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EC number: 206-992-3 | CAS number: 420-04-2
- 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:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-1 (Chronic Toxicity)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Cyanamide
- EC Number:
- 206-992-3
- EC Name:
- Cyanamide
- Cas Number:
- 420-04-2
- Molecular formula:
- CH2N2
- IUPAC Name:
- cyanamide
- Test material form:
- other: aqueous solution
- Details on test material:
- - Test substance: Aqueous Hydrogen cyanamide
- Purity: 50 % w/w, 53 % w/v active substance
- Appearance: Clear colourless liquid
- Lot/Batch number: 07-07-87
Constituent 1
Test animals
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: Hazelton Research Products, Inc., Cumberland, Virginia
- Age at study initiation: 6-8 months old
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- Results of analytical chemistry analysis indicated that the test solutions were generally prepared within the acceptable range of target concentrations. Stability evaluation of the low and high-dose solutions were established and showed stability over the entire range.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 52 weeks
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- for the first two weeks; corresponding to 0 mg/kg bw pure active substance Hydrogen cyanamide
- Dose / conc.:
- 0.2 mg/kg bw/day (actual dose received)
- Remarks:
- for the first two weeks; corresponding to 0.1 mg/kg bw pure active substance Hydrogen cyanamide
- Dose / conc.:
- 1 mg/kg bw/day (actual dose received)
- Remarks:
- for the first two weeks; corresponding to 0.5 mg/kg bw pure active substance Hydrogen cyanamide
- Dose / conc.:
- 5 mg/kg bw/day (actual dose received)
- Remarks:
- for the first two weeks; corresponding to 2.5 mg/kg bw pure active substance Hydrogen cyanamide
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- for the remaining 50 weeks; corresponding to 0 mg/kg bw pure active substance Hydrogen cyanamide
- Dose / conc.:
- 0.4 mg/kg bw/day (actual dose received)
- Remarks:
- for the first two weeks; corresponding to 0.2 mg/kg bw pure active substance Hydrogen cyanamide
- Dose / conc.:
- 2 mg/kg bw/day (actual dose received)
- Remarks:
- for the first two weeks; corresponding to 1 mg/kg bw pure active substance Hydrogen cyanamide
- Dose / conc.:
- 10 mg/kg bw/day (actual dose received)
- Remarks:
- for the first two weeks; corresponding to 5 mg/kg bw pure active substance Hydrogen cyanamide
- No. of animals per sex per dose:
- 4 animals per sex per dose
- Control animals:
- other: A concurrent control group administered with water by gavage
- Positive control:
- No positive control
Examinations
- Observations and examinations performed and frequency:
- All animals were observed twice daily for mortality and moribundity and once daily for clinical signs. Individual body weights and food consumption were recorded weekly for weeks 0 - 16, and every fourth week thereafter. Ophthalmoscopic examinations were performed pre-treatment to initiation and at termination. Evaluation of clinical pathology parameters (haematology, serum chemistry, thyroid function tests and urinalysis) were evaluated prior to initiation of treatment and at weeks 13, 26 and 52.
- Sacrifice and pathology:
- After 52 weeks of compound administration all animals were sacrificed and subjected to complete gross examination. Organ weight evaluations (absolute and relative) and histomorphological examinations were performed on selected organs.
- Statistics:
- The differences between the control groups and the test substance treated groups were statistically examined by the dunnets test criteria p< 0.05.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- General observations:
There were no deaths during the course of this study. As compound related clinical sign, salivations were noted in all high dose animals and in one medium-dosed female as well as tremors were seen in three high-dosed males and two high dose females. At termination of the study, no ophthalmological abnormalities occurred related to the test compound.
Mean body weights were reduced at week 13 and more pronounced in week 52 in both sexes at 5.0 mg/kg bw, when compared to the control groups Compared with the control animals, mean cumulative body weight gain, an indication of growth, was statistical significant decreased in the high-dose groups. Mean food consumption values were generally comparable between each dose group and control.
Compared with the control animals, mean cumulative body weight gain, an indication of growth, was statistical significant decreased in the high-dose groups. Mean food consumption values were generally comparable between each dose group and control.
Haematology and clinical chemistry:
Anaemia was seen in the female dogs of the high dose-group at week 13 with statistical significance based on reduced haemoglobin and haematocrit. The data of the males and of both sexes at week 52 were even suspected for anaemia. All erythrocyte parameters (MCV, MCH, MCHC) were reduced. The statistical significant decreases of MCV and MCH at 1.0 mg/kg bw at week 52 were not contributed to be substance-related, since no anaemia occurred at this dose.
Additionally, lymphocytes were decreased at week 13 and more pronounced at week 52 in the high-dose groups of both sexes. Leucocytes and segmented neutrophiles were reduced in the high dose males. Monocytosis was seen at 5.0 mg/kg bw in both sexes.
Following parameters were decreased in the high dose groups in week 13 and more pronounced in week 52: Serum albumine in both sexes and calcium in the female. Globulin was increased in week 13 and 52. Glucose and urea blood nitrogen was statistical significant decreased in females -and phosphorus in males- when compared to control animals. Statistically significant decreases were noted for aspartate aminotransferase (AST) in the high dose animals and for alanine aminotransferase (ALT) in the high dose males and females only at week 13. A statistical significant increase of cholesterol was seen at week 13 at 1 mg/kg bw in females and at 5 mg/kg bw in both sexes.
Decreased thyroxine values (T4) were observed in the high dose groups with statistically significance in the male at week 52 (-45 % vs –41 % in females). At 13 weeks the decrease was 28 % in the males and 46 % in the females compared to the control dogs. T3 values were lower in the high-dosed groups, but without statistical significance. The data of TSH were not shown, since not all animals were tested in the groups.
Results of urinalysis were generally unremarkable.
Gross pathology, organ weights and histopathology:
A pale area on the spleen was seen in one medium dose male and in two high dose females. Other findings were not related to treatment with the test compound.
The only significant finding in organ weight data was an increased thyroid/parathyroid weight-to-terminal body weight ratio value in the high dose females.
Compound-related histomorphologic alterations were observed in the high-dose groups. Thymic atrophy noted in one high dose female was accompanied by demodicosis. An increased incidence and severity of brown pigment was present in Kupfer cells of the livers in the high dose of both sexes, increased extramedullary hematopoiesis was present in the spleen of two high dose males and microcholeliths were present in the gallbladder of one high dose male and two high dose females. Other findings in high dose dogs were inflammation of the testes and decreased spermatogenic activity. Thymic atrophy was noted in all four high dose males and in one high dose female, that also showed demodicosis.
Other histopathological effects were not attributed to the treatment, since they were incidental and not dose-dependent.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- haematology
- other: The NOAEL is 1.0 mg/kg bw/day of the pure active subsatnce cyanamide. Haematological changes which correlated to histomorphological findings, macroscopic findings and histopathological changes at 5 mg/kg bw/day dose group.
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 5 mg/kg bw/day (actual dose received)
- System:
- endocrine system
- Organ:
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
Any other information on results incl. tables
Table 1: Body weight gain at week 13 and 52:
Pure active substance cyanamide (mg/kg bw/day)** (n = 4 each sex) | Males Body weight (kg) | Males Bw gain (kg) | Females Body weight (kg) | Females Bw gain (kg) | ||||
Week | week 13 | week 52 | week 13 | week 52 | week 13 | week 52 | week 13 | week 52 |
0 | 10.9 | 12.0 | 1.0 | 2.1 | 9.2 | 9.9 | 1.3 | 2.0 |
0.2 | 10.9 | 12.2 | 0.9 | 2.2 | 10.4 | 11.7 | 1.9* | 3.2 |
1.0 | 11.3 | 12.4 | 1.1 | 2.2 | 8.6 | 9.1 | 1.2 | 1.6 |
5.0 | 10.3 | 10.3 | 0.6 | 0.7* | 8.5 | 8.2 | 0.2* | 0.0* |
* Significantly different from control by the Dunnets test criteria, p<0.05
** Dose levels during weeks 0-2 were 0.1, 0.5 and 2.5 mg/kg bw/day pure active ingredient cyanamide
Table 2: Haematology in the dog (week 13 and 52):
Pure active substance cyanamide (mg/kg bw/day) (n = 4 each sex) | 0 | 0.2 | 1.0 | 5.0 | ||||
Week | week 13 | week 52 | week 13 | week 52 | week 13 | week 52 | week 13 | week 52 |
Males: |
|
|
|
|
|
|
|
|
Erythocytes (106/µL) | 7.07 | 6.90 | 6.84 | 6.93 | 7.03 | 7.72 | 6.68 | 7.03 |
Haemoglobin (g/dL) | 16.1 | 16.3 | 15.5 | 15.8 | 15.8 | 17.0 | 13.8 | 14.1 |
Haematocrit (%) | 46.2 | 46.3 | 44.1 | 45.3 | 45.1 | 49.0 | 40.5 | 41.5 |
MCV (fl) | 65.5 | 67.0 | 64.6 | 65.2 | 64.2 | 63.5* | 60.7 | 58.9* |
MCH (pg) | 22.9 | 23.6 | 22.6 | 22.7* | 22.4 | 22.1* | 20.7* | 20.1* |
MCHC (g/dL) | 34.9 | 35.1 | 35.1 | 34.8 | 35.0 | 34.8 | 34.1 | 34.1* |
Leucocytes+(103/µL ) | 9.8 | 8.7 | nd# | nd# | nd# | nd# | 9.2 | 7.4* |
Segmented neutrophils | 6.2 | 6.3 | nd# | nd# | nd# | nd# | 3.3* | 3.0* |
Lymphocytes | 2.8 | 1.8 | nd# | nd# | nd# | nd# | 5.0* | 3.6 |
Monocytes | 0.3 | 0.3 | nd# | nd# | nd# | nd# | 0.5 | 0.6* |
Females |
|
|
|
|
|
|
|
|
Erythocytes (106/µL) | 6.63 | 6.16 | 6.53 | 6.72 | 6.92 | 7.06 | 6.38 | 6.36 |
Haemoglobin (g/dL) | 15.6 | 14.5 | 15.2 | 15.6 | 15.3 | 15.1 | 13.5* | 13.0 |
Haematocrit (%) | 44.3 | 41.3 | 43.5 | 44.5 | 43.9 | 43.9 | 39.3* | 38.4 |
MCV (fl) | 66.8 | 67.1 | 66.6 | 66.3 | 63.4 | 62.3* | 61.6* | 60.4* |
MCH (pg) | 23.6 | 23.5 | 23.3 | 23.2 | 22.2 | 21.5* | 21.1* | 20.5* |
MCHC (g/dL) | 35.3 | 35.0 | 34.9 | 35.0 | 34.9 | 34.5 | 34.3* | 33.9* |
Leucocytes+(103/µL ) | 9.9 | 9.0 | nd# | nd# | nd# | nd# | 11.3 | 11.8 |
Segmented neutrophils | 6.5 | 6.6 | nd# | nd# | nd# | nd# | 5.0 | 7.4 |
Lymphocytes | 2.8 | 1.6 | nd# | nd# | nd# | nd# | 5.2* | 3.6* |
Monocytes | 0.3 | 0.3 | nd# | nd# | nd# | nd# | 0.8 | 0.9* |
* Significantly different from control, by Dunnetts test criteria, p < 0.05
+corrected count,#no data
Table 3: Clinical chemistry (week 13 and 52):
Pure active substance cyanamide (mg/kg bw/day) (n = 4 each sex) | 0 | 0.2 | 1.0 | 5.0 | ||||
Week | week 13 | week 52 | week 13 | week 52 | week 13 | week 52 | week 13 | week 52 |
Males: |
|
|
|
|
|
|
|
|
Total cholesterol (mg/dL) | 165 | 136 | 176 | 132 | 191 | 153 | 249* | 189 |
Serum albumine (g/dL) | 3.8 | 3.8 | 3.7 | 3.7 | 3.7 | 3.6 | 3.3* | 3.2* |
Globulin (g/dL) | 2.5 | 2.7 | 2.7 | 2.8 | 2.6 | 2.8 | 3.0 | 3.3 |
Phosphor (mg/dL) | 5.2 | 3.5 | 5.4 | 3.8 | 5.1 | 3.8 | 5.3 | 4.4* |
AST (U/L) | 28 | 30 | 25 | 30 | 25 | 27 | 16* | 25 |
ALT (U/L) | 54 | 72 | 42 | 41 | 56 | 64 | 26* | 55 |
Females |
|
|
|
|
|
|
|
|
Total cholesterol (mg/dL) | 158 | 153 | 195 | 165 | 218* | 230 | 222* | 215 |
Serum albumine (g/dL) | 3.7 | 3.6 | 3.7 | 3.6 | 3.6 | 3.5 | 3.1* | 2.8* |
Globulin (g/dL) | 2.4 | 2.8 | 2.5 | 2.9 | 2.8 | 2.9 | 3.3* | 3.5 |
Phosphor (mg/dL) | 5.2 | 8.6 | 5.9 | 5.6 | 5.6 | 5.0 | 5.6 | 4.1 |
Serum glucose (mg/dL) | 98 | 87 | 102 | 90 | 96 | 88 | 87 | 71* |
Blood urea nitrogen (mg/dL) | 14 | 15 | 11 | 12 | 13 | 13 | 9 | 8* |
Creatinine (mg/dL) | 0.9 | 0.9 | 0.9 | 0.8 | 0.9 | 0.8 | 0.8* | 0.6* |
Calcium (mg/dL) | 10.6 | 9.8 | 10.6 | 9.6 | 10.7 | 9.8 | 9.8* | 8.9* |
AST (U/L) | 28 | 30 | 27 | 28 | 26 | 37 | 17* | 23 |
ALT (U/L) | 58 | 45 | 31 | 33 | 33 | 31 | 23* | 25 |
Table 4: Thyroid hormones:
Pure active substance cyanamide (mg/kg bw/day) (n = 4 each sex) | 0 | 0.2 | 1.0 | 5.0 | ||||||||
Week | -2 | 13 | 52 | -2 | 13 | 52 | -2 | 13 | 52 | -2 | 13 | 52 |
Males |
|
|
|
|
|
|
|
|
|
|
|
|
T3 (ng/dL) | 75.6 | 61.9 | 54.0 | 58.9 | 66.3 | 56.7 | 66.0 | 64.6 | 66.2 | 75.5 | 48.3 | 62.6 |
T4 (µg/dL) | 3.1 | 2.5 | 1.8 | 2.6 | 2.5 | 1.9 | 2.9 | 2.2 | 1.6 | 2.6 | 1.8 | 1.0* |
Females |
|
|
|
|
|
|
|
|
|
|
|
|
T3 (ng/dL) | 72 | 56.1 | 56.0 | 75.3 | 69.7 | 61.5 | 77.4 | 62.6 | 65.8 | 77.8 | 39.3 | 41.4 |
T4 (µg/dL) | 3 | 2.6 | 2.2 | 3.3 | 3.2 | 2.3 | 2.8 | 2.4 | 2.4 | 3.8 | 1.4 | 1.3 |
Table 5: Organ weights:
Pure active substance cyanamide (mg/kg bw/day) (n = 4 each sex) | 0 | 0.2** | 1** | 5** |
Males: |
|
|
|
|
Absolute liver weight (g) | 287 | 266 | 278 | 291 |
Relative liver weight (%) | 2.5 | 2.2 | 2.3 | 2.9 |
Absolute thyroid/parathyroid weight (g) | 1.16 | 0.88 | 0.93 | 1.13 |
Relativeathyroid/parathyroid weight ( %) | 0.010 | 0.007 | 0.009 | 0.011 |
Females: |
|
|
|
|
Absolute liver weight (g) | 214 | 250 | 207 | 221 |
Relative liver weight (%) | 2.3 | 2.2 | 2.3 | 2.9 |
Absolute thyroid/parathyroid weight (g) | 0.87 | 0.92 | 0.84 | 1.08 |
Relativeathyroid/parathyroid weight ( %) | 0.009 | 0.008 | 0.009 | 0.014* |
aRelative weight is defined as the organ to body weight ratio.
* Significantly different from control by the Dunnets test criteria, p<0.05.
** Dose levels during weeks 0-2 were 0.1, 0.5 and 2.5 mg/kg bw/day pure active ingredient cyanamide
Applicant's summary and conclusion
- Conclusions:
- The NOAEL of pure active substance cyanamide is 1.0 mg/kg bw/day in beagle dogs.
- Executive summary:
Aqueous Hydrogen cyanamide was administered via gavage over a period of one year to 4 male and 4 female dogs of each sex and group, which were 6 - 8 months old at study begin. For the first two weeks the dose levels were 0, 0.2, 1.0 and 5.0 mg/kg bw/day corresponding to 0, 0.1, 0.5 and 2.5 mg/kg bw/day pure active substance Hydrogen cyanamide. The remaining 50 weeks doses of 0, 0.4, 2.0 and 10.0 mg/kg bw/day (corresponding to 0, 0.2, 1.0 and 5.0 mg/kg bw/day pure active substance Hydrogen cyanamide) were administered. An additional group of 4 dogs/sex was administered the vehicle (distilled water) and thus served as the concurrent control group. During the study time all animals were observed for mortality and moribidity, for clinical signs, individual body weights and food consumption, ophthalmoscopic examinations and clinical pathology parameters. After 52 weeks of compound administration all animals were sacrificed and subjected to complete gross examination. Organ weight evaluations (absolute and relative) and histomorphological examinations were performed on selected organs. Clinical pathology changes in the high dose group in males and females. Gross macroscopic findings in the spleen in one medium dose male and two high dose females. Increase in thyroid/parathyroid organ-to terminal body weight ratio in the high dose females. Histopathological effects in the high dose in the liver in males and females, in the spleen in two males, gallbladder in one male and two females, in the testes and in the thymus in 4 males and one female. The NOAEL was therefore determined to be 1 mg/kg bw/day pure active ingredient cyanamide for dogs based on the significantly reduced body weight/gain in both sexes, the occurrence of significant anaemia in female dogs (reduced red blood cell (RBC) parameters also in males) and significantly reduced T4 in dogs at 5 mg/kg bw/d and reduced (not statistically significant) T3. Whether the testicular findings in one dog were treatment-related could not be excluded with certainty.
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