrigerator
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Sulzfeld, Germany GmbH
- Females nulliparous and non-pregnant: yes
- Age at study initiation: males: 14 - 15 weeks, females: 13 weeks
- Housing: individually in polycarbonate cages
- Diet: ground Kliba maintenance diet mouse-rat “GLP” (supplied by Provimi Kliba SA, Kaiseraugst, Switzerland), ad libitum
- Water: drinking water, ad libitum
- Acclimation period: 28 days
DETAILS OF FOOD AND WATER QUALITY:
- The food used in the study was assayed for chemical and microbiological contaminants.
- The drinking water is regularly assayed for chemical contaminants as well as for the presence of microorganisms.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 -24
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5% sodium carboxymethyl cellulose in drinking water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was applied as a suspension. To prepare this suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, 0.5% sodium carboxymethyl cellulose in drinking water was filled up to the desired volume and subsequently released with a magnetic stirrer. The test substance preparations were produced weekly, at least.
VEHICLE
- Concentration in vehicle: 1.25, 4.0, 12.5 g/100 mL
- Amount of vehicle: 10 mL/kg bw/d - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The analytical investigations of the test substance preparations were carried out as a separate study. The study was carried out in compliance with the Principles of Good Laboratory Practice. At the beginning (during pre-mating), twice during gestation and once during lactation of the study each 3 samples were taken from the lowest and highest concentration for potential homogeneity analyses. These samples were used as a concentration control at the same time. At the time points mentioned above, one sample from the mid concentration was additionally taken for concentration control analysis. The samples collected at the beginning of the administration period and during the lactation period were analysed.
The stability of the test substance in 0.5% sodium carboxymethyl cellulose in drinking water was demonstrated over a period of 7 days at room temperature. As the test substance preparations were not stored longer than this time period, the stability was guaranteed. The concentrations of the test substance in 0.5% sodium carboxymethyl cellulose in drinking water were found to be in the range of 103-112% of the nominal concentration. These results demonstrated the correctness of the concentrations of the test substance in 0.5% sodium carboxymethyl cellulose in drinking water. - Duration of treatment / exposure:
- The duration of treatment covered a 2-week premating period and mating in both sexes as well as entire gestation and lactation period in females up to one day prior to the day of schedule sacrifice of the animals (End of treatment: males: Day 28, females: Day 58 or 63)
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 125 mg/kg bw/day (nominal)
- Remarks:
- Considering a purity of the test substance plus water (whole product), the effective dose levels of the test substance itself was 100 mg/kg bw/d.
- Dose / conc.:
- 400 mg/kg bw/day (nominal)
- Remarks:
- Considering a purity of the test substance plus water (whole product), the effective dose levels of the test substance itself was 300 mg/kg bw/d.
- Dose / conc.:
- 1 250 mg/kg bw/day (nominal)
- Remarks:
- Considering a purity of the test substance plus water (whole product), the effective dose levels of the test substance itself was 1000 mg/kg bw/d.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on dose range finding study
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations included: morbidity, pertinent behavioral changes and/or signs of overt toxicity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the administration period and thereafter at weekly intervals
- Detailed clinical observations included: abnormal behavior in handling, fur, skin, posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, gait abnormalities, lacrimation, palpebral closure, exophthalmos, assessment of the feces discharged during the examination (appearance/ consistency), assessment of the urine discharged during the examination, pupil size
BODY WEIGHT: Yes
- Time schedule for examinations: at study day 0 (start of the administration period) and thereafter once a week at the same time of the day (in the morning)
FOOD CONSUMPTION:
- Food consumption was determined.
FOOD EFFICIENCY:
- Food consumption was not determined.
WATER CONSUMPTION: Yes
- Time schedule for examinations: daily
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: males: at study termination (Day 29), females: PND 14 (Day 50)
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5 parental animals per sex and group
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: males: at study termination (Day 29), females: PND 14 (Day 50)
- Animals fasted: Yes
- How many animals: 5 parental animals per sex and group
- Parameters checked in table 2 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: males: Day 24, females: Day 55
- Dose groups that were examined: 5 parental animals per sex and group
- Battery of functions tested: sensory activity / grip strength / motor activity
IMMUNOLOGY: No
THYROID HORMONES: Yes
- Time schedule for collection of blood: males: at study termination (Day 29), females: PND 14 (Day 50)
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: Total thyroxine (T4) - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 3)
HISTOPATHOLOGY: Yes (see table 4) - Other examinations:
- ORGAN WEIGHTS: Yes (see table 5)
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Soft feces were observed in 2 of 10 males and 6 of 10 females of test group 3 (1000 mg/kg bw/d), starting on pre-mating day 10 until mating in both sexes and in 1 of 10 females of test groups 2 (300 mg/kg bw/d) and 1 (100 mg/kg bw/d), observed on pre-mating day 13.
The finding also occurred during mating in all males and 6 of 10 females of test group 3, starting on mating day 1 in both sexes until mating day 14 in males and mating day 2 in females, respectively. In each 1 of 10 females of test groups 2 and 1, soft feces were observed between mating day 1 and 3 as well as 1 and 8, respectively. During post-mating, soft feces were still observed in all males of test group 3 until sacrifice.
Soft feces were also observed in all females of test group 3 (1000 mg/kg bw/d) between gestation days 0 and 21. It was also observed in 1 of 10 females of test group 2 (300 mg/kg bw/d) between gestation days 0 and 4.
This finding was considered to be related to treatment but not assessed as an adverse and toxicologically relevant effect. - Mortality:
- no mortality observed
- Description (incidence):
- No animal died prematurely in the present study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test substance-related changes in mean body weights were observed for male and female animals of test groups 1-3 (100, 300 and 1000 mg/kg bw/d) when compared to the control group.
Mean body weight change values were significantly decreased in male animals of test groups 3 (1000 mg/kg bw/d) and 2 (300 mg/kg bw/d) between pre-mating days 7 and 13.
As the changes occurred rather sporadically and no significant deviations occurred in mean body weights, they were assessed to be non-adverse. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption values in female animals of test group 3 (1000 mg/kg bw/d) were significantly lower during pre-mating and significantly higher in females of test group 2 (300 mg/kg bw/d) on gestation day 20.
These values were still within a normal range typical for this strain of rats and, therefore, the deviations to the control were assessed to be without toxicological relevance. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- No test substance-related changes in water consumption were observed.
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes among hematological parameters were observed.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related, adverse changes among clinical chemistry parameters were observed.
In female animals of test groups 2 and 3 (300 and 1000 mg/kg bw/d) alkaline phosphatase (ALP) activities were significantly higher compared to controls. The values were marginally above the historical control range (ALP 0.78-1.11 µkat/L). However, the ALP mean in test group 3 was only 43% higher compared to that one of the controls. Moreover, the ALP increase was the only clinical pathology alteration in these individuals. Therefore, this change was regarded as maybe treatment-related, but not adverse (ECETOC Technical Report No. 85, 2002). - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Functional observational battery:
Deviations from "zero values" were obtained in several animals. However, as most findings were equally distributed between test-substance treated groups and controls, without a dose-response relationship or occurred in single animals only, these observations were considered as incidental.
The following examinations were performed during FOB and are assessed individually:
Quantitative Parameters:
Rearing was significantly increased in female animals of test group 1 (100 mg/kg bw/d). As no dose-response relationship occurred, the change was assessed as being spontaneous in nature and not related to treatment.
Home cage observations:
No test substance-related effects were observed.
Open field observations:
Male animal No. 33 of test group 3 (1000 mg/kg bw/d) had soft feces.
Sensorimotor tests/reflexes:
No test substance-related effects were observed.
Motor activity measurement:
Regarding the overall motor activity, no test substance-related deviations were noted for male and female animals.
Comparing the single intervals with the control groups, significantly decreased value was measured for male animals of test group 1 (100 mg/kg bw/d) at interval 8. The difference was regarded to be incidental and not related to treatment as single interval was not changed in a dose-dependent manner and the overall motor activity was not affected.
No changes were observed for female animals in test groups 1, 2 and 3 (100, 300 and 1000 mg/kg bw/d) when compared to the control group. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- When compared to control group 0 (set to 100%), all mean absolute and relative weight parameters did not show significant differences.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- All findings occurred individually. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment-related findings were observed in male and female animals.
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
The stages of spermatogenesis in the testes of males of the high dose test group were comparable to those of the controls. In the ovaries of control and high dose females the different stages of functional bodies (especially corpora lutea) were present and normal. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- Thyroid hormones:
No treatment-related findings were observed in male and female animals.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No test substance related adverse effects were observed.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- other: main constituent (corrected for purity, 100 % purity)
- Sex:
- male/female
- Basis for effect level:
- other: No test substance related adverse effects were observed.
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test, the oral administration by gavage of
ACVA (4,4'-Azobis[4-cyanovaleric] acid) to Wistar rats revealed no signs of systemic toxicity
up to a dose level of 1000 mg/kg bw/d in animals of both sexes.
Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 1000
mg/kg bw/d for male and female Wistar rats.
The NOAEL for reproductive performance and fertility was also set to 1000 mg/kg bw/d for
male and female Wistar rats.
The NOAEL for developmental toxicity was 1000 mg/kg bw/d.
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