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EC number: 278-859-8 | CAS number: 78181-99-4
- 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
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP and OECD testing guideline compliant study with well-characterized test material
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3650 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- [2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]ethyl][3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]propyl]dimethylammonium chloride
- EC Number:
- 278-859-8
- EC Name:
- [2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]ethyl][3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]propyl]dimethylammonium chloride
- Cas Number:
- 78181-99-4
- Molecular formula:
- C35H46N5O4.Cl
- IUPAC Name:
- 3-({2-cyano-3-[4-(diethylamino)phenyl]acryloyl}oxy)-N-[2-({2-cyano-3-[4-(diethylamino)phenyl]acryloyl}oxy)ethyl]-N,N-dimethylpropan-1-aminium chloride
- Test material form:
- other: liquid/reddish
- Details on test material:
- please refer to confidential details on test material
Constituent 1
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, Germany GmbH, Sulzfeld, Germany
- Age at study initiation: 10-11 weeks old
- Housing: During the study period, the rats were housed individually in Makrolon type M III cages supplied by Becker & Co., Castrop-Rauxel, Germany (floor area of about 800 cm²), with the following exceptions:
- For motor activity (MA) measurements the animals were housed individually in polycarbonate cages supplied by TECNIPLAST, Hohenpeißenberg, Germany with wire covers from Ehret, Emmendingen, Germany (floor area of about 800 cm²) and small amounts of bedding material.
- Diet: ad libitum
- Water: ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature : 20-24°C
- Humidity: 30-70%
- Air changes: 15 air per hour
- Photoperiod: day/night cycle was 12 hours
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test material was applied as a suspension. To prepare this suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, drinking water was filled up to the desired volume, subsequently released with a magnetic stirrer. During administration of the test substance, preparations were kept homogeneous by stirring with a magnetic stirrer. The test substance preparations were prepared daily. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test substance in drinking water for a period of 4 hours at room temperature was proven during the study. Homogeneity and concentration control analyses of the test-substance preparations were performed in all concentrations at the start of the administration period. Additionally, samples from all concentrations as reverse samples for concentration control analysis were taken at the end of the study.
- Duration of treatment / exposure:
- The duration of treatment covered a 2-week pre-mating and mating period (maximum: 2 weeks) in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation in females followed by an additional treatment until one day before sacrifice. Based on this, for male animals the administration period was maximum 31 days and for female animals the administration period was maximum 52 days.
- Frequency of treatment:
- daily at the same time in the morning
Doses / concentrations
- Remarks:
- Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 10 rats
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS:
- Time schedule:
1.) At least once daily: morbidity, pertinent behavioral changes, signs of overt toxicity, littering and lactation behavior of the dams
2.) On weekdays: the parturition behavior of the dams
3.) The day of littering was considered the 24-hour period from about 15.00 h of one day until about 15.00 h of the following day.
BODY WEIGHT:
Body weight was determined before the start of the administration period in order to randomize the animals. During the administration period body weight was determined on study day 0 (start of the administration period) and thereafter once a week at the same time of the day (in the morning). The body weight change of the animals was calculated from these results.
The following exceptions are notable for the female animals:
- During the mating period the parental females were weighed on the day of positive evidence of sperm gestation day (GD) 0 and on GD 7, 14 and 20.
- Females with litter were weighed on the day of parturition on postnatal day (PND) 0 and on PND 4.
- Females without a litter and without positive evidence of sperm in the vaginal smear were weighed weekly. These body weight data were solely used for the calculations of the dose volume.
FOOD CONSUMPTION :
Generally, food consumption was determined once a week for male and female parental animals, with the following exceptions:
- Food consumption was not determined during the mating period (male and female F0 animals).
- Food consumption of the F0 females with evidence of sperm was determined on GD 0-7, 7-14, 14-20.
- Food consumption of F0 females, which gave birth to a litter, was determined for PND 1-4.
Food consumption was not determined in females without positive evidence of sperm (during the mating period of dams used in parallel) and females without litter (during the lactation period of dams used in parallel).
WATER CONSUMPTION:
Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.
FUNCTIONAL OBSERVATION BATTERY:
A functional observational battery (FOB) was performed in five animals per sex and group at the end of the administration period. The FOB started with passive observations without disturbing the animals, followed by removal from the home cage, open field observations in a standard arena and sensorimotor tests as well as reflex tests. The findings were ranked according to the degree of severity, if applicable. The observations were performed at random.
MOTOR ACTIVITY ASSESSMENT:
The motor activity assessment (MA) was carried out in five animals per sex and group at the end of the administration period. Motor activity was measured on the same day as FOB was performed. - Sacrifice and pathology:
- CLINICAL PATHOLOGY:
In the morning blood was taken from the retroorbital venous plexus from overnight fasted animals. The animals were anaesthetized using isoflurane. The blood sampling procedure and subsequent analysis of blood and serum samples were carried out in a randomized sequence. For urinalysis the individual animals were transferred to metabolism cages (withdrawal of food and water) and urine was collected overnight. Urine samples were evaluated in a randomized sequence
The assays of blood and serum parameters were performed under internal laboratory quality control conditions with reference controls to assure reliable test results.
The results of clinical pathology examinations were expressed in International System (SI) units.
The following examinations were carried out in the first 5 surviving parental males and the first 5 surviving females per group:
HEMATOLOGY
The following parameters were determined:
- Leukocyte count (WBC),
- Erythrocyte count (RBC),
- Hemoglobin (HGB),
- Hematocrit (HCT),
- Mean corpuscular volume (MCV),
- Mean corpuscular hemoglobin (MCH),
- Mean corpuscular hemoglobin concentration (MCHC),
- Platelet count (PLT),
- Differential blood count,
- Reticulocytes (RET),
- Prothrombin time (Hepato Quick’s test) (HQT).
CLINICAL CHEMISTRY:
The following parameters were determined:
- Alanine aminotransferase (ALT),
- Aspartate aminotransferase (AST),
- Alkaline phosphatase (ALP),
- Gamma-Glutamyltransferase (GGT),
- Sodium (NA),
- Potassium (K),
- Chloride (CL),
- Inorganic phosphate (INP),
- Calcium (CA),
- Urea (UREA),
- Creatinine (CREA),
- Glucose (GLUC),
- Total bilirubin (TBIL),
- Total protein (TPROT),
- Albumin (ALB),
- Globulins (GLOB),
- Triglycerides (TRIG),
- Cholesterol (CHOL),
- Bile acids (TBA).
URINANALYSIS:
The following parameters were determined:
- pH,
- Protein,
- Glucose,
- Ketones,
- Urobilinogen,
- Bilirubin,
- Blood,
- Specific gravity,
- Sediment,
- Color, turbidity,
- Volume.
NECROPSY:
All parental animals were sacrificed by decapitation under isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology; special attention was given to the reproductive organs.
Weight PARAMETERS:
The following weights were determined in all animals sacrificed on schedule:
1. Anesthetized animals
2. Epididymides
3. Testes
The following weights were determined in 5 animals per sex/test group sacrificed on schedule (females with litters only, same animals as used for clinical pathological examinations):
1. Adrenal glands
2. Brain
3. Heart
4. Kidneys
5. Liver
6. Spleen
7. Thymus
ORGAN/TISSUS FIXATION:
The following organs or tissues of all parental animals were fixed in 4% buffered formaldehyde solution or modified Davidson’s solution:
1. All gross lesions
2. Adrenal glands
3. Aorta
4. Bone marrow (femur)
5. Brain
6. Cecum
7. Cervix
8. Coagulating glands
9. Colon
10. Duodenum
11. Eyes with optic nerve
12. Esophagus
13. Extraorbital lacrimal glands
14. Epididymides (modified Davidson’s solution)
15. Femur with knee joint
16. Heart
17. Ileum
18. Jejunum (with Peyer’s patches)
19. Kidneys
20. Larynx
21. Liver
22. Lungs
23. Lymph nodes (axillary and mesenteric)
24. Mammary gland (male and female)
25. Nose (nasal cavity)
26. Ovaries (modified Davidson’s solution)
27. Oviducts
28. Pancreas
29. Parathyroid glands
30. Pharynx
31. Pituitary gland
32. Prostate gland
33. Rectum
34. Salivary glands (mandibular and sublingual)
35. Sciatic nerve
36. Seminal vesicles
37. Skeletal muscle
38. Spinal cord (cervical, thoracic and lumbar cord)
39. Spleen
40. Sternum with marrow
41. Stomach (forestomach and glandular stomach)
42. Testes (modified Davidson’s solution)
43. Thymus
44. Thyroid glands
45. Trachea
46. Urinary bladder
47. Uterus
48. Vagina
HISTOPATHOLOGY:
Fixation was followed by histotechnical processing, examination by light microscopy and assessment of findings in the following tissues/organs:
Adrenal glands
All gross lesions
Bone marrow (femur)
Brain
Cecum
Cervix
Coagulating glands
Colon
Duodenum
Epididymides
Heart
Ileum
Jejunum
Kidneys
Liver
Lungs
Lymph nodes (axillary and mesenteric)
Ovaries
Oviducts
Prostate gland
Peyer’s patches
Rectum
Sciatic nerve
Seminal vesicles
Spinal cord (cervical, thoracic, lumbar)
Spleen
Stomach (forestomach and glandular stomach)
Testes
Thymus
Thyroid glands
Trachea
Urinary bladder
Uterus
Vagina
Special attention was given to stages of spermatogenesis in the male gonads. A correlation between gross lesions and histopathological findings was attempted.
- Statistics:
- Please refer to any other information on material and methods incl. tables
Results and discussion
Results of examinations
- Details on results:
- CLINICAL SIGNS AND MORTALITY:
No parental animal died prematurely in the present study. Brightly yellowish discolored urine and light yellow discolored feces were observed during the administration period at detailed clinical observations (DCO) in all dosed animals starting at DCO on study days 7 (urine) and 14 (feces).
The effects were related to the test substance but assessed as being non-adverse.
FOOD CONSUMPTION:
During the premating period food consumption was significantly decreased in female animals of test group 3 (1000 mg/kg bw/d), i.e. on study day 7 (-15%) and in mean of means (-11%). However, as the body weight gain of these animals did not show any impairment during the first week of treatment the finding was assessed as being spontaneous.
WATER CONSUMPTION:
No test substance-related, adverse findings were noted.
BODY WEIGHT DATA:
No test substance-related changes in body weight or body weight gain were observed for male and female animals of test groups 1-3 (100, 300 and 1000 mg/kg bw/d) when compared to control groups.
FUNCTIONAL OBSERVATION BATTERY:
Deviations from "zero values" were obtained in several rats. However, as most findings were equally distributed between test-substance treated groups and controls, were without a dose-response relationship or occurred in single rats only, these observations were considered to have been incidental.
MOTOR ACTIVITY MEASUREMENT:
There were no significant deviations concerning the overall motor activity (summation of all intervals) and regarding the single intervals in male and female animals of all test groups in comparison to the concurrent control group.
HEMATOLOGY:
No treatment-related changes among hematological parameters were observed.
CLINICAL CHEMISTRY:
In rats of both sexes of test group 3 (1000 mg/kg bw/d) creatinine values and, additionally, in females of the same test group urea levels were increased. Potassium levels were higher in females of test groups 1 and 3 (100 and 1000 mg/kg bw/d) but the potassium mean in test group 1 was within the historical control range. Therefore, the potassium level alteration in females of test group 1 (100 mg/kg bw/d) was regarded as incidental and not treatment-related.
URINALYSES:
No treatment-related changes among urinalysis parameters were observed.
ABSOLUTE WEIGHTS:
When compared to the control group 0 (set to 100%), none of the mean absolute weight parameters in male and female animals showed significant differences.
RELATIVE ORGAN WEIGHTS:
When compared to the control group 0 (set to 100%), the mean relative weight of the kidneys was significantly increased in females of test group 3 (1000 mg/kg bw/d). All other mean relative weight parameters in females and all weight parameters in males did not show significant differences when compared to the control group. For the increased relative kidney weight in female animals of test group 3 a treatment-related effect could not be ruled out.
GROSS LESIONS:
A treatment-related yellow discoloration of contents was observed in the forestomach, glandular stomach, and the cecum. Two males of test group 3 (1000 mg/kg bw/d) showed a yellow discoloration of the seminal vesicles. All further findings occurred individually. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
HISTOPATHOLOGY:
LIVER
In the centrilobular regions of the liver, the occurrence of single cell necrosis or apoptosis was minimally increased in male and female animals of test group 3 (1000 mg/kg bw/d). The increased number of single cell necroses or apoptotic bodies in animals of test group 3 (1000 mg/kg bw/d) was considered to be treatment-related.
SEMINAL VESICLES
For the yellow discoloration of the seminal vesicle in two males of test group 3 (1000 mg/kg bw/d), there were no histopathological correlates. All other 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.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: There were signs of systemic toxicity at a dose level of 1000 mg/kg bw/day in animals of both sexes. Thus, the NOAEL for general systemic toxicity was 300 mg/kg bw/day in males and females.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
STABILITY ANALYSES:
The stability of the test substance in drinking water was demonstrated over a period of 4 hours at room temperature. As the mixtures were stored no longer than this time period, the stability was guaranteed.
HOMOGENEITY CONTROL ANALYSES:
Considering the low relative standard deviation in the homogeneity analysis, it can be concluded that the test item was distributed homogeneously in drinking water.
CONCENTRATION CONTROL ANALYSES:
The concentration control analyses of all concentrations revealed that the values were in the expected range of the target concentrations, i.e. were always in a range of about 98-100% of the nominal concentrations. Taken together, the results demonstrate the correctness of the concentrations of the test item.
FOOD ANALYSES:
On the basis of duration of use and the analytical findings with respect to chemical and microbiological contaminants the diet was found to be suitable.
DRINKING WATER ANALYSES:
On the basis of the analytical findings the drinking water was found to be suitableApplicant's summary and conclusion
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.
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