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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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1993
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 993
- Report date:
- 1993
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.36 (Toxicokinetics)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 85-1 (Metabolism and Pharmacokinetics)
- Deviations:
- no
- GLP compliance:
- yes
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:
- solid
- Details on test material:
- Substance radiolabled
Constituent 1
- Radiolabelling:
- yes
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Source: SD rats from Harlan Sprague Dawley, Madison, Wisconsin, U.S.A
- All treated animals were housed individually in metabolism cages for the quantitative separation and collection of urine, faeces and expired air.
Administration / exposure
- Route of administration:
- other: 3 groups of rats (5 males, 5 females) were administered with the test substance through the oral route. One group (5 males, 5 females) were administered with the test substance intravenously.
- Vehicle:
- other: For the oral dose solutions: 0.05 M ammonium phosphate was used as an vehicle. For the intravenous dose solutions 0.9 % w/v sodium chloride was used as an vehicle.
- Details on exposure:
- The oral dose solutions of Hydrogen cyanamide were prepared by dissolving appropriate amounts of non-radiolabelled and radiolabelled substance in appropriate volumes of 0.05 M ammonium phosphate buffer (pH 4.5 to 4.75). Radiolabelled oral dosing solutions were prepared within 2 days of dosing, the non-radiolabelled dosing solutions were prepared within 7 days of dosing. The intravenous dose solutions were prepared by dissolving non-radiolabelled and [14C]-Hydrogen cyanamide in 0.9 % w/v sodium chloride.
- Duration and frequency of treatment / exposure:
- 3 groups administered with a single oral dose/intravenous dose followed by 7 days observation period (168 hours)). One group administered with a single oral (non-labeled) dose per day for 14 days followed by a single oral (radioactive material) dose (see table in " any other information on material and methods")
Doses / concentrations
- Remarks:
- Doses / Concentrations:
3 groups (low dose groups) were administered (oral/intravenous) with 1 mg/kg bw of the labeled test susbatnce. 1 group (high dose group) was administered (oral) with 20 mg/kg bw of the labeled test substance (see table in " any other information on material and methods")
- No. of animals per sex per dose / concentration:
- 5 animals per dose per sex
- Control animals:
- no
- Positive control reference chemical:
- No positive control
- Details on study design:
- - The experiments were carried out according to a preliminary test that elucidated adequate dose levels and showed if a collection of expired air is necessary (for the preliminary study design, see table in "any other informantion on materials and methods".
- Details on dosing and sampling:
- Expired air and organic volatiles were trapped in a mixture of 2-ethoxyethanol and ethanolamine (1:1). Activated charcoal, contained within glass tubing, was used to trap expired organic volatiles. The CO2 trapping solution and the charcoal were collected 12 and 24 hours after dose administration and daily thereafter for 7 days postdose. Urine and faeces samples were collected 12 and 24 hours postdose and daily thereafter for 7 days postdose. At the end of the collection period organs and tissues (blood, bone, brain, carcass, fat, heart, kidneys, liver, lungs, muscle, ovaries, spleen, thyroid and uterus) were prepared for analysis of residual radioactivity.
A composite urine sample for each group as prepared by combining proportional aliquots of urine from collection intervals that contained more than 90 % of the urinary radioactivity for each sex/group (with the exception of the group A male urine composite sample, which contained 86.6 %). The collection intervals were 0 to 48 hours postdose for composite urine samples for group A, B and C and 0 to 24 hours postdose for group D. Aliquots of the composite urine samples were fortified with N-acetylcyanamide reference standard for analysis.
Composite faeces samples for male and females in group A were prepared by combining proportional aliquots of faeces collected from 0 to 24 hours postdose.
Kidneys, liver and other organs and tissues did not obtain sufficient amounts of radioactivity to allow the isolation or identification of metabolites
For isolation, characterisation and identification of metabolites, preparative TLC, HPLC and mass spectrometry were used. Co-chromatography with reference standards was also used for the identification of metabolites.
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- After a single oral dose of 1 mg/kg bw at 168 hours organs (blood, bone, brain, fat, heart, kidneys, liver, lungs, muscle, ovaries, spleen, thyroid and uterus) accounted for 4.36 % for males and 3.3 % for females, carcass contained 2.31 % for males and 1.37 % for females of the radioactivity.
After a single oral dose of 20 mg/kg bw at 168 hours organs (blood, bone, brain, fat, heart, kidneys, liver, lungs, muscle, ovaries, spleen, thyroid and uterus) contained little radioactivity (0.85 % for males and 0.45 % for females); carcass accounted for 2.26 % (males) and 2.4 % (females).
After a single intravenous dose of 1 mg/kg at 168 hours organs (blood, bone, brain, fat, heart, kidneys, liver, lungs, muscle, ovaries, spleen, thyroid and uterus) contained little radioactivity (1.89 % males and 1.23 % females); carcass accounted for 4.31 % (males) and 3.24 % (females).
After 14 days of 1 mg/kg bw (non-radiolabelled, followed by a single oral dose of 1 mg/kg bw) at 168 hours tissues contained a total of 1.53 % for males and 1.0 % for females, residual carcass accounted for 4.0 % in males and 2.9 % in females. - Details on distribution in tissues:
- The amounts of radioactivity in blood collected 168 hours post-dose ranged from 0.46 % to 0.92 % in males and 0.26 % to 0.61 % in females. All tissues (blood, bone, brain, fat, heart, kidneys, liver, lungs, muscle, ovaries, spleen, thyroid and uterus) collected 168 hours after postdose contained 0.03 % or less of the radioactivity, except liver and kidney. Livers from males contained 0.33 % to 1.18 %, from females 0.14 % to 0.60 %. Kidneys form males from all groups contained 0.03 % to 0.09 % of the 14C dose and from females 0.2 % to 0.07 %.
The concentration of radioactivity in tissues at 168 hours post-dose was consistently highest in the blood, followed by the liver and kidneys, regardless of route of administration or dose level. The concentration of radioactivity was 40 % less in the livers of animals given 14 consecutive days 1 mg/kg bw Hydrogen cyanamide before a single [14C] Hydrogen cyanamide dose when compared with animals given only a single 1 mg/kg oral dose. This data is in agreement with the data regarding 14CO2 formation of these groups and suggests that metabolism of Hydrogen cyanamide is altered after repeated dosings.
- Details on excretion:
- Radioactivity was rapidly excreted, regardless of the route of administration. A total of approximately 67 % to 92 % was excreted by all routes in the first 24 hours postdose. The main route of excretion was via the urine. The faeces and CO2 accounted for 26 % and 19 % for the intravenous dose and less than 15 % for oral dose.
The amounts of radioactivity eliminated in the urine, faeces and CO2 were influenced by the route of administration, dose level and sex of the animal. The fecal excretion of radioactivity was 3 to 4 times higher after an intravenous dose compared with a similar oral dose. This suggests that biliary excretion may be an important mechanism after intravenous administration. The elimination of radioactivity as 14CO2 was reduced by approximately 30 % in animals repeatedly dosed with Hydrogen cyanamide when compared with animals given a single oral dose, indicating that metabolism of the compound was somewhat different after single or by repeated dosing. The percent of the administered dose eliminated in the CO2 was much lower for animals given the high dose compared with those animals given the low dose. The opposite result was observed for the percent of dose in the urine. This data suggest, that the metabolic route resulting in the metabolism of Hydrogen cyanamide to CO2 has a limited capacity. For animals administered the low dose, the excretion of radioactivity as CO2 was approximately twice as high in males when compared with females. Conversely, the amount of radioactivity eliminated in the urine tended to be greater in females than in males in the low dose group.
The amounts of radioactivity eliminated in the urine, faeces and CO2 were influenced by the route of administration, dose level and sex of the animal. The fecal excretion of radioactivity was 3 to 4 times higher after an intravenous dose compared with a similar oral dose. This suggests that biliary excretion may be an important mechanism after intravenous administration. The elimination of radioactivity as 14CO2 was reduced by approximately 30 % in animals repeatedly dosed with Hydrogen cyanamide when compared with animals given a single oral dose, indicating that metabolism of the compound was somewhat different after single or by repeated dosing. The percent of the administered dose eliminated in the CO2 was much lower for animals given the high dose compared with those animals given the low dose. The opposite result was observed for the percent of dose in the urine. This data suggest, that the metabolic route resulting in the metabolism of Hydrogen cyanamide to CO2 has a limited capacity. For animals administered the low dose, the excretion of radioactivity as CO2 was approximately twice as high in males when compared with females. Conversely, the amount of radioactivity eliminated in the urine tended to be greater in females than in males in the low dose group.
The amounts of radioactivity eliminated in the urine, faeces and CO2 were influenced by the route of administration, dose level and sex of the animal. The fecal excretion of radioactivity was 3 to 4 times higher after an intravenous dose compared with a similar oral dose. This suggests that biliary excretion may be an important mechanism after intravenous administration. The elimination of radioactivity as 14CO2 was reduced by approximately 30 % in animals repeatedly dosed with Hydrogen cyanamide when compared with animals given a single oral dose, indicating that metabolism of the compound was somewhat different after single or by repeated dosing. The percent of the administered dose eliminated in the CO2 was much lower for animals given the high dose compared with those animals given the low dose. The opposite result was observed for the percent of dose in the urine. This data suggest, that the metabolic route resulting in the metabolism of Hydrogen cyanamide to CO2 has a limited capacity. For animals administered the low dose, the excretion of radioactivity as CO2 was approximately twice as high in males when compared with females. Conversely, the amount of radioactivity eliminated in the urine tended to be greater in females than in males in the low dose group.
Toxicokinetic parameters
- Key result
- Toxicokinetic parameters:
- other: 67-92% total excretion by all routes (i.e. oral and i.v.) during the first 24 h post dose.
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Metabolites determined were N-acetylcyanamide as the major biotranformation product both in urine and faeces. Other metaboiltes were formed at levels of less than 10% of the dose given and were not further characterized.
Any other information on results incl. tables
Table 1: Excretion balance (in % of administered radioactivity) after single oral dose of 1 mg/kg bw at 168 hours:
Urine | Faces | Expired CO2 | Total excreted* | Residual carcass and tissues | Recovery | |
Males | 79.00 % | 4.15 % | 10.00 % | 93.15 % | 7.66 % | 99.90 % |
Females | 86.20 % | 4.07 % | 5.77 % | 96.04 % | 3.68 % | 101.00 % |
* includes cage wash
Table 2: Excretion balance (in % of administered radioactivity) after single oral dose of 20 mg/kg bw at 168 hours
| Urine | Faces | Expired CO2 | Total excreted* | Residual carcass and tissues | Recovery |
Males | 95.30 % | 2.76 % | 2.31 % | 100.37 % | 3.11 % | 103.00 % |
Females | 97.70 % | 3.26 % | 1.45 % | 102.41 % | 2.85 % | 105.00 % |
* includes cage wash
Table 3: Excretion balance (in % of administered radioactivity) after single intravenous dose of 1 mg/kg at 168 hours:
| Urine | Faces | Expired CO2 | Total excreted* | Residual carcass and tissues | Recovery |
Males | 82.6 % | 4.14 % | 7.08 % | 93.82 % | 5.53 % | 99.3 % |
Females | 90.7 % | 2.86 % | 3.78 % | 97.34 % | 3.9 % | 101 % |
*includes cage wash
Metabolism
The major metabolic reaction of [14C] Hydrogen cyanamide was acetylation of the nitrogen. The major metabolite observed in urine and faeces was N-acetylcyanamide. N-acetylcyanamide accounts for 58 % to 74 % of the radioactivity in the composite urine samples analysed and for over 80 % of the radioactivity in the composite faeces sample analysed (group A). The other radioactive areas observed in the TLC profile accounted for less than 10 % of the administered dose and therefore were not characterised (with the exception of another metabolite, described as UM-1). The radioactive area UM- 1 accounted for 9.7 % and 11.9 % of the administered dose for group A males and females, respectively. Subsequent attempts to isolate this compound by preparative TLC were unsuccessful due to the unstable nature of the compound.
Applicant's summary and conclusion
- Conclusions:
- Cyanamide is rapidly absorbed and excreted after oral and i.v. administration indicating no potential for bioaccumulation. According to the amounts excreted with the urine, cyanamide can be regarded to be nearly quantitatively bioavailable both after single low, single high and repeated low dose administration via the oral route.
- Executive summary:
A study that examined absorption, distribution, metabolism, and excretion in Harlan Sprague Dawley rats was conducted with the test substance (labelled and non-radiolabeled) Hydrogen cyanamide. The test substance was applied to 5 male and 5 female rats per group orally and intravenously in two different doses in a single and repeated dose as described in the following: An oral high dose (20 mg/kg bw) group, an oral low dose (1 mg/kg bw) group, an intravenous dose (1 mg/kg bw) group and a group which was administered orally with the test substance 1 mg/kg bw (unlabelled material) for 14 days followed by single oral dose of 1 mg/kg bw (radioactive material).
Results showed that [14C]-Hydrogen cyanamide was rapidly excreted, regardless of the route of administration. A total of approximately 67 % to 92 % was excreted by all routes in the first 24 hours postdose. The main route of elimination for [14C]-Hydrogen cyanamide was in the urine for all animals. The percent excreted in the urine after oral administration ranged from approximately 79.0 % to 97.7 % at 168 hours postdose. Differences among groups and sexes were noted in the amount of radioactivity eliminated in CO2, in the faeces or remaining as residues in the liver. Radioactivity of [14C]-Hydrogen cyanamide was apparently completely absorbed after oral administration. Biliary excretion of radioactivity was not an important mechanism for the high dose, however it may be important for an intravenous dose. Repeated doses of Hydrogen cyanamide resulted in a decrease in the amount of radioactivity as CO2 and in the concentration of radioactivity remaining in the liver at 168 hours postdose. This suggests that the disposition of radioactivity was influenced by repeated administration of cyanamide. The metabolism of cyanamide after oral and intravenous dosing can be described as follows: Starting with the unchanged parent compound, the major metabolic reaction was acetylation of the nitrogen, forming N-acetylcyanamide. N-acetylcyanamide is the major metabolite in both urine and faeces. Other radioactive metabolites were present in the urine and faeces but they represented less than 10 % of the administered dose in each case.
It can be concluded that results indicated that cyanamide has no potential for bioaccumulation as it is rapidly absorbed and excreted after oral and i.v. administration. According to the amounts excreted with the urine, cyanamide can be regarded to be nearly quantitatively bioavailable both after single low, single high and repeated low dose administration via the oral route.
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