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Endpoint summary

Description of key information

In order to evaluate the skin irritating property of Dodicor V 5654 an in vivo OECD TG 404 GLP conform study is provided.

In order to evaluate the eye irritating property of Dodicor V 5654 an in vivo OECD TG 405 GLP conform study is provided.

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:

2007-05-16 to 2007-06-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

adopted April 24, 2002

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Version / remarks:

April 29, 2004

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 07SK021
- Description: Liquid, dark brownish
- Expiration date of the lot/batch: n.a.
- Purity test date: 94%
- Expiry date: March 2009

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature (range of 20 ± 5° C), light protected

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Netherlands BV, Kreuzelweg 53, NL-5961 NM Horst / The Netherlands
Postbus 6174, NL-5960 AD Horst / The Netherlands

- Age at study initiation: one male12 weeks; two females 13 weeks
- Weight at Day1 of treatment: females 2044 g and 2500 g, male 2373 g
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks and haysticks were provided for gnawing.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15
- Photoperiod: 12 hrs dark / 12 hrs light

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.5 mL

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- Type of wrap if used: The patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes with lukewarm tap water
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
The skin reaction was assessed at approximately 1, 24, 48 and 72 hours, as well as 7, 10 and 14 days after exposure (removal of the dressing, gauze patch and test item).

SCORING SYSTEM:
The skin reaction was assessed according to the numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 10 days after treatment

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 7 days

Irritation parameter:

other: scaling

Basis:

mean

Time point:

other: 72 hour reading up to 10 day reading

Score:

0

Max. score:

0

Reversibility:

fully reversible within: 14 days

Irritant / corrosive response data:

Well-defined erythema was noted at the application site of all animals between 1 hour and 72 hours after treatment. The severity of the erythema decreased to very slight at the 7-day observation and was no longer evident 10 days after treatment. Very slight oedema was recorded in all animals between 1 hour and 72 hours after treatment. All animals showed scaling from 72 hours up to 10 days after treatment and inelastic and dry skin from 72 hours up to 7 days after treatment. All these skin reactions were reversible and no longer evident 14 days after treatment, the end of the observation period for all animals.

Interpretation of results:

other: Not skin irritant according to Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 Dec. 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC

Conclusions:

not skin irritant

Executive summary:

In order to evaluate the skin irritating property of Dodicor V 5654, an OECD TG 404 GLP conform study in rabits is provided.

Four days before treatment, the left flank was clipped with an electric clipper, exposing an area of approximately 100 cm2 (10 cm x 10 cm). The skin of the animals was examined one day before treatment, and regrown fur of all animals was clipped again. Animals with overt signs of skin injury or marked irritation which may have interfered with the interpretation of the results were not used in the test. On the day of treatment, 0.5 mL of Dodicor V 5654 was placed on a surgical gauze patch (ca. 2.5 cm x 2.5 cm). This gauze patch was applied to the intact skin of the clipped area. The patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape. The duration of treatment was 4 hours. Then the dressing was removed and the skin was flushed with lukewarm tap water to clean the application site so that any reactions (erythema) were clearly visible at that time. No staining produced by the test item of the treated skin was observed. The body weights of all rabbits were considered to be within the normal range of variability.

The mean score was calculated across 3 scoring times (24, 48 and 72 hours after patch removal) for each animal for erythema/eschar grades and for oedema grades, separately. For each of the three animals the mean erythema/eschar score was 2.00 and the mean oedema score was 1.00. Well-defined erythema was noted at the application site of all animals between 1 hour and 72 hours after treatment. The severity of the erythema decreased to very slight at the 7-day observation and was no longer evident 10 days after treatment. Very slight oedema was recorded in all animals between 1 hour and 72 hours after treatment. All animals showed scaling from 72 hours up to 10 days after treatment and inelastic and dry skin from 72 hours up to 7 days after treatment. All these skin reactions were reversible and no longer evident 14 days after treatment, the end of the observation period for all animals.

Based on the results of this study, Dodicor V 5654 is not a skin irritant.

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:

2007-05-30 to 2007-06-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

adopted April 24, 2002

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Version / remarks:

April 29, 2004

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 07SK021
- Description: Liquid, dark brownish
- Expiration date of the lot/batch: n.a.
- Purity test date: 94%
- Expiry date: March 2009

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature (range of 20 ± 5° C), light protected

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan Netherlands BV, Kreuzelweg 53, NL-5961 NM Horst / The Netherlands
Postbus 6174, NL-5960 AD Horst / The Netherlands

- Age at study initiation: one male12 weeks; two females 13 weeks
- Weight at Day1 of treatment: females 2044 g and 2500 g, male 2373 g
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks and haysticks were provided for gnawing.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15
- Photoperiod: 12 hrs dark / 12 hrs light

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.1 mL

Observation period (in vivo):

The eyes of each animal were examined approximately 1, 24, 48, 72 hours, as well as 7, 10, 14 and 21 days after administration.

Number of animals or in vitro replicates:

3 (one male two females)

Details on study design:

On the day of treatment, 0.1 mL of DODICOR V 5654 was placed in the conjunctival sac of the left eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of test item. The right eye remained untreated and served as the reference control.

REMOVAL OF TEST SUBSTANCE

- Washing (if done): no

SCORING SYSTEM: The eye reactions were assessed according to the numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004

TOOL USED TO ASSESS SCORE: hand-slit lamp (Cliptrix diagnostic-lamp)

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0.67

Max. score:

1

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 21 days

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

not fully reversible within: 21 day

Remarks on result:

probability of moderate irritation

Remarks:

At day 21 reading the score was still 1.

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1.67

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.33

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1.33

Max. score:

2

Reversibility:

fully reversible within: 14 days

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0.67

Max. score:

1

Reversibility:

fully reversible

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48/72 h

Score:

1.19

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Remarks:

At 21 day reading in one animal conjunctiva reddining was still present.

Remarks on result:

probability of moderate irritation

Remarks:

The test item did not induce significant or irreversible damage to the rabbit eye.

TABLE 1:       EYE IRRITATION SCORES - MEAN VALUES AFTER 24, 48 AND 72 HOURS

 

Animal Number	Sex	Corneal Opacity	N	Iris	N	Conjunctivae
						Redness	N	Chemosis	N
4	M	0.00	3	0.00	3	2.00		1.33	3
5	F	1.00	3	0.00	3	2.00		1.33	3
6	F	0.67	3	0.00	3	1.67		0.67	3

N = number of available data points

Interpretation of results:

other: Cat 2 (irritating to eyes) based on CLP criteria

Conclusions:

Based on the results of a.m. study, Dodicor V 5654 is irritating to the eye.

Executive summary:

The primary eye irritation potential of DODICOR V 5654 was investigated according toOECD test guideline no. 405. The test item was applied by instillation of 0.1 mL into the lefteye of each of three young adult New Zealand White rabbits. Scoring of irritation effects wasperformed approximately 1, 24, 48 and 72 hours, as well as 7, 10, 14 and 21 days after testitem instillation.The mean score was calculated across 3 scoring times (24, 48 and 72 hours afterinstillation) for each animal for corneal opacity, iris, redness and chemosis of theconjunctivae, separately. The individual mean scores for corneal opacity were 0.00, 1.00 and0.67, respectively and for iris 0.00 for each of all three animals. The individual mean scores for the conjunctivae were 2.00, 2.00 and 1.67 for reddening and 1.33, 1.33 and 0.67 forchemosis, respectively.

The instillation of DODICOR V 5654 into the eye resulted in mild to moderate, early-onsetocular changes, such as corneal opacity, reddening of the conjunctivae and sclerae,conjunctival swelling and discharge. The severity of the local reactions decreased throughthe 22 days of observation and the study was closed with a slight conjunctival redness in oneanimal.No abnormal findings were observed in the iris of any animal at any of the examinations. No corrosion was observed at any of the measuring intervals. No staining of the treated eyes by the test item was observed and no clinical signs were observed.

Thus, the test item did not induce significant or irreversible damage to the rabbit eye.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006,the test substance Dodicor V 5654 has not to be classified for skin irritation.

According to Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006, the test substance Dodicor V 5654 has to be classified as irritant to the eyes, Cat 2.