Registration Dossier

Administrative data

Description of key information

Two in vivo studies are available to evaluate the irritant potential of DPTU.
DPTU is slightly irritant to the skin (OECD 404, 2012) and not irritating to the eyes (OECD 405, 2012).

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:
30 December 2011 - 20 January 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder: Charles River Laboratories France, l’Arbresle, France
- Age at study initiation: 5 months old on the day of treatment
- Mean body weight at study initiation: a mean body weight of 3850 g (3740 g to 3984 g)
- Fasting period before study: no
- Housing: noryl cages
- Diet: 110 pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h (7:00 - 19:00)

IN-LIFE DATES: 10 January 2012 to 20 January 2012.
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: A dosage-volume of 500 mg/flank was used.
Duration of treatment / exposure:
3 minutes, 1 hour, 4 hours.
Observation period:
1, 24, 48 and 72 h after removal of the dressing; if relevant, daily until reversibility of reactions
Number of animals:
3 females.
Details on study design:
TEST SITE
- Area of exposure: During each exposure time, a dry gauze pad was applied to the opposite flank, in order to check that no alteration of the skin is induced by the semi-occlusive dressing and restraining bandage.
The untreated flank acted as control.
- Coverage: 6 cm2
- Type of wrap if used: gauze pad held in place by a non-irritation semi-occlusive dressing and a restraining bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: using a dry cotton pad
- Time after start of exposure: at removal of each dressing (see Duration of exposure)

SCORING SYSTEM:

- Erythema and eschar formation:
0 no erythema
1 very slight erythema (barely perceptible)
2 well-defined erythema
3 moderate to severe erythema
4 severe erythema (beet redness) to slight eschar formation (injuries in depth)

- Edema formation:
0 no edema
1 very slight edema (barely perceptible)
2 slight edema (edges of area well-defined by definite raising)
3 moderate edema (raised approximately 1 millimeter)
4 severe edema (raised more than 1 millimeter and extending beyond area of exposure)

- Any other lesions were noted
Irritation parameter:
erythema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24, 48, 72 h (mean)
Score:
0.7
Max. score:
4
Remarks on result:
other: Individual scores = 0.7 - 0.3 - 0.3
Irritation parameter:
edema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24, 48, 72 h (mean)
Score:
0
Max. score:
4
Remarks on result:
other: All individual scores = 0
Irritant / corrosive response data:
After 3-minute and 1-hour exposures (animal 101), a very slight erythema (grade 1) was noted from day 1 up to day 3.
After a 4-hour exposure (three animals), a very slight erythema (grade 1) was noted in all animals from day 1 up to day 2 (animals 102 and 103) or 3 (animal 101).
Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:
. erythema: 0.7, 0.3, 0.3; showing no significant inflammation,
. edema: 0.0, 0.0, 0.0; showing no significant inflammation.
Other effects:
No unscheduled deaths occurred during the study. No clinical signs were noted in any animals.
The body weight of the animals was unaffected by the test item treatment.
Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: Regulation EC 1272/2008
Conclusions:
The test item was slightly irritant when applied topically to rabbits.
However, the test item is not classified as irritating to skin according to the criteria of CLP Regulation.
Executive summary:

The objective of this study was to evaluate the potential corrosive and irritant properties of the test item following dermal application on rabbits.

 

Methods

The test item was first applied for periods of 3 minutes, 1 hour and 4 hours to a single female New Zealand White rabbit.

After the 4-hour application, since the mean value from grading at 24, 48 and 72 hours after patch removal is < 2.3 for erythema and for edema, the test item was applied on the skin of two other animals for 4 hours.

A dosage-volume of 500 mg/flank was used.

The test item was placed on a gauze pad, moistened with drinking water treated by reverses osmosis, which was then applied to a skin area of approximately 6 cm2. The gauze pad was held in place by a non‑irritation semi-occlusive dressing and a restraining bandage. After required period of contact with the skin, the dressing was removed.

Each animal was observed once a day for mortality and clinical signs. For each exposure period, cutaneous reactions were evaluated approximately 1 hour, 24, 48 and 72 hours after removal of the dressing and then daily until the end of the observation period. The mean values of the scores for erythema and edema were calculated for each animal. Body weight was recorded at the beginning and the end of the observation period.

On completion of the observation period, the animals were used subsequently for the evaluation of the ocular irritation potential of the same test item.

 

Results

No unscheduled deaths occurred and no clinical signs were noted during the study.The body weight of the animals was unaffected.

 

After 3-minute and 1-hour exposures (one animal), a very slight erythema was noted from day 1 to day 3.

 

After a 4-hour exposure (three animals), a very slight erythema was noted from day 1 to day 2 (2/3 animals) or 3 (1/3 animals).

 

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

.            erythema: 0.7, 0.3, 0.3; showing no significant inflammation,

.            edema: 0.0, 0.0; 0.0; showing no significant inflammation.

 

Conclusion

The test item was slightly irritant when applied topically to rabbits.

However, the test item is not classified as irritating to skin according to the criteria of CLP Regulation.

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:
24 January 2012 - 04 February 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: breeder: Charles River Laboratories France, l’Arbresle
- Age at study initiation: 6 months old on the day of treatment
- Mean body weight at study initiation: 3975 g (range: 3827 g to 4120 g)
- Fasting period before study: no
- Housing: noryl cages
- Diet: 110 pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 11 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h (7:00 - 19:00)

IN-LIFE DATES: 25 January 2012 to 04 February 2012.
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated right eye served as a control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 g/animal.
Duration of treatment / exposure:
single application not followed by rinsing.
Observation period (in vivo):
1, 24, 48 and 72 h; if relevant, daily until reversibility of reactions
Number of animals or in vitro replicates:
Three females.
Details on study design:
REMOVAL OF TEST SUBSTANCE: No

SCORING SYSTEM: Draize scale.

- Conjunctival chemosis (lids and/or nictitating membranes):
0 no swelling
1 any swelling above normal (includes nictitating membranes)
2 obvious swelling with partial eversion of lids
3 swelling with lids about half-closed
4 swelling with lids more than half-closed

- Conjunctival redness (palpebral and bulbar conjunctivae, cornea and iris):
0 blood vessels normal
1 a number of blood vessels definitely hyperemic (injected)
2 diffuse, crimson colour, individual vessels not easily discernible
3 diffuse, beefy red

- Discharge:
0 absence of discharge
1 slight discharge (does not include small amounts normally found in inner canthus)
2 discharge with moistening of lids and hairs adjacent to lids
3 discharge with moistening of lids and hairs on wide area around the eye

- Iris lesions
0 normal
1 markedly deepened rugae, congestion, swelling, moderate circum-corneal hyperemia,or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive)
2 no reaction to light, haemorrhage, gross destruction (any or all of these)

- Cornea intensity of opacity (direct examination and, if necessary, with an UV lamp)
0 no ulceration or opacity
1 scattered or diffuse areas of opacity (other than slight dulling or normal lustre), details of iris clearly visible
2 easily discernible translucent area, details of iris slightly obscured
3 nacreous areas, no details of iris visible, size of pupil barely discernible
4 opaque cornea, iris not discernible through the opacity

- Cornea area of opacity (direct examination and, if necessary, with an UV lamp)
1 one quarter (or less) but not zero
2 greater than one quarter but less than a half
3 greater than one half but less than three quarters
4 greater than three quarters up to whole area

- Any other lesions observed were noted

TOOL USED TO ASSESS SCORE: UV lamp after instillation of 0.5% sodium fluorescein solution
Irritation parameter:
conjunctivae score
Remarks:
(chemosis)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24, 48 and 72 h (mean)
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: Individual scores = 1 - 0 - 0
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24, 48 and 72 h (mean)
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 5 days
Remarks on result:
other: Individual scores = 1.33 - 0.3 - 0
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24, 48 and 72 h (mean)
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Remarks:
(intensity)
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24, 48 and 72 h (mean)
Score:
0
Max. score:
4
Irritant / corrosive response data:
No ocular reactions were observed in the right untreated control eye.
In the left treated eye, a slight or moderate chemosis of the conjunctiva (grade 1 or 2) was observed in all animals on day 1, then a slight chemosis (grade 1) persisted until day 5 in animal 101.
A slight or moderate redness of the conjunctiva (grade 1 or 2) was noted in all animals on day 1, and it persisted on day 2 in animal 102 and until day 4 in animal 101.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:
. chemosis : 1.0, 0.0 and 0.0; showing no significant eye irritation,
. redness of the conjunctiva: 1.3, 0.3 and 0.0; showing no significant eye irritation,
. iris lesions: 0.0, 0.0 and 0.0; showing no significant eye irritation,
. corneal opacity: 0.0, 0.0 and 0.0; showing no significant eye irritation
Other effects:
No unscheduled deaths occurred during the study. No clinical signs were noted in any animals.
The body weight of the animals was unaffected by the test item treatment.
Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: Regulation EC 1272/2008
Conclusions:
The test item, 1,3 Diphenyl-2-thiourea, was slightly irritant when administered by ocular route to rabbits.
However, the test item is not classified as irritating to the eyes according to the criteria of CLP Regulation.
Executive summary:

The objective of this study was to evaluate the potential irritant properties of the test item for the eye, 1,3‑Diphenyl-2 -thiourea, following a single administration to rabbits.

The study was performed according to the international guidelines (OECD guideline No. 405, 24th April 2002, and Commission Regulation (EC) No. 440/2008, B.5, 30 May 2008) and in compliance with the principles of Good Laboratory Practice.

 

Methods

 

The test item, 1,3‑Diphenyl-2-thiourea, was first administered to a single female New Zealand White rabbit.

As mean value from grading at 24, 48 and 72 hours after instillation was < 2 for conjunctival edema (chemosis) and for conjunctival redness, < 1 for iris lesion and for corneal opacity, the test item was administered in the left eye of two other animals.

 

The test item was administered inthe conjunctival sac of the left eye. The right eye remained untreated and served as control.

A quantity of 0.1 g/animal was used.

The eyes of the first animal were not rinsedjust after the 1-hour scoring, whereas, both eyes of two other animals were rinsed with a sterile isotonic saline solution (0.9% NaCl).

Each animal was observed once a day for mortality and clinical signs.Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration and then daily until the reversibility of the ocular reactions. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal. Body weight was recorded on the day of treatment and the end of the observation period.

On completion of the observation period, the animals were sacrificed then discarded without macroscopic post‑mortem examination.

 

Results

A slight or moderate chemosis of the conjunctiva was observed in all animals on day 1, then a slight chemosis persisted until day 5 in 1/3 animals.

A slight or moderate redness of the conjunctiva was noted in all animals on day 1, and it persisted on day 2 in 1/3 animals and until day 4 in another animal.

 

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

.          chemosis: 1.0, 0.0 and 0.0; showing no significant eye irritation,

.          redness of the conjunctiva: 1.3, 0.3 and 0.0; showing no significant eye irritation,

.          iris lesions: 0.0, 0.0 and 0.0; showing no significant eye irritation,

.          corneal opacity: 0.0, 0.0 and 0.0; showing no significant eye irritation.

 

Conclusion

The test item, 1,3‑Diphenyl-2-thiourea, was slightly irritant when administered by ocular route to rabbits.

However, the test item is not classified as irritating to the eyes according to the criteria of CLP Regulation.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In vivo skin irritation study (OECD 404, Queudot 2012):

The objective of this study was to evaluate the potential corrosive and irritant properties of the test item following dermal application on rabbits.

 The test item was first applied for periods of 3 minutes, 1 hour and 4 hours to a single female New Zealand White rabbit. A dosage-volume of 500 mg/flank was used. The test item was placed on a gauze pad, moistened with drinking water treated by reverses osmosis, which was then applied to a skin area of approximately 6 cm2. The gauze pad was held in place by a non‑irritation semi-occlusive dressing and a restraining bandage. After required period of contact with the skin, the dressing was removed.

Each animal was observed once a day for mortality and clinical signs. For each exposure period, cutaneous reactions were evaluated approximately 1 hour, 24, 48 and 72 hours after removal of the dressing and then daily until the end of the observation period. The mean values of the scores for erythema and edema were calculated for each animal. Body weight was recorded at the beginning and the end of the observation period.

On completion of the observation period, the animals were used subsequently for the evaluation of the ocular irritation potential of the same test item.

No unscheduled deaths occurred and no clinical signs were noted during the study.The body weight of the animals was unaffected. After 3-minute and 1-hour exposures (one animal), a very slight erythema was noted from day 1 to day 3. After a 4-hour exposure (three animals), a very slight erythema was noted from day 1 to day 2 (2/3 animals) or 3 (1/3 animals).

The test item was slightly irritant when applied topically to rabbits. However, the test item is not classified as irritating to skin according to the criteria of CLP Regulation.

In vivo eye irritation study (OECD 405, Queudot 2012):

The objective of this study was to evaluate the potential irritant properties of the test item for the eye, 1,3-Diphenyl-2 -thiourea, following a single administration to rabbits.

The test item, 1,3‑Diphenyl-2-thiourea, was first administered to a single female New Zealand White rabbit.

The test item was administered inthe conjunctival sac of the left eye. The right eye remained untreated and served as control. A quantity of 0.1 g/animal was used. The eyes of the first animal were not rinsed just after the 1-hour scoring, whereas, both eyes of two other animals were rinsed with a sterile isotonic saline solution (0.9% NaCl).

Each animal was observed once a day for mortality and clinical signs.Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration and then daily until the reversibility of the ocular reactions. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal. Body weight was recorded on the day of treatment and the end of the observation period. On completion of the observation period, the animals were sacrificed then discarded without macroscopic post‑mortem examination.

A slight or moderate chemosis of the conjunctiva was observed in all animals on day 1, then a slight chemosis persisted until day 5 in 1/3 animals. A slight or moderate redness of the conjunctiva was noted in all animals on day 1, and it persisted on day 2 in 1/3 animals and until day 4 in another animal.

The test item, 1,3‑Diphenyl-2-thiourea, was slightly irritant when administered by ocular route to rabbits. However, the test item is not classified as irritating to the eyes according to the criteria of CLP Regulation.


Justification for selection of skin irritation / corrosion endpoint:
Only one reliable study (klimisch score = 1) is available to evaluate the skin irritant potential.

Justification for selection of eye irritation endpoint:
Only one reliable study (klimisch score = 1) is available to evaluate the eye irritant potential.

Justification for classification or non-classification

No classification is required for the irritation of DPTU according to the Regulation EC 1272/2008 or the Directive 67/548/EEC.

DPTU is slightly irritating for skin and eyes, the scores of irritation are very smaller than the threshold for classification.