Calcium cyanamide

Endpoint summary

Description of key information

Oral: There are several subacute and subchronic studies on calcium cyanamide available using the oral route. One subacute and one subchronic oral toxicity studies are available for calcium cyanamide technical grade and one subacute and four subchronic/chronic oral toxicity studies were performed with calcium cyanamide purum. Two studies were identified as key studies and were assessed together to derive a reasonable NOAEL. The one-year feeding study in rats was defined as key study as the test substance was administered over the longest period of time and the observation period was the most extended one among the evaluated studies. In addition, a 6-month repeated dose study with dogs was also chosen as the key study as dogs represent a second non-rodent species. Both key values (rat: LOAEL = 16 mg/kg bw/day, NOAEL = 1.3 mg/kg bw/day and dog: NOAEL = 14.6 mg/kg bw/day) are in the same range and represent reasonable reference figures. For derivation of the DNELs by the dermal and oral route, the chronic study in rats was chosen as the study period was longer compared to the dog study.

Inhalation/dermal: In accordance with column 2 of REACH Annex IX, the test repeated dose toxicity after inhalation and dermal application (required in section 8.6) do not need to be conducted as repeated dose toxicity studies for oral application are available. Reference figures for dermal and inhalation exposure are thus, extrapolated from oral studies/ human data (oral).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1959-1960

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of rats were fed for 17-50 weeks with dosages of 0.003%, 0.012%, 0.05% and 0.2% calcium cyanamide in the diet. The study was then either terminated or animals were subjected to an additional recovery period of 4 weeks (0.2% dosage) or 4 month (0.05% dosage). Bodyweights were taken twice per week for the first three weeks and once per week thereafter. Clinical observations were recorded once per month for the first 6 month and once every 6 weeks thereafter. At termination, packed cell volume was determined, circulating leucocyte counts and differential counts were made and autopsy was performed including histopathology. Bodyweights and organ weights were examined by rank test method for statistical difference from controls (plain diet).

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Supplier American Cyanamide Company

Species:

rat

Strain:

Sherman

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Wyckoff breeding colony
- Age at study initiation: 19-23 days
- Weight at study initiation: 30-70 g
- Fasting period before study: no
- Housing: individual in galvanized metal cages with wire mesh floor and front
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: one week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): about 24°C
- Humidity (%): 40-60%
- Air changes (per hr): air-conditioned room, no data on ventilation rate
- Photoperiod (hrs dark / hrs light): artificial light for 10 hours each day and 4 hours on Saturday and Sunday

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): sufficient amounts of drug diets were mixed weekly. At the end of each week the remaining diet was weight and discarded.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

17-50 weeks

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0.003%, 0.012%, 0.05% and 0.2%
Basis:
nominal in diet

No. of animals per sex per dose:

18/sex/dose

Control animals:

yes, plain diet

Details on study design:

No details on study design are provided in the report.

Positive control:

no data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes; gross observations were made daily

DETAILED CLINICAL OBSERVATIONS: Yes; Clinical observations on condition of skin, hair, eyes, teeth, feet, tail and behaviour were recorded once a month for the first 6 months and once every 6 weeks thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: twice per week for the first 3 weeks and once per week thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption was measured weekly for each group and compound intake (as mg/kg/rat/day) was calculated from food consumption and bodyweight figures.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to termination of the experiment

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

No data

Statistics:

Bodyweights and organ weights were examined by a rank test method for statistical differences from controls.

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):

effects observed, treatment-related

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:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

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:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
Twelve males and twelve females died in the course of the one-year study period. The mortality rate of the animals at the highest dosage level (0.2% calcium cyanamide) was very high and, therefore, it was to be expected that animals would not survive a one-year drug administration period. Thus, animals were treated for 7 month instead. Of the 18 males and 18 females of the 0.2% group, only 8 and 10 survived until seven month of treatment, respectively. Of the 0.05% group, one male and two females died and of the 0.012% group one female died. All other animals survived until termination one year after start of the study.
Respiratory infections were present in the control animals as well as in the four treatment groups. Weight loss accompanied prolonged infection. Skin lesions were observed in areas around the neck, chin, shoulder girdle and back, which is frequently seen in the rat colony of the performing laboratory. Skin irritation in the mouth/nose area was observed in animals fed the 0.2% diet after the first week of treatment which might be due to the irritating properties of calcium cyanamide. Other signs of intolerance seen at this dosage level were ptosis, excitability, priapism among males during the first month of treatment, poor balance, urinary incontinence, stiffness of the hind quarters, hunched posture and poor coats with bristle-like hair.

BODY WEIGHT AND WEIGHT GAIN
Bodyweights of the animals treated at 0.2% and 0.05% were significantly reduced compared to controls. The weight gain of animals of the 0.003% and 0.012% groups did not differ significantly from controls, although females of the 0.003% group exhibited an average bodyweight greater than controls.

FOOD CONSUMPTION AND COMPOUND INTAKE:
Consumption of food was significantly decreased at the two highest dose levels (0.2% and 0.05%), whereas the lower dosage groups (0.012% and 0.003%) did not show reduction in food consumption except for the males of the 0.012% group. Females of the 0.003% group consumed more food than control animals.
The average drug intake was 1.3-3.8 mg/kg/day for the 0.003% group, 5.5-14.9 mg/kg/day for the 0.012% group, 24-63.9 mg/kg/day for the 0.05% group and 134-229 mg/kg/day for the 0.2% group.
HAEMATOLOGY
Haematology data from treated animals did not differ from those of controls.

ORGAN WEIGHTS
Animals of the 0.2% group showed reduced weights of salivary glands, spleen, heart, lungs, liver, kidneys and brain when compared to controls. No statistical significant differences in organs weights were found in animals of the 0.05%, 0.012% and 0.003% groups.

GROSS PATHOLOGY
Rats of the highest dosage group (0.2%) showed granular appearance of liver surface, enlarged, dark red thyroid and changes related to the reproductive system. Animals treated at 0.05% showed enlarged, red thyroid.

HISTOPATHOLOGY:
Overall, of the effects found in this investigation on calcium cyanamide, the liver cirrhosis, dental anomalies, thyroid hyperplasia, decrease of acidophils and the presence of thyroidectomy cells in the anterior lobe of the pituitary are the only morphological changes, which according to their distribution and/or nature can be attributed to drug treatment. All other pathological findings are spontaneous diseases known to occur in rats and neither their distribution within the groups nor their morphological nature allows their classification as harmful drug effects. Therefore, only those effects related to treatment with calcium cyanamide are described in the following for the different dosage groups.
Extensive morphological activation of the thyroid was seen in animals treated at 0.2% calcium cyanamide. As well, proliferation of bile ducts and mesenchymal elements with liver cell necrosis was found at this dose level. In addition, thyroidectomy cells were found in the anterior lobe of the pituitary of these animals. When calcium cyanamide was discontinued and animals were examined four weeks later, repair processes were observed both in thyroid and liver. Dental anomalies were observed consisting predominantly of worn or broken incisors leading to overgrowth of the respective partner and subsequent ulceration of gums and lips. The high incidence of this finding suggests that this might be a drug effect, although these changes occur spontaneously on rare occasions in the animal colony, but were not observed in the 5-month study on calcium cyanamide. Hypoplasia of the reproductive system was especially pronounced in the males whereas the females were somewhat more resistant. The interpretation of these hypoplastic changes is difficult since the experimental design does not allow for the differentiation between starvation effects and hypothyroid state, both of which are possible triggers of this finding. Therefore, these effects cannot be attributed to treatment with calcium cyanamide alone.
Rats of the 0.05% group showed moderate to extensive morphological activation of the thyroid, thyroidectomy cells and a decreased number of acidophils in the pituitary and mesenchymal infiltration of liver. Rats that were treated at 0.05% calcium cyanamide for one year and were then subjected to a four month recovery period showed transformation of the thyroid into a diffuse colloid-goiter and no signs of malignancy were observed.
At 0.012% morphological activation of the thyroid and thyroidectomy cells in the pituitary were observed.
At 0.003% the only pathologic finding was moderate chronic tracheitis and in rare cases moderate morphological activation of the thyroid.

The high degree of morphological activation of the thyroid which were noted at all dose levels required a more elaborate evaluation, especially since some of the histological findings were indicative of malignant transformation. Destructive infiltration and vascular invasion as well as formation of papillary pattern, which was regarded as secondary, were observed. Animals of the 0.012% dose level did not show any of these signs. In the recovery studies it was shown that at least three animals of the 0.2% group show histological signs of regression as documented by the disappearance of colloid, flattening of the follicular epithelium and absence of capillary hyperamia. In addition, acidophil elements were visible in the pituitaries of these animals and the number of thyroidectomy cells decreased. Additional evidence for this regression was found in the 0.5 % group which were treated with 0.1% sodium iodide in the diet for 4 months for recovery. The three histological signs of malignancy disappeared completely and the thyroids of all animals showed histological pattern indicative of the transformation into a diffuse colloid goiter except for one animal where a large undifferentiated structure was observed. The recovery studies indicate that the pituitary and the thyroid show tendencies towards regression and repair in most of the cases. Therefore, it is extremely difficult, if not impossible, to justify a diagnosis of malignancy on the basis of histological examination alone. Thus, it is necessary that additional biological proof of malignancy of these structures should be given. On the basis of the regression studies and in spite of the histological criteria used for the determination of malignancy the described thyroid changes at the end of the drug feeding period cannot be regarded as malignant.

The postnecrotic liver cirrhosis which was found at the 0.2% and 0.05% diet levels in this investigation and found at the 0.2% group in the 5-month study, puts calcium cyanamide in the group of chemical substances which cause liver cirrhosis in rats. Most of these compounds are carcinogens. It is, however, very unlikely that calcium cyanamide, when given at the 0.2% dose level will ultimately cause hepatic neoplasms, since these animals will probably die before developing liver tumours. Since the maximum dose level for clinical uses in humans is 2 mg/kg/day, no development of hepatic tumours is to be expected as the highest dose administered to rats corresponds to 180 mg/kg/day which will never be applied to human beings. Although the incidence of liver cirrhosis in the 0.05% group (corresponding to 45 mg/kg/day) is very low, it cannot be stated that this dosage is safe regarding hepatotoxicity.

Key result

Dose descriptor:

LOAEL

Effect level:

ca. 0.012 other: %

Sex:

male/female

Basis for effect level:

other: Corresponding to 11 mg/kg bw/day. Based on the histopathological findings in thyroid and liver observed at the next higher dosage level.

Dose descriptor:

NOAEL

Effect level:

0.003 other: %

Sex:

male/female

Basis for effect level:

other: Corresponding to 1.3 mg/kg bw/day.

Critical effects observed:

not specified

no remarks

Conclusions:

The 0.012 % dose level causes a few cases of thyroid hyperplasia and was, thus, considered the borderline adverse effect level (LOAEL). This dosage corresponds to a daily intake of 11 mg/kg bw Calcium cyanamide, purum, considering the bodyweights of rats and daily food consumption, which is equal to 16 mg/kg Calcium cyanamide, technical grade.

Executive summary:

A previous one-year feeding experiment of calcium cyanamide had to be terminated after 5 months because of an accident in the animal quarters. This study was therefore performed to investigate the potential toxicological properties of calcium cyanamide when fed to rats for a period of one year.

Dosages of 0.2, 0.05, 0.012 and 0.003 % calcium cyanamide, purum were applied to rats with the diet for a period of up to one year. In addition, a recovery period of 4 weeks (in case of the highest dosage) or 4 months (for animals treated at 0.05 %) was added for some of the animals to investigate for reversibility of effects induced by treatment.

In the course of the one-year study period, twelve animals died, most of them being treated at the highest dosage (0.2 %). After seven months of treatment it was decided to examine the effects of treatment in the animals of the 0.2% group, because of their poor condition. The other dosage groups were kept on treatment for the remaining time.

Both, bodyweights and food consumption were significantly decreased in the 0.2 and 0.05 % groups. The lower dosage groups did not show reduction in food consumption or bodyweight gain.

Results revealed that oral administration of 0.2 % calcium cyanamide (180 mg/kg/day) up to 7 months caused extreme degree of thyroid hyperplasia, thyroidectomy cells and decrease of acidophilic cells in the anterior pituitary, postnecrotic liver cirrhosis and dental disorders. Similar findings but less pronounced and with lower frequency were observed in animals receiving 0.05 % (45 mg/kg/day) for one year.

The 0.012 % dose level (11 mg/kg/day) caused a few cases of thyroid hyperplasia with the occurrence of thyroidectomy cells and the decrease of acidoplhilic cells in the anterior pituitary.

Thyroid hyperplasia was in rare instances noticeable in animals receiving the 0.003 % diet, but was not considered as treatment related effect, but reflecting biological variation.

The significance of hyperplasia of the reproductive system and the decrease of bodyweight gain both found in animals of the 0.2% and the 0.05% group cannot be clearly attributed to treatment since two mechanisms, the decrease of food consumption and hypothyroidism, can be responsible for these phenomena.

The liver changes observed at the two highest dose levels have been defined as postnecrotic cirrhosis.

The occurrence of thyroidectomy cells and the decrease of acidophils in the anterior pituitary indicate a complete inhibition of the thyroid. The thyroids of the 0.2 % group were extremely hyperplastic and showed histological signs of malignancy after 7 months of drug administration. Similar thyroid hyperplasia was found in the 0.05 % group. The recovery studies showed that all histological signs of malignancy disappeared after the discontinuation of drug treatment, a phenomenon which is not compatible with the biological definition of a malignant neoplasm.

Under the conditions of the study, and regarding the histopathological changes in thyroid and liver observed at the two highest dose levels, a dosage of 0.012 % Calcium cyanamide, purum in the diet can be regarded as borderline effect level (LOAEL), which is equal to 0.017 % Calcium cyanamide, technical grade.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

1.3 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Findings from supporting studies with other exposure time and other species (dog) conform the results of the key study.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

One subacute and one subchronic oral toxicity studies are available for Calcium cyanamide, technical grade and one subacute and four subchronic/chronic oral toxicity studies were performed with Calcium cyanamide, purum. Two studies were identified as key studies and were assessed together to derive a reasonable NOAEL. The one-year feeding study in rats was defined as key study, as the test substance was administered over the longest period of time and the observation period was the most extended one. In addition, a 6 month repeated dose study with dogs was chosen as key study, as dogs represent a second non-rodent species.

Key studies:

In an one-year study, 0.003%, 0.012%, 0.05% and 0.2% calcium cyanamide purum in the diet were administered to rats, including a recovery period of 4 weeks which was added to some of the animals of the highest dosage group. After seven months of treatment it was decided to examine the effects of treatment in the animals of the 0.2% group, because of their poor condition. The other dosage groups were kept on treatment for the remaining time. Both, bodyweights and food consumption were significantly decreased in the 0.2% and 0.05% groups. The lower dosage groups did not show reduction in food consumption or bodyweight gain. Results revealed that oral administration of 0.2% Calcium cyanamide, purum (about 180 mg/kg/day) up to 7 months caused extreme degree of thyroid hyperplasia, thyroidectomy cells and decrease of acidophilic cells in the anterior pituitary, postnecrotic liver cirrhosis and dental disorders. Similar findings but less pronounced and with lower frequency were observed in animals receiving 0.05% (about 45 mg/kg/day) for one year. The 0.012% dose level (about 11 mg/kg/day) did not cause any morphological changes attributable to treatment with the exception of a few cases of thyroid hyperplasia with the occurrence of thyroidectomy cells and the decrease of acidophilic cells in the anterior pituitary. The thyroid hyperplasia was in rare instances noticeable in animals receiving the 0.003% diet. The significance of hyperplasia of the reproductive system and the decrease of bodyweight gain both found in animals of the 0.2% and the 0.05% group cannot be clearly attributed to treatment since two mechanisms, the decrease of food consumption and hypothyroidism, can be responsible for these phenomena. The liver changes observed at the two highest dose levels have been defined as postnecrotic cirrhosis. Under the conditions of the study, and regarding the histopathological changes in thyroid and liver observed at the two highest dose levels, a dosage of 0.012% Calcium cyanamide in the diet was regarded to cause slight effects. This dosage corresponds to a daily intake of 11 mg/kg bw, considering individual bodyweights of rats as well as the daily food consumption. Thus, the LOAEL of this chronic study in rats was set at 11 mg/kg bw/day of Calcium cyanamide, purum, which is equal to 16 mg/kg Calcium cyanamide, technical grade. The NOAEL was reported by the author as 1.3 mg/kg/d (0.003% Calcium cyanamide, purum in the diet)

A six-month toxicity study in dogs, treated at 2, 10 or 30 mg/kg/day of Calcium cyanamide in gelatine capsules or receiving gelatine capsules without test substances as control, showed severe toxic symptoms like ulcers in the upper gastrointestinal tract, fatal lung edema and leukopenia at the highest dosage group. These animals died on Days 9 and 13 of the study, respectively, and were replaced by two dogs receiving 7.5 mg/kg bw/day for the remaining study period. Daily doses as high as 10 mg/kg/day were well tolerated and pathological findings in these groups represented mostly minor changes known to occur in the dog colony and were therefore not attributed as treatment effect. The NOAEL derived on the basis of the results and under the conditions of the study is, thus, 10 mg/kg/day of Calcium cyanamide, purum, which is equal to 14.6 mg/kg Calcium cyanamide, technical grade.

Supporting studies:

Subchronic/chronic studies:

A three-month study on Calcium cyanamide, purum in combination with thyroid powder indicates that thyroid powder (80 mg/kg/day) concurrently administered with Calcium cyanamide, purum (10, 20, 40 or 80 mg/kg/day) minimized the effect of Calcium cyanamide, purum on bodyweight gain. The NOAEL was established at 20 mg/kg bw/day of Calcium cyanamide, purum, which is equal to 29.1 mg/kg Calcium cyanamide, technical grade.

An investigation over a period of five month in which rats were administered 0.003%, 0.012%, 0.05% and 0.2% Calcium cyanamide in the diet showed a decrease in food consumption and bodyweight gain as well as hypoplasia of the thyroid in the two highest dosage groups. Furthermore, for animals treated at the top dose level, hyperplasia of the reproductive system, slight postnecrotic liver cirrhosis and thyroidectomy cells in the pituitary were noted. At the two lowest dose levels, no adverse findings were described. In view of the fact that a considerable number of drugs cause moderate hyperplasia in the rat thyroid and are used clinically without any undesirable side effects, the 0.05% dose level (corresponding to approximately 20-times the recommended therapeutic dose of 1 - 2 mg/kg/day) can be regarded as tolerable as far as toxic effects in the thyroid are concerned. The significance of the hyperplasia of the reproductive system at the highest dosage level cannot clearly be defined since two mechanisms, decreased food consumption and hypothyroidism, may be responsible for this phenomenon. The NOAEL was defined at 0.012% Calcium cyanamide, purum in the diet, which corresponds to 9.3 mg Calcium cyanamide/kg bw/day (equal to 13.5 mg Calcium cyanamide, technical grade) taking into consideration the mean bodyweight and mean food consumption of the rats throughout the study period.

In a 10-month study in rabbits, the influence of Calcium cyanamide on the activity of fermentation processes in the organism was investigated. Animals were treated at dosages corresponding to 1/100, 1/1000 or 1/1500 the LD 50 of Calcium cyanamide over 10 months. Serum was examined once per month for changes in activity of fructose-1,6 -biphosphate aldolase (FDA) and sorbitdehydrogenase (SDG). At the end of the investigation, liver homogenate and subcellular fractions of liver were checked for the activity of FDA and SDG as well. Results revealed changes in serum activity of FDA in all of the treatment groups, but no clear result indicating elevation or reduction in activity when compared to control levels was found. Activity of SDG did not change during the 10-month treatment period when determining serum levels. At 1/100 the LD50, animals showed elevated SDG activity from the 8th month of treatment on and elevated activity was found as well in liver homogenate and all of the subcellular fractions of liver tested at termination in this dosage group. For the lower dosage groups no difference in activity of SDG was found. No NOAEL was established in this non-standard investigation.

Subacute studies:

In a 5-day study, male rats were treated at either stock diet or stock diet supplemented with 0.05% Calcium cyanamide, technical grade. All rats remained in good health and mean bodyweights were comparable in the treatment and control group. The food intake figures revealed that when given the choice between stock diet and stock diet containing test substance, animals' preferred stock diet. From the results it can be concluded that Calcium cyanamide, technical grade showed repellent activity. No adverse effects related to substance intake were noted and, thus, 0.05% of Calcium cyanamide, technical grade in the diet can be regarded as NOAEL. This dosage is equivalent to 17.5 mg/kg bw/day, taking into consideration the mean bodyweight and food consumption of rats during the study period.

The 4-week dose range finding study in rats treated at 0.008, 0.04, 0.2 and 1% Calcium cyanamide, purum in the diet revealed that animals of the highest dosage group were in poor condition and died within Day 5-7 of the study. As well, animals of the 0.2% group were poor in condition throughout the study, whereas animals of the 0.04 and 0.008% group showed no toxic symptoms. For rats treated at 0.2% reduced weight of all organs examined was observed except for thyroid which showed increased weight and signs of morphological activation. As well in the 0.04% group, thyroid weight was increased. The increase in thyroid weight together with the morphological activation is an evidence for an antithyroidal activity of the test substance. Animals of the lowest dosage group (0.008%) representing an actual intake of Calcium cyanamide, purum of 8.3 -12.6 g/kg (equal to 12.1 to 18.3 mg/kg Calcium cyanamide, technical grade), i.e. approximately 10 -times the daily dose in humans when used as a drug, showed no disadvantageous effects and can, therefore, be regarded as safe under the conditions of the study.

Disregarded studies on cyanamide:

Even though calcium cyanamide can rapidly hydrolyse to cyanamide (e.g. in aqueous solutions), due to the differences in physicochemical properties (e.g. chemical composition) and dissolution kinetics (e.g. in the stomach under low pH conditions) as well as the dissimilar outcomes between cyanamide and calcium cyanamide observed in some of the toxicity studies (e.g. acute toxicity and developmental toxicity), the use of data from cyanamide as read-across or weight-of-evidence approach for evaluating the repeated dose toxicity potential of calcium cyanamide technical grade is not appropriate (for more information, see report "Scientific Rationale for not using Cyanamide as Read-Across Substance for Calcium Cyanamide on Toxicological Endpoints" in Section 13.2). Furthermore, there are existing repeated dose toxicity studies of calcium cyanamide, including an one-year study performed in rats and a six-month study performed in dogs, that are considered as suitable for the evaluation of this specific endpoint. Nevertheless, the repeated dose toxicity studies of cyanamide are copied to the calcium cyanamide dossier here to demonstrate full consideration of all cyanamide study data in the overall substance assessment and classification of calcium cyanamide.

Conclusion for risk assessment:

The key value for deriving DNELs for the dermal and oral route was taken from a 1-year feeding study in rat (NOAEL 1.3 mg/kg/d). A NOAEL of 14.6 mg/kg bw/day was derived from a 6-month study in dogs, providing a reasonable reference figure. For the inhalation route, the DNEL was derived from studies in humans, in line with the proposal by SCOEL and other institutions. Since human data are preferable to animal data, it follows that the available information from workers exposed to calcium cyanamide should be preferred.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; glandular: thyroids; neurologic: pituitary

Justification for classification or non-classification

Based on the results of repeated oral toxicity testing, calcium cyanamide has not to be classified with respect to specific organ toxicity according to Regulation (EC) No 1272/2008 (GHS/CLP).