Registration Dossier

Administrative data

Description of key information

1,3-Diphenylguanidine is severely irritating to the eye and non-irritating to the skin

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 Feb.15, 1988 to June 13, 1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
no guideline followed
Principles of method if other than guideline:
Three rabbits received the substance on an eye and skin. In the skin irritation test, 0.5 g of 1,3 -diphenylguanidine (Soxinol-D) was administered for 4 hours on 2 areas (scratched and intact areas) of the closed skin on the back of rabbits.
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Japan Lab Animals Co., Ltd (Osaka, Japan)
- Age at study initiation: no data
- Weight at study initiation: 2.12 to 2.67 kg
- Housing: individually in an aluminium net cage with a suspension system
- Diet (e.g. ad libitum): ca. 100g/day solid rabbit food (CR-1, CLEA Japan, Inc, Osaka, Japan)
- Water (e.g. ad libitum): freely access to purified well water filtered
- Acclimation period: 21 to 35 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24+/-3°C
- Humidity (%): 60+/-15%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
other: corn oil
Controls:
not required
Amount / concentration applied:
Patch was cut into 2,5 x 2,5 cm squares and damped with a small acount of corn oil, and then 0.5 g each of the test substance was evently dropped on the patches. The treated patches were administered to both of the scratched and intact areas and closed with a surgical tape for 4 hours.
Duration of treatment / exposure:
4 hours
Observation period:
4.5, 24, 48, 72 hours after administration
Number of animals:
3 rabbits (2 males, 1 female)
Details on study design:
TEST SITE
The furs on the back of 3 rabbits were shaved with an electric shaver at the size of 15 x 15 cm.
Two areas (one each on the both sides of the median plane) were designated for administration. One of the two areas for each animal was scratched , while the other area remained intact.
The scratches were made in a way so that only the stratum corneum was damaged and no bleeding or damage to corium was caused.

REMOVAL
After the 4 hours of administration, the patches were removed and the test substances left in the skin was wiped off with cotton containing acetone.

SCORING SYSTEM:
Skin reactions were numerically recorded followed the evaluation standards by Draize.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No skin reaction, including erythema and edema, to the test substance was observed on either of the scratched or intact areas at 4.5, 24, 48 and 72 hours after the administration.
The primary irritation index is 0.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on these results, 1,3 -diphenylguanidine was considered to be non-irritating to rabbit skin.
Executive summary:

Three rabbits received the substance on an eye and skin. In the skin irritation test, 0.5 g of 1,3 -diphenylguanidine (Soxinol-D) was administered for 4 hours on 2 areas (scratched and intact areas) of the closed skin on the back of rabbits. No skin reaction, including erythema or edema, was observed on either of the scratched or intact during the observation period (72h).

Based on these results, 1,3 -diphenylguanidine was considered to be non-irritating to rabbit skin.

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 Fab.15, 1988 to June 13,1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test substance was administered to 6 rabbits. Three rabbits received the substance on an eye and skin. The other 3 rabbits received the substance on an eye and their eyes were washed after the administration.
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Japan Lab Animals Co., Ltd (Osaka, Japan)
- Age at study initiation: no data
- Weight at study initiation: 2.12 to 2.67 kg
- Housing: individually in an aluminium net cage with a suspension system
- Diet (e.g. ad libitum): ca. 100g/day solid rabbit food (CR-1, CLEA Japan, Inc, Osaka, Japan)
- Water (e.g. ad libitum): freely access to purified well water filtered
- Acclimation period: 21 to 35 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24+/-3°C
- Humidity (%): 60+/-15%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 g of the test substance on the conjunctival sac of the one side of lower eyelid.
The eyelids were held for 1 second after the administration to prevent the substance to overflow from the eye.
Duration of treatment / exposure:
For the "unwashed group" (2 males, 1 female), the eyes with administration were not washed and the other eyes were treated as control.
The "washed group" (1 male, 2 females) was separately treated with the same administration but the eyewash with 300 ml of slightly warm water for 1 minute 30 seconds after administration.
Observation period (in vivo):
Observations was conduted at 1, 24, 48, 72 hours after the administration for the washed group, and 96h, 1, 2, 3, 4, 5, 6 weeks for the unwashed group.
Number of animals or in vitro replicates:
"unwashed group" (2 males, 1 female),
"washed group" (1 male, 2 females)
Details on study design:
Local reactions were numerically recorded following the evaluation standards by Draize.
Irritation parameter:
cornea opacity score
Remarks:
(severity)
Basis:
mean
Remarks:
3 rabbits "unwashed"
Time point:
other: mean 24-48-72 hours
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 6 weeks
Remarks on result:
other: Individual scores : 2 - 2 - 2
Irritation parameter:
cornea opacity score
Remarks:
(area)
Basis:
mean
Remarks:
3 rabbits "unwashed"
Time point:
other: mean 24-48-72 hours
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 6 weeks
Remarks on result:
other: Individual scores : 4 - 4 - 4
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 rabbits "unwashed"
Time point:
other: mean 24-48-72 hours
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 4 weeks
Remarks on result:
other: Individual scores : 1 - 1 - 1
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
3 rabbits "unwashed"
Time point:
other: mean 24-48-72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 3 weeks
Remarks on result:
other: Individual scores : 2 - 2 - 2
Irritation parameter:
conjunctivae score
Remarks:
(chemosis)
Basis:
mean
Remarks:
3 rabbits "unwashed"
Time point:
other: mean 24-48-72 hours
Score:
1.89
Max. score:
4
Reversibility:
fully reversible within: 3 weeks
Remarks on result:
other: Individual scores between 1 and 3
Irritation parameter:
conjunctivae score
Remarks:
(discharge)
Basis:
mean
Remarks:
3 rabbits "unwashed"
Time point:
other: mean 24-48-72 hours
Score:
1.67
Max. score:
3
Reversibility:
fully reversible within: 3 weeks
Remarks on result:
other: Individual scores between 1 and 2
Irritant / corrosive response data:
At 1 hour after the administration of the test substance, all 3 animals in unwashed group showed iris congestion (grade 1), conjunctival redness (grade 2), and conjunctival chemosis (grade 3), and 2 animals in the same group showed cornea opacity (severity: grade 1; area : grade 3 or 4).
At 24 hours after the administration, the conjunctival chemosis was wakened to grade 2 and 3, but the iris congestion and conjunctival redness remained at the same grade. At this point, all 3 animals showed cornea opacity (severity grade 2, area grade 4), and all 3 animals showed new occurrence of discharge at grade 1 or 2. These local reactions were still observed at 96 hour at the similar grades.
Cornea opacity at the grade 3 was observed 2 weeks after the administration. The local reactions at the conjunctivae and iris congestion disappeared by 3 and 4 weeks, respectively, after the administration, but cornea opacity remained aven 6 weeks after the administration. Starting at 1 week after the administration, neavascular in cornea were observed.

In the washed group, at 1 hour after the administration of the test substance, all 3 animals showed iris congestion (grade 1) and conjunctival redness (grade 1), and conjunctival chemosis (grade 1 or 2). At 24 hours after the administration, the only reactions such as conjunctival redness (grade 1) and conjunctival chemosis (grade 1) were shown in 2 animals. At 72 hours, no local reaction was observed in any rabbit.
Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
1,3-diphenylguanidine was considered to be extremely irritating to the eyes in rabbits.
Executive summary:

The test substance was administered to 6 rabbits. Three rabbits received the substance on an eye and skin. The other 3 rabbits received the substance on an eye and their eyes were washed after the administration.

In the eye irritation test, a dose of 0.1g of 1,3-diphenylguanidine (Soxinol-D) was administered to one eye of each rabbit. After the administration, strong cornea opacity, conjunctival chemosis, obvious iris congestion, conjunctival redness, a low level of eye discharge and neovascular in cornea were observed. The local reaction on the conjunctivae and the iris congestion disappeared in 3 weeks and 4 weeks, respectively, but local reactions in cornea were still recognized 6 weeks after the administration.

Based on these results, 1,3-diphenylguanidine was considered to be extremely irritating to the eyes in rabbits.

When the test was repeated with a group of 3 rabbits and eyes were washed 30 seconds after administration, obvious iris congestion, conjunctival chemosis, and a low level of conjunctival redness were observed after the administration. All of these local reactions disappeared within 72 hours after the administration, and therefore, there was a washing effect.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

In the key skin irritation study (Takatsuka 1988), 0.5 g of 1,3 -diphenylguanidine was administered for 4 hours on 2 areas (scratched and intact areas) of the closed skin on the back of 3 rabbits. No skin reaction, including erythema or edema, was observed on either of the scratched or intact during the observation period (72h). Based on these results, 1,3 -diphenylguanidine was considered to be non-irritating to rabbit skin.

These results were confirmed in the supporting study (Birch 1977) : The acute dermal irritation of DPG (1,3 -diphenylguanidine) was evaluated in rabbits according to the Draize test. 0.5g of DPG was applied undiluted to the intact and abraded skin of 6 New-Zealand White albino rabbits and held in contact for 24 hours by means of an occlusive dressing. Mean scores over 24, 48 and 72 hours for the 6 animal were 0 for erythema and 0 for oedema for both the intact and abraded skin. DPG is considered as non-irritant when applied topically to rabbits.

Eye irritation

In the key eye irritation study (Takatsuka 1988), the test substance was administered to 6 rabbits. Three rabbits received the substance on an eye and skin. The other 3 rabbits received the substance on an eye and their eyes were washed after the administration.

In the eye irritation test, a dose of 0.1g of 1,3-diphenylguanidine (Soxinol-D) was administered to one eye of each rabbit. After the administration, strong cornea opacity, conjunctival chemosis, obvious iris congestion, conjunctival redness, a low level of eye discharge and neovascular in cornea were observed. The local reaction on the conjunctivae and the iris congestion disappeared in 3 weeks and 4 weeks, respectively, but local reactions in cornea were still recognized 6 weeks after the administration.

Based on these results, 1,3-diphenylguanidine was considered to be severely irritating to the eyes in rabbits.

When the test was repeated with a group of 3 rabbits and eyes were washed 30 seconds after administration, obvious iris congestion, conjunctival chemosis, and a low level of conjunctival redness were observed after the administration. All of these local reactions disappeared within 72 hours after the administration, and therefore, there was a washing effect.

In the supporting study (Birch 1977 (1)), a draize test was made on rabbit to study the irritant power of 1,3 -diphenylguanidine (DPG). New Zealand White rabbit were exposed to 100 mg DPG, and were observed 1, 24, 48, 72, 120 and 168 hr after exposition. Maximal Irritation score was 56.6 at 24 hours (over 110). The irritation was not fully reversible after 7 days.


Justification for classification or non-classification

Mandatory classification :

- Regulation (EC) No 1272/2008 Annex VI Table 3.1

Skin irrit. 2, H315 (Causes skin irritation)

Eye irrit. 2, H319 (Causes serious eye irritation)

STOT SE 3, H335(May cause respiratory irritation)

 

Proposed self-classification

- Regulation (EC) No 1272/2008 : Eye Dam. 1, H318 (Causes serious eye damage)