Registration Dossier

Administrative data

Description of key information

Studies were performed to assess the irritancy potential of the (1,4,5,6-Tetrahydro-4,6-dioxopyrimidin-2-yl)cyanamide to the skin and eye of the New Zealand white rabbit. The methods followed were OECD guidelines no. 404 and 405 (Methods B4 and B5 of the Commission Directive 84/449/EEC).

The test item is not classified for skin corrosion/irritation or eye damage/eye irritation according to CLP criteria.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 5 December 1991 to 8 December 1991.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
1981
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
84/449/EEC
GLP compliance:
yes (incl. certificate)
Test material information:
Composition 1
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Description: off-white powder
- Sponsor's identification: CYDI

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Container: white plastic jar (x2)
- Data relating to the identity, purity and stability of the test material are the responsibility of the sponsor.


Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Age at study initiation: twelve to sixteen weeks old
- Weight at study initiation: 2.28 - 2.43 kg
- Housing: individual housing in suspended metal cages
- Diet (e.g. ad libitum): Spillers Rabbit Diet, Dalgety Agriculture Ltd., Almondsbury, Bristol; free access was allowed throughout the study
- Water (e.g. ad libitum): Spillers Rabbit Diet, Dalgety Agriculture Ltd., Almondsbury, Bristol; free access was allowed throughout the study
- Acclimation period: five days each animal

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-21°C
- Humidity (%): 37-47%
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): continuous 12 hours light and 12 hours of darkness
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
not required
Amount / concentration applied:
A quantity of 0.5g of the test material, moistened with 0.6 ml of distilled water, was introduced under a 2.5 cm x 2.5 cm gauze patch and placed in position on the shorn skin. The patch was secured in position with a strip of surgical adhesive tape.
Duration of treatment / exposure:
4 hours
Observation period:
24, 48 and 72 hours
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure:
2.5 cm x 2.5 cm
- Type of wrap if used:
The patch was secured in position with a strip of surgical adhesive tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done):
gentle swabbing with cotton wool soaked in distilled water
- Time after start of exposure:
4 hours

OBSERVATION TIME POINTS
- Approximately one hour following the removal of the patches, and 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation

SCORING SYSTEM:
- Method of calculation: according to the scale from Draize J.H. (1959) Association of Food and Drug Officials of the United States, Austin, Texas, "The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics". See Table 1.

INTERPRETATION OF THE RESULTS:
- The scores for erythema and oedema at the 24 and 72-hour readings were totalled for the three test rabbits (12 values) and this total was divided by 6 to give the primary irritation index of the test material. The test material was classified according to the sceme displayed in Table 2 below.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of reaction
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of reaction
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of reaction
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of reaction
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of reaction
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of reaction
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No adverse dermal reactions were noted during the study.
Interpretation of results:
GHS criteria not met
Conclusions:
The test material produced a primary irritation index of 0.0 and was classified as a non-irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test material was classified as non-irritant to rabbit skin according to EEC labelling regulations.
Executive summary:

A study was performed to assess the irritancy potential of the test material (1,4,5,6-Tetrahydro-4,6-dioxopyrimidin-2-yl)cyanamide to the skin of the New Zealand white rabbit. The method used followed that described in the OECD guideline no. 404 and Method B4 in Commission Directive 84/449/EEC. A single 4-hour, semi-occluded application of the test material to the intact skin of three rabbits produced no adverse dermal reactions. The test material produced a primary irritation index of 0.0 and was classified as a non-irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test material was also classified as non-irritant according to EEC labelling regulations.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 15 January 1992 to 19 January 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
1987
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
84/449/EEC
GLP compliance:
yes (incl. certificate)
Test material information:
Composition 1
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Description: off-white powder
- Sponsor's identification: CYDI

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Container: white plastic jar (x2)
- Data relating to the identity, purity and stability of the test material are the responsibility of the sponsor.


Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Age at study initiation: twelve to sixteen weeks old
- Weight at study initiation: 2.67 - 2.82 kg
- Housing: individual housing in suspended metal cages
- Diet (e.g. ad libitum): Spillers Rabbit Diet, Dalgety Agriculture Ltd., Almondsbury, Bristol; free access was allowed throughout the study
- Water (e.g. ad libitum): Spillers Rabbit Diet, Dalgety Agriculture Ltd., Almondsbury, Bristol; free access was allowed throughout the study
- Acclimation period: five days each animal

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-21°C
- Humidity (%): 49-56%
- Air changes (per hr): approximately 15 changes per hour
- Photoperiod (hrs dark / hrs light): continuous 12 hours light and 12 hours of darkness
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 ml of the test material, approximately 69 mg
Duration of treatment / exposure:
72h
Observation period (in vivo):
Assessment of ocular damage/irritation was made approximately 1h, 24h, 48h and 72 h following treatment.
Number of animals or in vitro replicates:
3
Details on study design:
TREATMENT WITH TEST SUBSTANCE:
A volume of 0.1 ml of the test material, which was found to weigh approximately 69 mg (as measured by gently compacting the required volume into an adapted syringe) was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second imediately after application, to prevent loss of the test material, and then released. The left eye remained untreated and was used for control purposes. Immediately after administration of the test material, an assessment of the initial pain reaction was made.
In order to minimise pain on instillation of the test material, one drop of local anaesthetic ('Ophthaine', 0.5% proxymetacaine hydrochloride, E.R. Squibb & Sons, Limited Hounslow, iliddlesex, U.K.) was instilled into both eyes of these animals 1 - 2 minutes before treatment.

TOOL USED TO ASSESS SCORE: standard ophthalmoscope

SCORING SYSTEM: Assessment of ocular damage/irritation ras made approximately 1 hour and 24, 48 and 72 hours following treatment, according to the numerical evaluation given in Table 1 (from Draize J.H. 1959, Association of Food and Drug Officials of the United States, Austin, Texas, 'The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics").

INTERPRETATION OF RESULTS:

The numerical values corresponding to each animal, tissue and observation time were recorded. The data relating to the conjunctivae were designated by the letters A (redness), B (chemosis) and C (discharge), those relating to the iris designated by the letter D and those relating to the cornea by the letters E (degree of opacity) and F (area of opacity). For each tissue the score was calculated as follows:
Score for conjuctivae = (A+B+C) x 2
Score for iris = D x 5
Score for cornea = (E x F) x 5

Using the numerical data obtained a modified version of the system described by Kay J.H. and Calandra J.C., J. Soc. Cosmet. Chem., 1962 13 281-289 was used to classify the ocular irritancy potential of the test material (Table 2).

Irritation parameter:
cornea opacity score
Basis:
animal: #1; #2; #3
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 48h
Irritation parameter:
cornea opacity score
Basis:
animal: #1; #2; #3
Time point:
other: 48h, 72h
Score:
0
Max. score:
4
Reversibility:
fully reversible within:
Irritation parameter:
iris score
Basis:
animal: #1; #2; #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
animal: #1; #3
Time point:
24 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 48h
Irritation parameter:
conjunctivae score
Basis:
animal: #1; #3
Time point:
other: 48h, 72h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 48h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
48 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal: #1; #2; #3
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 48h
Irritation parameter:
chemosis score
Basis:
animal: #1; #2; #3
Time point:
other: 48/72h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 48h
Irritant / corrosive response data:
Diffuse corneal opacity was noted in all treated eyes one and 24 hours after treatment. No other adverse corneal effects were noted.
Other effects:
Residual test material was noted around the treated eyes of all animals during the study.
Iridial inflammation was noted in all treated eyes one hour after treatment. No other adverse iridial effects were noted.
Moderate conjunctival irritation was noted in all treated eyes one hour after treatment with minimal to moderate conjunctival irritation at the 24-hour observation. Minimal conjunctival irritation was noted in one treated eye at the 48-hour observation.
All treated eyes appeared normal 72 hours after treatment.

Individual scores are provided below for eye irritation

 

Animal # 1 (female)

Animal # 2 (female) +

Animal # 3 (female) +

 

Time after treatment

1h

24h

48h

72h

1h

24h

48h

72h

1h

24h

48h

72h

 

Cornea

E = degree of opacity

1

1

0

0

1

1

0

0

1

1

0

0

 

F = area of oapacity

2

1

0

0

4

1

0

0

3

1

0

0

 

Score (ExF)x5

10

5

0

0

20

5

0

0

15

5

0

0

 

Iris

D

1

0

0

0

1

0

0

0

1

0

0

0

 

Score (Dx5)

5

0

0

0

5

0

0

0

5

0

0

0

 

Conjunctivae

A = Redness

2

1

0

0

1

2

1

0

2

1

0

0

 

B = Chemosis

2

1

0

0

1

1

0

0

2

1

0

0

 

C = Discharge

3 RE

0

0

0

2 RE

1 RE

0

0

2 RE

0 RE

0

0

 

Score (A+B+C)x2

14

4

0

0

8

8

2

0

12

4

0

0

 

Total score

29

9

0

0

33

13

2

0

32

9

0

0

 

 

RE = residual test material around treated eyes

+ = one drop of ophtaine instilled into each eye 1-2 minutes prior to dosing

Interpretation of results:
GHS criteria not met
Conclusions:
(1,4,5,6-Tetrahydro-4,6-dioxopyrimidin-2-yl)cyanamide produced a maximum group mean score of 31.3 and was classified as a MODERATE IRRITANT (CLASS 5 ON A 1 T0 8 SCALE) to the rabbit eye according to a modified Kay and Calandra classification system. The test material did not produce positive criteria in any rabbit according to the EEC labelling regulations and was classified as NON-IRRITANT to the rabbit eye. According to CLP (2017), the test item is not classified for eye corrosion/irritation.
Executive summary:

The study was performed to assess the irritancy potential of (1,4,5,6-Tetrahydro-4,6-dioxopyrimidin-2-yl)cyanamide following a single application to the rabbit eye according to OECD Guideline 405 (1987), also referenced as method B5 of Comission Directive 84/449/EEC. One hour after treatment iridial inflammation and moderate conjunctival irritation was noted in all treated eyes. Minimal to moderate conjunctival irritation at the 24-hour observation and minimal conjunctival irritation was noted in one treated eye at the 48-hour observation. All treated eyes appeared normal 72 hours after treatment. (1,4,5,6-Tetrahydro-4,6-dioxopyrimidin-2-yl)cyanamide produced a maximum group mean score of 31.3 and was classified as a MODERATE IRRITANT (CLASS 5 ON A 1 T0 8 SCALE) to the rabbit eye according to a modified Kay and Calandra classification system. The test material did not produce positive criteria in any rabbit according to the EEC labelling regulations and was classified as NON-IRRITANT to the rabbit eye. According to CLP (July 2017), the test item is not classified for eye corrosion/irritation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The test item is not classified for skin corrosion/irritation or eye damage/eye irritation according to CLP criteria.