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EC number: 205-861-8 | CAS number: 156-62-7
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Testing proposal: No data on toxicity to reproduction (fertility) is available for calcium cyanamide. An extended one-generation study (cohort 1A + 1B without extension) in rats is proposed.
Using data from cyanamide as read-across for calcium cyanamide technical grade is considered not a suitable approach of filling the data gap for this endpoint for multiple reasons such as differences in physicochemical properties as well as in dissolution kinetics (especially in acidic environment such as the stomach) between the two substances. Furthermore, there are limitations in the reproductive toxicity studies of cyanamide that resulted in the harmonised CLP classification of Repr. 2 (H361f) such that it is not prudent to use limited reproductive toxicity findings from cyanamide as read-across for reproductive toxicity potential of calcium cyanamide technical grade. Please refer to the report " Scientific Rationale for not using Cyanamide as Read-Across Substance for Calcium Cyanamide on Toxicological Endpoints” in Section 13.2 for more explanation.
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available (further information necessary)
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Effects on developmental toxicity
Description of key information
Oral (gavage) administration of calcium cyanamide technical grade to Sprague-Dawley rats from days 6 to 19 of gestation at doses of 7, 21 and 49 mg/kg/day (study performed in accordance with OECD Test Guideline 414) was associated dose-related reductions in overall mean body weight gain and food consumption in dams in the 21 and 49 mg/kg/day groups. The low dose of 7 mg/kg/day was considered a No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity. Evidence of embryo-foetal effects was restricted to slightly lower mean foetal body weight in the 21 and 49 mg/kg/day groups. There was no adverse effect on morphological development at any dose. The NOAEL for embryo-foetal toxicity was 49 mg/kg/day.
The prenatal developmental toxicity study (OECD Test Guideline 414) in a second species (rabbit) is proposed. Using data from cyanamide as read-across for calcium cyanamide technical grade is considered not a suitable approach of filling the data gap for this endpoint for multiple reasons such as differences in physicochemical properties as well as in dissolution kinetics (especially in acidic environment such as the stomach) between the two substances. Furthermore, the findings from the OECD Test Guideline 414 rat study with calcium cyanamide technical grade appear to differ from findings from prenatal developmental studies performed with cyanamide. Also, there are limitations in the developmental toxicity studies of cyanamide that resulted in the harmonised CLP classification of Repr. 2 (H361d) such that it is not prudent to use limited reproductive toxicity findings from cyanamide as read-across for reproductive toxicity potential of calcium cyanamide technical grade. Please refer to the report " Scientific Rationale for not using Cyanamide as Read-Across Substance for Calcium Cyanamide on Toxicological Endpoints” in Section 13.2 for more explanation.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2014-03-24 to 2014-10-22
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories France, Domaine des Oncins, 69210 Saint-Germain-Nuelles, France
- Age at study initiation: 10 to 13 weeks old
- Weight at study initiation: 187 to 281 g
- Housing: Females were individually housed in plastic cages with autoclaved sawdust and shredded paper as bedding
- Diet: Rat pelleted commercial complete rodent diet ad libitum
- Water: Softened and filtered (0.2 μm) mains drinking water was available ad libitum (via bottles)
- Acclimation period: 6 days between animal arrival and the start of treatment
ENVIRONMENTAL CONDITIONS
- Temperature: 22 + 3 °C
- Humidity: Between 35 and 70 %
- Air changes: At least 10 air changes per hour
- Photoperiod: 12 hours light (artificial)/12 hours dark (except when required for technical acts). - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Remarks:
- Explanation for suitabillity of vehicle "Corn oil" see "any other information on materials and methodes incl. tables"
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Preparation: The test item was prepared as a suspension in the vehicle, at the concentrations of 3.5, 10.5 and 24.5 mg/mL
- Frequency: once daily
- Method: Gavage using a plastic canula. Formulations were brought to room temperature for at least 15 minutes prior to dosing
- Volume of administration: 2 mL/kg/day. Individual dose volumes were calculated using the latest body weight. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Stability, Homogeneity and formulation analyses were conducted.
- Analysis of formulations: 4 x 3 g samples were taken under magnetic stirring from the top, middle and bottom of each formulation (middle only for control), used on one of the first days of treatment and again during the last week of dosing.
In addition, 5 x 3 g samples were taken from the middle of Groups 2 and 3 formulations for additional analysis.
One set (2 x 3 g) of samples was analysed at the Test Facility using a validated method (WIL study no. AB20445).
- Results: All formulations at 3.5, 10.5 and 24.5 mg/mL of Calcium Cyanamide used for treatment on the first and last days of treatment were in agreement with acceptance criteria since the deviations from the nominal concentrations ranged from -12.3 % to +9.4 %. No test item was detected in control samples. - Details on mating procedure:
- The female animals (n= 100) were mated at the supplier and delivered the same day to the test facility (day 0 of gestation (GD 0)).
- Duration of treatment / exposure:
- From day 6 (G6) to day 19 (G19) of gestation inclusive
- Frequency of treatment:
- Once daily, in the morning, at approximately the same time of day (+ 30 minutes), except for the first treatment on 31 March 2014 when treatment was performed in the afternoon. This delay was due to late availability of the first analytical results required prior to the start of dosing.
- Duration of test:
- Experimental starting date (first animal arrival): 25 March 2014
Experimental completion date (last caesarean): 17 April 2014 - No. of animals per sex per dose:
- 25 female animals
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected by the study sponsor based on the results of the dose range-finding study by the oral route (gavage) in the pregnant rat
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were observed daily for clinical signs. During the treatment period, the animals were observed before and at least once after dosing to detect any clinical signs or reaction to treatment. A full clinical examination was performed on each weighing day
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed individually on days 0, 6, 9, 12, 15, 18 and 20 of gestation.
FOOD CONSUMPTION: Yes
- Individual food consumption of each animal was measured for the periods (days) 0 to 6, 6 to 9, 9 to 12, 12 to 15, 15 to 18 and 18 to 20 during gestation.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Animals were dissected and examined for macroscopic pathological changes. The ovaries and uterus of each female were removed and examined. The placentae were also examined - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number and distribution of live foetuses
- Individual foetal weights
- Foetal sex
The uterus of all females was placed in ammonium sulphide solution in order to stain any previously undetected implantation sites. - Fetal examinations:
- - External examinations: Yes, each foetus
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Approximately one half of each litter was examined for fresh visceral anomalies and then processed for skeletal examination. The ossified skeleton was stained with Alizarin red following maceration of the soft tissues in potassium hydroxide solution. The stained specimens were preserved in glycerol
- Head examinations: Yes: half per litter
The remaining half of the foetuses in each litter was fixed in Harrison’s fixative for subsequent examination of the head only by serial sectioning. The remaining foetal carcasses were retained fixed but not examined further. - Statistics:
- Statistical analysis was performed, where appropriate, by the data acquisition software, as follows:
- the data were checked for homogeneity of variance using Bartlett’s test
- homogenous data were then analysed by ANOVA and resulting intergroup differences were analysed with a Dunnett's t-test
- non-homogenous data were analysed with a Kruskal-Wallis test followed by Dunn’s test if the Kruskal-Wallis was significant.
Data were then analysed to test for a dose-related trend to detect the lowest dose at which there was a significant effect, based on the Williams test for parametric data or the Shirley's test for non-parametric data.
Homogeneity of means was assessed by analysis of variances (ANOVA) for parametric data or Kruskal-Wallis test for non parametric data.
If no trend was found and means were not homogeneous, the data were analysed by parametric or non-parametric Dunnett's test to look for significant differences from the control group.
The number of resorptions, number of dead foetuses and all litter-based percentages were analysed using non-parametric methods, i.e. Kruskal-Wallis test followed by non-parametric Dunnett’s test if the Kruskal-Wallis was significant. Selected incidence data were analysed using a chi2 test for all groups followed by Fisher’s two-tailed test with Bonferroni correction for each treated group versus the control if the chi2 was significant. - Indices:
- For each group, the following parameters were calculated:
Pre-implantation loss (in %): Number of corpora lutea - Number of implantations x 100 / Number of corpora lutea
Post-implantation loss (in %): Number of implantations - Number of viable foetuses x 100 / Number of implantations - Historical control data:
- The data concerning the control pregnant females and the historical data were used to evaluate the effects of the test item.
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: Dose-related reductions in overall mean body weight gain and food consumption in the 21 and 49 mg/kg/day groups
Details on maternal toxic effects:
- Mortality
There was no mortality in any group.
- Clinical signs
There were no treatment related clinical signs in any group.
One control female had a mass in the abdominal region. Scab(s), chromodacryorrhea, localised hairloss and white teeth occasionally observed amongst treated groups were considered incidental.
- Body weight
On average, there was a dose-related and statistically significant lower mean body weight gain during the dosing period (G 6 to G 20) in the 21 and 49 mg/kg bw/day groups (-9 % and -23 %, respectively) compared with the control. This finding was confirmed for net mean body weight gain following adjustment for gravid uterus weight (-23 % and -43 %, respectively compared with the control). Mean terminal body weight and carcass weight were only slightly affected in the 49 mg/kg bw/day group (-6 % compared with the control). Mean body weight gain in the 7 mg/kg bw/day group was comparable with that in the control.
- Food consumption
On average, there was a dose-related and statistically significant reduction in mean food consumption during the dosing period (days 6 to 20 of gestation) in the 21 and 49 mg/kg bw/day groups (-6 and -10 %, respectively) compared with the control. Mean food consumption in the 7 mg/kg bw/day group was comparable with that in the control.
-Necropsy findings of adult females
There was no treatment-related macroscopic finding at necropsy. Consistent with the clinical observations, one control female had a mass in the abdominal region.
-Gravid uterus weight
Consistent with lower mean foetal weight, mean gravid uterus weight in the 49 mg/kg bw/day group was slightly lower (-7 %) than in the control. Despite lower mean foetal weight, there was no similar finding in the 21 mg/kg bw/day group due to a marginally superior litter size (see 10.7.3). Mean gravid uterus weight in the lower dose groups was therefore comparable with that in the control. - Dose descriptor:
- NOAEL
- Effect level:
- ca. 7 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 49 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
- Pregnancy incidence
There were 24, 25, 23 and 24 pregnant females at the terminal caesarean sections in groups 1 to 4, respectively, all of which had viable foetuses.
- Pre-implantation data
The pre-implantation data (mean numbers of corpora lutea and implantation sites and the percentage pre-implantation loss) were comparable in all groups.
- Post-implantation data
There was no obvious influence of treatment on embryo-foetal survival in any group. Two females in the 49 mg/kg bw/day group had 1 or 3 late resorptions and another had a dead foetus compared with one female with a single late resorption in the control. In the absence of a similar trend amongst the other females in the high dose group, and since the percentage post-implantation loss remained comparable with that in the concurrent control and historical control data, these isolated cases was considered incidental. Mean live litter size was comparable with, or marginally superior to, that in the control group for all treated groups.
- Foetal data
There was a slight but statistically significant lower mean foetal weight in the 21 and 49 mg/kg bw/day groups (3.7 and 3.5 g corresponding to -7 % and -11 %, respectively) in comparison with the concurrent control (3.9 g) and historical control data (4.1 g). There was no effect of treatment on mean foetal weight in the 7 mg/kg bw/day dose group. Foetal sex ratio in treated groups was comparable with that in the control.
- External observations
There was no treatment-related external malformation in any group. One foetus from control female no. 4 had micrognathia.
- Soft tissue findings
There was no foetal visceral malformation noted in any treated group. The incidences of less severe visceral anomalies and variations such as absent innominate artery, pulmonary arteries with a common origin, discolored adrenal gland, transposed umbilical artery and dilated and/or convoluted ureter(s), did not suggest any association with treatment.
- Skeletal observations
There were three foetuses, one in the control group and two from separate litters in the 7 mg/kg bw/day group, with skeletal malformations.
The foetus from the control group had a short mandible confirmed with fused symphysis and one foetus from the 7 mg/kg bw/day group had a short premaxilla and misshapen maxilla. One other foetus from the 7 mg/kg bw/day group had multiple abnormalities of the cervical and thoracic vertebrae leading to scoliosis. These isolated findings in the control and low dose groups were considered to be incidental due to the absence of any similar findings in the higher dose groups.
There was a slightly higher incidence of increased ossification of the 1st centrum of the cervical vertebrae and bipartite ossification of thoracic vertebrae centra in the 49 mg/kg bw/day group compared with the control and historical control data. Although possibly associated with treatment, these minor changes are considered to be of no physiological or toxicological significance and represent normal variation that exists in the rate of development of some skeletal elements.
There were no other differences between the treated groups and the control amongst the remaining minor skeletal changes to suggest any association with treatment. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 49 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effect of treatment on morphological development at any dose
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- Oral (gavage) administration of calcium cyanamide technical grade to Sprague-Dawley rats from days 6 to 19 of gestation at doses of 7, 21 and 49 mg/kg/day (performed in accordance with OECD Test Guideline 414) was associated with dose-related reductions in overall mean body weight gain and food consumption in the 21 and 49 mg/kg/day groups. The low dose of 7 mg/kg/day was considered a No Observed Adverse Effect Level (NOAEL) for maternal toxicity. Evidence of embryo-foetal effects was restricted to dose-related slightly lower mean foetal weight in the 21 and 49 mg/kg/day groups. There was no adverse effect of treatment on morphological development at any dose. Since there were no other findings, including the absence of any adverse effect on morphological development, associated with the slightly lower mean foetal weight, the NOAEL for embryo-foetal toxicity was therefore 49 mg/kg/day.
- Executive summary:
A developmental toxicity study was conducted according to OECD TG 414 to evaluate the effects of the test item on embryonic and foetal development of the Sprague-Dawley rat when administered by the oral route (gavage) from implantation to the day before caesarean section.
The test item, Calcium Cyanamide (technical grade), was administered by daily gavage at dose levels of 7, 21 and 49 mg/kg bw/day to groups of 25 mated female Sprague-Dawley rats. A control group received the same volume (2 mL/kg bw) of the vehicle, corn oil. The females were treated from days 6 to 19 of gestation inclusive. Clinical condition, body weight and food consumption were monitored throughout the study. The females were submitted to a caesarean examination on day 20 of gestation and litter parameters were recorded. At necropsy, the females were examined macroscopically, and the gravid uterus and all foetuses were weighed. All live foetuses were examined for external abnormalities. Half of the foetuses in each litter were then examined internally and sexed prior to processing for skeletal examination. The remaining foetuses (approximately one half of the foetuses in each litter) were fixed for examination of the head only by serial sectioning.
There were no unscheduled deaths and no treatment-related clinical signs during the study in any group. There was a dose-related reduction in body weight gain and food consumption during the dosing period (G 6 to G 19) in the 21 and 49 mg/kg bw/day group leading to lower terminal body weight in the 49 mg/kg bw/day group only compared with the control. There was no treatment-related macroscopic observation in any group. There were 24, 25, 23 and 24 pregnant females in Groups 1 to 4, respectively, at the terminal caesarean sections, all of which had viable foetuses. There was no effect of treatment on embryo-foetal survival in any group. There was a slight dose-related reduction in mean foetal weight in the 21 and 49 mg/kg/day groups leading to slightly lower mean gravid uterus weight in the 49 mg/kg bw/day group only. Foetal sex ratio was normal in all groups. There were 1 (1) and 2 (1) malformed foetuses (litters) in Groups 1 and 2, respectively, none of which were considered to be associated with treatment.
The low dose of 7 mg/kg/day was considered a No Observed Adverse Effect Level (NOAEL) for maternal toxicity. Evidence of embryo-foetal effects was restricted to dose-related slightly lower mean foetal weight in the 21 and 49 mg/kg bw/day groups. There was no adverse effect of treatment on morphological development at any dose. Since there were no other findings, including the absence of any adverse effect on morphological development, associated with the slightly lower mean foetal weight, the NOAEL for embryo-foetal toxicity was therefore 49 mg/kg bw/day.
Reference
Summary of Malformations (includes external, visceral and skeletal examinations:
Dose level (mg/kg bw/day) | Female number | Foetus number | Malformations |
0 | 4 | 2 | Micrognathia (lower jaw) Cervical vertebrae with multiple abnormalities (absent or misshapen arches) |
7 | 31 | 1 | Cervical vertebra with an absent archThoracic vertebrae with multiple abnormalitiesof the centra (scoliosis) |
35 | 1 | Upper jaw with multiple abnormalities(misshapen maxilla and short premaxilla) | |
21 | - | - | - |
49 | - | - | - |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 49 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- OECD guideline study
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the results of the OECD Test Guideline 414 rat study, calcium cyanamide does not need to be classified with regard to reproductive toxicity according to Regulation (EC) No 1272/2008 (GHS/CLP).
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