Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 228-787-8 | CAS number: 6358-85-6
- 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
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 26 JUL 2000 to 02 OCT 2000
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- Guideline study (OECD TG 422)
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
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)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2,2'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[3-oxo-N-phenylbutyramide]
- EC Number:
- 228-787-8
- EC Name:
- 2,2'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[3-oxo-N-phenylbutyramide]
- Cas Number:
- 6358-85-6
- Molecular formula:
- C32H26Cl2N6O4
- IUPAC Name:
- 2-[2-(3,3'-dichloro-4'-{2-[2-oxo-1-(phenylcarbamoyl)propyl]diazen-1-yl}-[1,1'-biphenyl]-4-yl)diazen-1-yl]-3-oxo-N-phenylbutanamide
- Test material form:
- solid: nanoform
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- strain: Wistar Crl:(WI) BR (outbred, SPF)
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 14 weeks
- Weight at study initiation: group means males: 489-501 g; group means females: 267-271 g
- Fasting period before study: no
- Housing:
acclimatisation period: 5 animals per sex per cage, stainless steel suspended cages with wire mesh floors
mating period: 1 female together with 1 male, stainless steel suspended cages with wire mesh floors
after mating: animals were housed individually, Macrolon cages (Type III)
- Diet: standard pelleted laboratory animal diet (Carfil Quality BVBA, Oud-Turnhout, Belgium), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 26 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: polyethylene glycol 400
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- formulations (w/w) were prepared daily within 4 hours prior to dosing
- storage at ambient temperature
VEHICLE
- vehicle: polyethylene glycol 400, specific gravity: 1.125
- Justification for use and choice of vehicle: based on trial fromulations
- Concentration in vehicle: 0 mg/g; 4.45 mg/g; 17.8 mg/g; 89.9 mg/g
- Amount of vehicle: 10 ml/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical study was performed to check accuracy of preparation and to determine stability and homogeneity of test substance preparation.
Test samples were dissolved in chloroform by sonication and analysed spectrophotometrically. - Duration of treatment / exposure:
- F0-males:
- for 2 weeks prior to mating, throughout mating and after mating at least until the minimum total dosing period of 28 days had been completed
F0-females:
2 weeks prior to mating, throughout mating, and pregnancy and at least up to, and including the day before sacrifice - Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 50 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of a dose range finding study with the test item (5 days oral exposure of male and female rats to 50, 200 and 1000 mg/kg bw/day did not cause changes in clinical appearance, body weights, food consumption, macroscopic examination and organ weights)
- Positive control:
- none
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily in the home cage and twice during the complete study in a standard arena
BODY WEIGHT: Yes
- Time schedule for examinations:
F0-males and F0-females: on the first day of dosing and weekly thereafter
mated females were weighed daily from day 0 until day 20 of gestation inclusive
F0-females were weighed daily during lactation
F1-pubs were weighed on day 1 and 4 post partum
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly, but not during the mating period
WATER CONSUMPTION: Yes
- Time schedule for examinations: subjective appraisal during the study, no quantitative investigation
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: just prior to killing
- Anaesthetic used for blood collection: Yes (ether anaesthesia)
- Animals fasted: Yes (overnight with a maximum of 20 hours)
- How many animals: 5 males and 5 females randomly selected from each group
- Parameters: erythrocyte count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count, red cell distribution width, total leucocyte count, differential leucocyte count, prothrombin time, partial thromboplastin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just prior to killing
- Animals fasted: Yes (overnight with a maximum of 20 hours)
- How many animals: 5 males and 5 females randomly selected from each group
- Parameters: alanine aminotransferase, aspartate aminotransferase, total bilirubin, total cholesterol, triglycerides, creatinine, glucose, urea, total protein, albumin, globulin, albumin globulin ratio, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorus
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once, males during week 4 of treatment, femals during lactation (all before blood sampling)
- Dose groups that were examined: all dose groups
- Battery of functions tested: hearing ability / pupillary reflex / static righting reflex / grip strength / motor activity
OTHER:
Observations on females and litters, calculation of reproduction parameters are reported in section 7.8. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (cranial, thoracic, abdominal tissues and organs with special attention to the reproductive organs)
HISTOPATHOLOGY: Yes
from all animals:
accessory sex organs
epididymides (fixed in Bouin's fixative)
ovaries
testes (fixed in Bouin's fixative)
all macroscopic lesions
from 5 animals/sex/group:
adrenal glands
bone marrow
brain
cervix
heart
kidneys
liver
lung, infused with formalin
lymph nodes - mandibular, mesenteric
oesophagus
sciatic nerve
small and large intestines (including Peyer's patches)
spinal cord -cervical, midthoracic, lumbar
spleen
stomach
thymus
thyroid including parathyroid
trachea
urinary bladder
uterus
vagina
all gross lesions - Other examinations:
- ORGAN WEIGHTS
- from all males: epididymides, testes
- from 5 animals/sex/group: adrenal glands, brain, heart, kidneys, liver, spleen, thymus - Statistics:
- - Dunnett-test
- Steel-test
- exact Fisher-test
Results and discussion
Results of examinations
- 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 examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No treatment related clinical signs were observed.
Almost all animals of the control and treated groups showed scabbing, red/brown staining of various body parts, and diarrhoea. Erythema of the anus was seen in all males during the last three weeks of the study period, and piloerection was observed in almost all females. The vehicle (polyethylene glycol) that was used, is known to cause these effects. Therefore, these findings were considered to be of no toxicological significance.
Almost all animals showed alopecia of various parts of the body. Alopecia is commonly seen in group housed rats and therefore no toxicological significance was attached to this finding. Greenish/yellowish faeces and yellow staining of various body parts were observed in almost all animals of the treated groups. This was probably due to the staining properties of the test substance.
Incidental findings included lethargy, rales, hunched posture, laboured respiration, piloerection and reddish faeces in males, chromodacryorrhoea, salivation, and emaciation and are commonly.
One male receiving 200 mg/kg was killed in extremis after showing severe clinical signs. Two males (one of the control and one of the 50 mg/kg dose group) died spontaneously. These three deaths were considered to be unrelated to treatment, because there were no macroscopic findings suggesting a relation with treatment and there were no other death among the animals. No unscheduled deaths occurred among the females.
BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain of treated animals remained in the same range as controls.
Except on day 8 of the pre-mating period, when the males of the treatment groups showed a statistical significant reduction in body weight gain when compared to the control group. And on days 2 and 3 of lactation, when females of the 50 mg/kg dose group showed a statistical significant reduced body weight gain. These incidental reductions were considered to have arisen by chance and not to represent a change of toxicological significance.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no differences in food consumption (absolute and relative) between treated and control animals.
Except on days 2-3 of lactation, when females of the 50 mg/kg dose group showed a statistical significant reduced food consumption (absolute and relative) when compared to the control group. This incidental difference showed no dose relationship and was considered to has arisen by chance and to be of no toxicological relevance.
HAEMATOLOGY
The haematological profile was not disturbed by treatment.
Statistically significant differences for Erythrocyte counts (RBC) of males and females in group 2 (50 mg/kg) did not form a dose response relationship. Therefore, this finding was considered to be of no toxicological relevance.
Monocyte counts were statistically significant decreased in males of group 3 (200 mg/kg). Haemoglobin (HB), haematocrit (HCT), and mean corpuscular haernagiobin (MCHC) values of females in group 2 were statistically significant increased when compared to that of the controls. However, similar findings in the opposite sex were absent and no dose relationship was observed. Therefore, the toxicological significance of these findings was considered to be doubted.
CLINICAL CHEMISTRY
The clinical blochemistry parameters were not changed by treatment.
Alanine aminotransferase (ALAT) activity, Aspartate aminotransferase (ASAT) activity, and inorganic phosphate values were statistically significant decreased and total protein values were statistically significant increased in the males of group 3 (200 mg/kg) when compared of the control values. Alanine aminotransferase (ALAT) activity, Aspartate aminotransferase (ASAT) activity, bilirubin, and triglyceride values were increased among high dose females, being mainly attributable to one high individual value (female no. 77). On exclusion of this value, average values were slightly decreased for ALAT and ASAT, and bilirubin and triglyceride were similar when compared to the controls.
Creatine values were statistically significant decreased in females of group 2 (50 mg/kg), and glucose values were statistically significant increased in females of group 3 (200 mg/kg) when cempared to the control values. However, similar findings in the opposite sex were absent and no dose relationship was observed. Therefore, the toxicological significance of these findings were considered to be irrelevant.
Chloride values of males of group 4 (1000 mg/kg) were statistical significant decreased, and total globuline values were statistical significant increased in males of groups 3 and 4. This was considered to be due to slightly high or low control values respectively.
NEUROBEHAVIOUR
No changes were observed in hearing ability, pupillary reflex, static righting reflex and grip strength in the treated animals, when compared to control animals.
Extremely increased motor activity was noted by the high sensors for the 200 mg/kg treated males (no. 23, 25 and 28). Since an increase in motor activity recorded by the high sensors is unlikely to occur without an concurrent change recorded by the low sensors, the increased motor activity was considered to have occurred by chance and of no toxicological significance.
Increased motor activity was noted by the low sensors for the 50 mg/kg (no. 14) and 1000 mg/kg treated males (no. 32 and 33). Since no corroborative findings were noted during clinical observations of the animals, this was considered to have occurred by chance without any toxicological relevance.
Decreased motor activity was noted by the low sensors for one control female (no. 41) and one 1000 mg/kg treated female (no. 71). Since the counts per sample period were often very low or even zero, these recordings were excluded from interpretation.
ORGAN WEIGHTS
Organ weights and organ:body weight ratios of treated animals were considered to be similar to those of control animals.
GROSS PATHOLOGY
Macroscopic observations of the remaining animals at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.
Six males of the 1000 mg/kg and 2 males of the 200 mg/kg dose group showed a greenish contents in the gastro-intestinal tract. In the absence of correlated microscopic findings these findings were considered to be due to the presence of undigested pigment, and although treatment-related, of limited toxicological significance.
At the 1000 mg/kg dose group, one male showed yellow foci on the lungs, and another male showed yellow foci on the lungs, a yellowish discolouration of the trachea and oesophagus. These findings were considered to be due to gavage errors, and without toxicological significance.
One male of the control group which died spontaneously showed a thoracic cavity containing cloudy gray/white fluid. One male of 200 mg/kg dose group was killed in extremis and showed a gastro-intestinal tract which contained fluid and was distended with gas, a dark red discolouration of the glandular mucosa of the stomach, and a spleen reduced in size.
Incidental findings included an enlarged caecum or adrenal glands, the testes, epididymis or seminal vesicles reduced in size, and red foci on the thymus.
Three females in the 200 mg/kg dose group and one female in the 50 mg/kg dose group showed a dark red discolouration of the mandibular lymph node. Incidental findings included a caecum with a greenish contents, pelvic dilatation of the kidney, a red-brown discolouration of the clitoral gland, irreguter surface of the spleen, and a thymus reduced in size.
HISTOPATHOLOGY: NON-NEOPLASTIC
There were no microscopic findings recorded which could be attributed to treatment with the test substance.
All microscopic findings were within the range of background pathology encountered in Wistar rats of this age and strain and occurred at similar incidences and severity in both control and treated rats.
The assessment of the integrity of the spermatogenetic cycle did not provide any evidence of impaired spermatogenesis.
OTHER:
There were no treatment related findings on reproduction. Details are presented in section 7.8.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- There were no changes in clinical appearance, functional observations, body weights, food consumption, clinical laboratory investigations, reproduction, litter observation, macroscopic examination, organ weights and microscopic examination that were considered to be an effect of treatment.
From the results presented in this report a definitive No Observed Adverse Effect Level (NOAEL) for parental and reproduction/developmental toxicity for the test item of 1000 mg/kg/day was established. - Executive summary:
A combined repeated dose toxicity study with reproduction/developmental toxicity screening test with the test item administered by oral gavage in Wistar rats (10/sex/dose) was performed according to OECD TG 422. The dose levels for this study were 0, 50, 200 and 1000 mg/kg/day. Oral dosing of male and fernale Wistar rats (10 per sex and group) with the test item at dose levels of 50, 200 or 1000 mg/kg b.w./day for at least 28 days, revealed no treatment-related findings on parental animals, on fertility, on embryo-foetal development, or on pup development. From the results presented in this report a definitive No Observed Adverse Effect Level (NOAEL) for parental and reproduction/developmental toxicity for the test item of 1000 mg/kg/day was established.
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.