Registration Dossier

Administrative data

Description of key information

The sensitizing potential of Dicyandiamid (DCD) was tested in 16 male albino guinea pigs according to the Landsteiner/Draize method. Boman et al. (1985) conducted a Guinea pig maximization test according to Magnusson & Kligman (1970). The results were supported by a negative FCA-test conducted as part of an occupational case study by von Senff et al. 1988.
In addition there are human data reported by von Senff et al. (1988), Jirasek and Kalensky 1962 and Szczeklik-Franek et al. (1977).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
number of test animals should be 10 (here: 8)
Principles of method if other than guideline:
The Landsteiner/Draize method was used. The test substance was administered by intra-dermal injections.
GLP compliance:
not specified
Remarks:
pre-GLP
Type of study:
Draize test
Justification for non-LLNA method:
A Skin sensitisation study from 1977 is available
Species:
guinea pig
Strain:
other: not specified; albino guinea pigs
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 198 - 282 g
Route:
intradermal
Vehicle:
other: 0.85 % saline
Concentration / amount:
2 % solution in 0.85 % saline
Route:
intradermal
Vehicle:
other: 0.85 % saline
Concentration / amount:
2 % solution in 0.85 % saline
No. of animals per dose:
- 8 animals per group
- 2 groups: 1 test group, 1 control group
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: test group animals were treated repeatedly (10 injections), the control group animals were only treated once
- Duration: 3 weeks
- Test groups: 1
- Control group: 1
- Site: right flank
- Frequency of applications: 3 times weekly
- Concentrations: 2 % colution of the substance in 0.85 % saline
- details on injections: test animals received a total of 10 injections; as the first injection each animal received 0.05 ml of the 2.0 % suspension; in the 2nd to 10th injection 0.1 ml was applied per animal


B. CHALLENGE EXPOSURE
- Two weeks after 10th injection the challange-dose was given: 0.05 ml per animal
- At this time the control animals were injected with 0.05 ml of the 2.0 % suspension of the test sample


OTHER:
- shaving of treatment site: some days before starting the treatment the right flank of the animals was shaved with electric clippers; shaving was repeated before each injection and reading if necessary
- The reaction sites were examined 24 hours after the injection; diameter, colour, and thickness were used as criteria for the intensity of the reaction
Challenge controls:
Yes: control animals were injected with 0.05 ml of the 2.0 % suspension of the test sample at challenge exposure.
Positive control substance(s):
no
Positive control results:
Not applicable
Key result
Reading:
1st reading
Group:
test group
Dose level:
0.05 ml of 2 % solution of test substance in 0.85 % saline
No. with + reactions:
0
Total no. in group:
8
Clinical observations:
Not reported
Remarks on result:
other: Reading: 1st reading. Group: test group. Dose level: 0.05 ml of 2 % solution of test substance in 0.85 % saline. No with. + reactions: 0.0. Total no. in groups: 8.0. Clinical observations: Not reported.
Reading:
1st reading
Group:
negative control
Dose level:
0.05 ml of 2 % solution of test substance in 0.85 % saline
No. with + reactions:
1
Total no. in group:
8
Clinical observations:
Reaction to injection at the same time as the challenge
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. Group: negative control. Dose level: 0.05 ml of 2 % solution of test substance in 0.85 % saline. No with. + reactions: 1.0. Total no. in groups: 8.0. Clinical observations: Reaction to injection at the same time as the challenge.
Group:
positive control
Remarks on result:
not measured/tested

Table 1: Individual positive reactions (marked with + signs) observed during the induction and challenge period with Dicyandiamid EH

Test animals

Control animals

No.

Individual direct reaction

Challenge

No.

Reaction to injection at the same time as the challenge

1

2

3

4

5

6

7

8

9

10

1575

 

 

 

 

+

 

+

+

+

 

 

1583

 

1576

 

 

 

 

+

 

+

 

+

 

 

1584

 

1577

 

+

+

+

+

+

+

 

+

 

 

1585

 

1578

 

 

 

 

+

 

+

 

 

 

 

1586

 

1579

 

 

 

 

+

+

+

+

+

 

 

1587

+

1580

 

 

 

 

 

+

+

+

 

+

 

1588

 

1581

 

+

 

 

+

 

+

 

 

 

 

1589

 

1582

 

 

 

 

+

 

+

 

 

 

 

1590

 

 

0

2

1

1

7

3

8

3

4

1

0

 

 1

Degree of reaction: + = mild

Interpretation of results:
not sensitising
Conclusions:
Dicyandiamid EH is not sensitizing to male guinea pigs under the conditions of this test.
Executive summary:

The test substance was administered by intradermal injections following the Landsteiner/Draize method. Sixteen male albino guinea pigs, were divided into 2 groups (test and control). The test animals were treated repeatedly with a 2 % solution of the substance in 0.85 % saline. During the induction period the test animals received a total of 10 injections, 3 times weekly for 3.weeks. Two weeks after the 10th injection the challenge-dose was given in an amount of 0.05 ml per animal. The reaction sites were examined 24 hours after the injection.

Dicyandiamid EH caused positive skin reactions upon repeated intradermal injections in all test animals. The reaction was mild. None of the test animals reacted positively upon the challenge-dose. One out of 8 controls showed a positive mild reaction to injection at the same time as the challenge.

From these results it can be concluded that Dicyandiamid EH was not sensitizing under the conditions of this study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Animal Experiments:

The Landsteiner/Draize test was carried out on 16 guinea pigs to investigate the sensitizing potential; for induction, 8 animals initially received 0.05 ml intradermally and then 0.1 ml of 2% dicyanodiamide in physiological saline on three days of the following three weeks. Two weeks after the last injection, the treated and the 8 control animals were given a further injection of 0.05 ml of 2% dicyanodiamide in physiological saline. Slight irritation during the treatment and challenge phases was seen in all animals treated. 24 hours after the challenge treatment, only one guinea pig of the control group, but no other animal showed a reaction. Dicyanodiamide was therefore classified as nonsensitizing (Til, 1977), but no reading was carried out at later dates. In a maximization test, the sensitizing effect of dicyanodiamide was investigated in 20 guinea pigs, with an aqueous 1.75% (w/w) preparation with Freund’s complete adjuvant being used for intradermal induction and an aqueous 25% (w/w) solution for epicutaneous induction. The reactions to 0.5, 2.5 and 5% dicyanodiamide showed no significant differences between treated and control animals immediately after the 24- hour occlusive challenge treatment carried out on the 21st day or 24 and 48 hours later (Boman et al. 1985). In a study which was not described in more detail, dicyanodiamide was tested for sensitization in the Freund’s complete adjuvant test on 10 guinea pigs. No sensitizing potential was observed (Senff et al. 1988).

Effects in Humans:

In a prophetic patch test (no other details), dry, pulverized material was investigated on 200 persons for skin irritation and sensitizing properties. Dicyanodiamide was not found to be either sensitizing or irritating (ACC 1959, referenced in MAK 2007).

34 persons with acute eczema of the upper extremities, who came from different areas of the industry processing or producing epoxy resins and from research institutes, were investigated. The skin lesions occurred one week to two years after the first contact with epoxy resin, with the most frequent latency period being one to three months. The persons affected were investigated in the patch test with 2% dicyanodiamide in water. Dicyanodiamide did not lead to skin changes among any of the 34 persons affected (Jirasek and Kalensky 1962, referenced in MAK 2007).

One worker from a factory for flame retardants developed ambilateral dyshidrosiform hand eczema after four years of working there. The epicutaneous testing with dicyanodiamide (pure substance and 10% preparation) revealed a highly positive reaction after 24 hours, which was marked even with the 1% preparation. The positive result was confirmed in another epicutaneous testing carried out one year after the worker had given up his job. It is not clear from the documentation whether and at what time a further reading was made. The patient showed no reactions to substances from a standard test series or to rubber chemicals, substances from the coating, plastic and adhesive series or to disinfectants. No reactions to 1% and 10% dicyanodiamide or to pure dicyanodiamide were obtained among 25 control persons (Senff et al. 1988).

Dermatoses were observed among 19 workers in the department of a chemical plant which produces melamine starting from calcium cyanamide via cyanamide and dicyanodiamide. Therefore, patch tests according to Jadassohn and Bloch were carried out with a 1% dicyanodiamide preparation in petrolatum or with petrolatum alone as a negative control on the persons affected and on 61 persons with healthy skin (a total of 57 men and 23 women between 18 and 65 years old). The 19 workers affected (24%) were additionally subjected to a patch test for a standard group of allergens. Reactions to dicyanodiamide assessed as allergic by the authors were observed on 7 workers affected and on 2 of the healthy workers (Szczeklik-Franek and Masalska 1977). Aetiopathology as well as morphology indicate that the clinical picture is an allergic contact dermatitis caused by DCD. This is supported by the results of the Jadassohn & Bloch test. However, anamnesis gives evidence that in almost all cases drinking of alcoholic beverages / beer has been the reason for the dermatosis.



Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

no data

Justification for classification or non-classification

Based on available data from animal tests and occupational exposure, Dicyandiamide does not show a significant potential for skin sensitization. This conclusion is supported by the fact that a very large number of individuals (105) have frequent and long-term exposure, and no or only a very few isolated cases of allergic contact dermatitis are observed. Classification for skin sensitization is therefore not warranted.