Calcium cyanamide

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

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:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.7600 (Dermal Penetration)

Deviations:

yes

Remarks:

There was no sampling after dermal application in order to observe serial non-detects in excreta.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Cyanamide

EC Number:

206-992-3

EC Name:

Cyanamide

Cas Number:

420-04-2

Molecular formula:

CH2N2

IUPAC Name:

cyanamide

impurity 1

Reference substance name:

Cyanoguanidine

EC Number:

207-312-8

EC Name:

Cyanoguanidine

Cas Number:

461-58-5

Molecular formula:

C2H4N4

IUPAC Name:

2-cyanoguanidine

additive 1

Reference substance name:

Water

EC Number:

231-791-2

EC Name:

Water

Cas Number:

7732-18-5

Molecular formula:

H2O

IUPAC Name:

Dihydrogen oxide

additive 2

Reference substance name:

Orthophosphoric acid

EC Number:

231-633-2

EC Name:

Orthophosphoric acid

Cas Number:

7664-38-2

Molecular formula:

H3O4P

IUPAC Name:

phosphoric acid

Test material form:

liquid - solid: mixture of

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male

Details on test animals or test system and environmental conditions:

The rats were obtained from Charles River Laboratories (Massachusetts U.S.A)

Administration / exposure

Type of coverage:

other: Non-occlusive

Vehicle:

water

Duration of exposure:

Up to 24 hours

Doses:

0.1, 1 and 10 mg of Hydrogen cyanamide for a rat in a volume of 100 µl.

No. of animals per group:

24 animals per group

Control animals:

yes

Details on study design:

- The dosing solutions were prepared by mixing appropriate amounts of [14C] Hydrogen cyanamide stock solution in deionized water (adjusted to pH 4.5 with phosphoric acid). Three dosing solutions were prepared to deliver 0.1, 1 and 10 mg of Hydrogen cyanamide in a volume of 100 µl on an area of 12.5 cm2.
- Approximately 24 hours before dosing, the back and shoulders of each rat were shaved and the shaved area was washed with acetone. At 0 hour, the test material solution was applied evenly to the test site. The application site was then covered with a non-occlusive cover to prevent disturbance of the application site and mechanical loss of the test material.
- A single cumulative faeces sample was collected from each rat from the time of dosing to the time of sacrifice. After all urine and faeces samples had been collected, each cage was rinsed and the cage wash was collected. Four rats from each group were sacrificed at each of the six times (0.5; 1; 2; 4; 10 and 24 hours) after application of the test substance. Blood was collected via cardiac puncture. The skin at the application site (with cover in place) and carcass were collected for analysis. All samples were assayed by liquid scintillation counting (LSC).
- A single cumulative urine sample was collected from each rat from the time of dosing to the time of sacrifice. Any residual urine present at sacrifice was collected and added to the appropriate urine sample.

Results and discussion

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

Blood:
For the animals in the lowest dose group (0.1 mg dose) mean blood radioactivity concentrations ranged from non-detectable at 2 and 4 hours to 0.002 µg equivalents/g at 24 hours. Higher concentrations were observed for the animals in the mid (1 mg dose) and the high (10 mg dose) dose with mean values for each group generally increasing with time of exposure up to 10 hours. For the mid dose group the mean blood radioactivity concentration ranged from 0.006 µg equivalents/g at 0.5 hours to 0.37 µg equivalents at 10 hours. For the high dose group the mean concentrations ranged from 0.029 µg equivalents/g at 0.5 hours to 1.04 µg equivalents/g at 10 hours.

Urine and faeces:
The amount of radioactivity found in urine ranged between n.d. and 0.22 % during the period from 0.5 to 4 h when considering all dose levels. After 10 h exposure the recoveries of radioactivity in urine were 0.7, 1.45 and 4.38 % for the low, mid and high dose, respectively. In faeces of the low dose animals, no radioactivity was found up to and including 10 h exposure. The recoveries after 24 application were 0.05, 0.02, < 0.01 and 0.07 % for the individual test animals. In faeces of the mid dose animals, no radioactivity was found up to and including 4 h exposure. The recovery after 10 h application was 0.07 %. After 24 h application, < 0.01, 0.04, 0.06 and 0.08 % of radioactivity was recovered in the faeces of individual test animals. In faeces of the high dose animals, no radioactivity was found up to and including 4 h exposure. The recoveries after 10 h application was < 0.01, < 0.01 and 0.23 %. After 24 h application, 0.28, 0.12, 0.19 and 0.22 % of radioactivity was recovered in the individual animals.

Carcass:
Radioactivity was detectable in the carcass of animals from all three dose levels with highest amounts of mean radioactivity at 10 and 24 hours. The result are also consistent with the blood data.

The result indicate some systemic absorption of the test material at all dose levels. The amounts of absorbed dose increased with exposure time and reached maximum values at 24 hours.

Amount of dose remaining in or on the skin after washing:
The amount of radioactivity found in the skin of all test groups after wash is constant between 0.5 h and 10 h. The amount in the skin ranged between 4.4 and 8.7 % for the low and mid dose in the time period 0.5 to 10 h. The variation over time observed for the high dose animals was larger. However, the mean recovery over time (0.5 – 10 h) is comparable to the low and mid dose.

Amount of unabsorbed dose:
For all three dose groups the amount of radioactivity recovered was inversely related to the amount of absorbed dose and skin radioactivity observed at the later time points. At 0.5 hours the mean radioactivity recovered in the skin rinses as approximately 97 % for the low and mid dose group and approximately 90 % for the high dose group. The values decreased to 69 %, 68 % and 53 % for the low, mid and high dose group respectively at 24 hours.

The average material balance indicate that there was no appreciable loss of radioactivity due to formation of volatile products either on the skin or from absorbed dose. The mean material balance was between 93.34 % and 98.61 %.

Percutaneous absorption

Percutaneous absorption 1

Dose:

0.1 mg/rat

Parameter:

percentage

Absorption:

1.2 %

Remarks on result:

other: After 10 hours exposure

Remarks:

The total means systemically absorbed dose including the amount located in the skin is 8.23%.

Percutaneous absorption 2

Dose:

1 mg/rat

Parameter:

percentage

Absorption:

2.6 %

Remarks on result:

other: After 10 hours

Remarks:

The total means systemically absorbed dose including the amount located in the skin is 9.45%.

Percutaneous absorption 3

Dose:

10 mg/rat

Parameter:

percentage

Absorption:

7.5 %

Remarks on result:

other: After 10 hours exposure

Remarks:

The total means systemically absorbed dose including the amount located in the skin is 14.34%.

Conversion factor human vs. animal skin:

Conversion factor C (rat ->human) is not indicated in the study report.
Based on the following calculation C can be received as follows:
C (rat, in vito ->human, in vitro) = % absorbance in an in-vitro rat study / % absorbance in-vitro human
Based on the resulting C the % absorbance in-vivo human can be calculated by:
% absorbance in-vivo human = % absorbance in an in-vivo rat study (present study) / C

Any other information on results incl. tables

Mean percent dose in urine, faeces and carcass at specified time postdose:

Sacrifice time (hours)	Mean percent dose in urine			Mean percent dose in faeces			Mean percent dose in carcass
	0.1*	1.0*	10.0*	0.1*	1.0*	10.0*	0.1*	1.0*	10.0*
0.5^a)	nd**	nd**	< 0.01	nd**	nd**	nd**	0.07	0.16	0.12
1^a)	0.02	nd**	nd**	nd**	nd**	nd**	0.17	0.29	0.65
2^a)	0.05	< 0.01	nd**	nd**	nd**	-	0.08	0.65	0.91
4^a)	0.17	nd**	0.22	-	-	nd**	0.10	0.53	1.63
10	0.7	1.45	4.38	nd**	0.02	0.06	0.5	1.07	2.35
24	0.93	1.69	7.65	0.04	0.05	0.2	0.65	0.89	2.05

*mg/animal in a volume of 100 µL on an area of 12.5 cm² **not detectable

Amount of [¹⁴C] Hydrogen cyanamide systemically absorbed as indicated by the total radioactivity found in carcass, excreta, cage wash and cage wipe:

Sacrifice time (hours)	Total radioactivity found in carcass, excreta, cage wash and cage wipe
	0.1 (mg/animal)	1.0 (mg/animal)	10.0 (mg/animal)
0.5	0.07 %	0.16 %	0.12 %
1	0.19 %	0.29 %	0.66 %
2	0.13 %	0.69 %	0.91 %
4	0.27 %	0.53 %	1.85 %
10	1.2 %	2.64 %	7.53 %
24	1.79 %	2.84 %	11.1 %

Amount of [¹⁴C]-Hydrogen cyanamide in skin:

Sacrifice time (hours)	Mean percent dose in skin at specified times postdose
	0.1 (mg/animal)	1.0 (mg/animal)	10.0 (mg/animal)
0.5	6.57 %	4.41 %	7.47 %
1	6.80 %	4.03 %	11.7 %
2	7.48 %	8.67 %	9.46 %
4	6.48 %	5.99 %	5.33 %
10	7.03 %	6.81 %	6.81 %
24	17.0 %	13.5 %	11.1 %

Total amount of [¹⁴C]-Hydrogen cyanamide absorbed as calculated by including the amount located in the rat skin:

Dose levels	% absorbed of dose applied after 10 h exposure
	systemically	total*
10 mg/rat	7.53	14.34
1 mg/rat	2.64	9.45
0.1 mg/rat	1.20	8.23

* total means systemically absorbed dose including the amount located in the skin

 

 

Applicant's summary and conclusion

Conclusions:

Hydrogen cyanamide is absorbed through rat skin (Total amount of systemically absorbed dose at 10 h:1.2% (low dose) to 7.53% (high dose). At 10 h: 1.2% (low dose) to 11.1% (high dose)).

Executive summary:

The study was performed using male Crl:CD(SD)BR rats. Each dose group consisted of 24 animals. The dosing solutions were prepared by mixing appropriate amounts of [14C] hydrogen cyanamide stock solution in deionized water (adjusted to pH 4.5 with phosphoric acid). Three dosing solutions were prepared to deliver 0.1, 1 and 10 mg of hydrogen cyanamide in a volume of 100 µl on an area of 12.5 cm2. A single cumulative faeces sample was collected from each rat from the time of dosing to the time of sacrifice. After all urine and faeces samples had been collected, each cage was rinsed and the cage wash was collected. Four rats from each group were sacrificed at each of the six times (0.5; 1; 2; 4; 10 and 24 hours) after application of the test substance. Blood was collected via cardiac puncture. The skin at the application site (with cover in place) and carcass were collected for analysis. All samples were assayed by liquid scintillation counting (LSC). At 0 hour, the test material solution was applied evenly to the test site. The application site was then covered with a non-occlusive cover to prevent disturbance of the application site and mechanical loss of the test material. The control animals were treated in the same way as the treated animal, but dosed with the vehicle.

The amount of systemically absorbed [14C] hydrogen cyanamide increased with the dose level and with time of exposure. Maximum blood concentration of radioactivity were observed at 24 hours for the low and mid dose and at 10 hours for the high dose. Urinary excretion of radioactivity increased with time and amount of the test material applied. The amount of radioactivity associated with the washed skin was relatively constant (average 5 % to 10 % of the applied dose). The majority of the applied dose was recovered in the skin wash. The amount of radioactivity in the skin wash generally decreased with time through 24 hours and did not appear to be related to the applied dose. The total amount of systemically absorbed dose averaged 1.2 %, 2.64 % and 7.53 % of the dose at 10 hours and 1.79 %, 2.84 % and 11.1 % of the dose at 24 hours for low, mid and high dose, respectively.