Registration Dossier

Administrative data

Description of key information

The key study is an OECD 404, GLP study in rabbits.

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:
January 13, 1998 - March 17, 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4470 (Acute Dermal Irritation)
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Qualifier:
according to guideline
Guideline:
other: US DOT Section 173.137
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
Adult male New Zealand White rabbits were obtained from Covance Research Products, Inc., Denver, PA. Upon arrival, all animals were examined for physical abnormalities, identified by uniquely numbered ear tags, and quarantined for approximately two weeks. The animals were individually housed in stainless steel cages (46x61x37cm) suspended above absorbent-paper pan liners which were changed 3 times per week. Throughout the test period, all rabbits had free access to water (via automatic watering) purified by reverse osmosis and were fed approximately 125 g/day of PMI Certified High Fiber Rabbit Diet 5325 (Purina Mills Inc., Richmond, IN). All animal rooms were
environmentally controlled with controls set to maintain a temperature of approximately 18°C and a relative humidity range of 30-70%. The temperature and relative humidity were monitored 24 hrs a day. During the study, the average daily temperature ranged from 18 to 19° C and average daily humidity ranged from 49 to 65%. Any excursions beyond these ranges were minimal and did not affect the integrity of the study. Temperature and humidity remained in compliance with acceptable ranges defined in the "Guide for the Care and Use of Laboratory Animals" ISBN 0-309-05377-3, Revised 1996. The light cycle was automatically controlled, 12 hrs on and 12 hrs off.

One day prior to dosing, rabbits were selected from a healthy stock population. At the time they were dosed, the animals were approximately 18 to 27 weeks old and their body weights ranged from 2717 to 3295 g.
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 ml, as received
Duration of treatment / exposure:
4 hr
Observation period:
14 days
Number of animals:
6 male
Details on study design:
Approximately 24 hrs prior to the application of the test substance, the hair around the entire trunk between the flank and shoulders was shaved closely with electric clippers. The test substance, as received (0.5 ml), was applied onto a 1.0-in. square gauze-lined adhesive bandage which was applied to the shaved intact skin of six rabbits for 4 hrs. A semioccluded dressing (i.e., fabric cuff secured with adhesive tape) was used to wrap the entire trunk of each animal. The rabbits were returned to their cages for a 4 hr exposure period. An additional six rabbits were tested on two separate sites for a 1 hr (right side) and 3 minute (left side) exposure. The 1 hr site was treated in the same manner as the 4 hr. The animal remained uncuffed during the 3 minute exposure. The cuff and patch were removed after the appropriate exposure period and the application sites were wiped with paper towels saturated with tap water. The application sites were then blotted dry with paper towels.

Skin irritation was evaluated at approximately 1, 24, 48, and 72 hrs and at 7 and 14 days after patch removal. The degree of irritation was evaluated according to the criteria of Draize et al. (J. Pharmacol. Exp. Therap. 82,377-390, 1944). In addition, all other skin reactions or signs of systemic toxicity were recorded. Animals were observed daily for mortality and reaction to treatment
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
3.5
Max. score:
3.67
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
On the 4-hr site, skin effects indicative of corrosivity (i.e., concave eschar, scar formation andlor lack of hair growth) were evident on day 14.

At the 1 hr site, slight to severe erythema was observed in most rabbits beginning at 1 hr and continued through day 7. On day 14, 1 of 6 rabbits still had slight erythema. Very slight to severe edema was noted in all rabbits at 1 hr through 72 hrs. On day 7, moderate to severe edema was present in 2 rabbits and very slight edema was still evident in one rabbit on day 14.

At the 3 min. site, very slight erythema was noted at 1 and 24 hrs in a single rabbit. Erythema was no longer evident by 48 hrs. Very slight edema was observed in 3 of 6 rabbits at 1 hr only.
Other effects:
No mortality or clinical signs of systemic toxicity were observed during the study.

Table 1. 4 Hour Exposure - 24, 48, 72 hr Average Scores

Animal No.

Average Erythema Score (24, 48, 72 hr)

Average Edema Score (24, 48, 72 hr)

Comments

97-27251

4

3.67

Pocketing at 24, 48 hrs; Concave eschar at 72 hrs

97-27250

4

3.67

Pocketing at 24 hrs

97-27210

4

3.33

Pocketing at 24, 48 hrs

97-27232

4

3.33

Pocketing at 24 hrs; Concave eschar at 72 hrs

97-27240

4

3.67

Pocketing at 24 hrs

97-27257

4

3.33

Pocketing at 24 hrs; Concave eschar at 72 hrs

Table 2. 4 Hour Exposure - Mean Erythema and Edema Scores

Time After Patch Removal

1 hr

24 hrs

48 hrs

72 hrs

7 days

14 days

Mean Erythema Score

2.7

4

4

4

4

3.3

Mean Edema Score

4

4

3.5

3

2

0

Table 3. 4 Hour Exposure - Individual Animal Scores

Time After Patch Removal

1 hr

24 hrs

48 hrs

72 hrs

7 days

14 days

Erythema

97-27251

2

4

4

4 b

4 b

4 bd

97-27250

3

4

4

4

4 c

0 def

97-27210

3

4

4

4

4

4 bd

97-27232

3

4

4

4 b

4 bc

4 bdef

97-27240

3

4

4

4

4 c

4 bdef

97-27257

2

4

4

4 b

4 bc

4 bde

Edema

97-27251

4

4 a

4 a

3

0

0

97-27250

4

4 a

4

3

2

0

97-27210

4 a

4 a

3 a

3

2

0

97-27232

4 a

4 a

3

3

3

0

97-27240

4 a

4 a

4

3

3

0

97-27257

4

4 a

3

3

2

0

a. Pocketing; b. Concave eschar; c. Blanching; d. Thickened; e. Desiccation; f. No hair growth

Table 4. 1 Hour Exposure - Individual Animals Scores

Time After Patch Removal

1 hr

24 hrs

48 hrs

72 hrs

7 days

14 days

Erythema

98-27003

1

2

3

3

4 b

0 c

98-27009

0

3

3

3

3

1 cd

98-27091

2

2

3

3

2 c

0 c

98-27094

2

2

3

3

3

0 c

98-27033

1

2

2

2

0 c

0 c

98-27042

1

2

3

3

0 c

0 c

Edema

98-27003

4 a

4 a

4 a

2

0

0

98-27009

4 a

4 a

4 a

4 a

4

1

98-27091

4

3

3

2

0

0

98-27094

4 a

4 a

3

3

3

0

98-27033

2

2

1

1

0

0

98-27042

4

2

3

3

0

0

a. Pocketing edema; b. Eschar; c. Desiccation; d. Thickened

Table 5. 3 Min Exposure - Individual Animal Scores

Time After Patch Removal

1 hr

24 hrs

48 hrs

72 hrs

7 days

14 days

Erythema

98-27003

0

0

0

0

0

0

98-27009

0

0

0

0

0

0

98-27091

0

0

0

0

0

0

98-27094

0

0

0

0

0

0

98-27033

1

0

0

0

0

0

98-27042

0

1

0

0

0

0

Edema

98-27003

0

0

0

0

0

0

98-27009

1

0

0

0

0

0

98-27091

1

0

0

0

0

0

98-27094

0

0

0

0

0

0

98-27033

1

0

0

0

0

0

98-27042

0

0

0

0

0

0

Interpretation of results:
Category 1 (corrosive) based on GHS criteria
Conclusions:
OXEMA caused full thickness destruction on intact skin tissue within an observation period up to 14 days starting after an exposure time of more than 60 minutes, but not more than 4 hours.
Executive summary:

Skin irritation of OXEMA was assessed in New Zealand White rabbits. The test substance, as received (0.5 ml), was applied topically to the shaved intact skin of six male rabbits. The application sites were semioccluded for 4 hrs. After the 4-hr exposure, the application sites were wiped with paper towels saturated with tap water and blotted dry with paper towels. Skin irritation was evaluated according to Draize criteria at approximately 1, 24, 48, and 72 hrs and 7 and 14 days after patch removal.

No mortality or clinical signs of systemic toxicity were observed during the study. On the 4hr site, skin effects indicative of corrosivity (i.e., concave eschar, scar formation and/or lack of hair growth) were evident on day 14.

Since corrosive findings were evident at 4 hrs, additional rabbits were tested to determine U.S. Department of Transportation (DOT) Packing Group classification. The undiluted test substance (0.5 ml) was applied topically to the shaved intact skin of six male rabbits on two separate sites for 1 hr (left side) and 3 minutes (right side). The 1 hr application site was semi-occluded with a fabric cuff and the 3 minute site was uncuffed during the exposure period. After each exposure period, the application sites were wiped with paper towels saturated with tap water and blotted dry with paper towels. Skin irritation was evaluated according to Draize criteria at approximately 1, 24, 48, 72 hrs and at 7 and 14 days after patch removal.

At the 1 hr site, very slight to severe erythema was observed in most rabbits beginning at 1 hr and continued through day 7. On day 14, 1 of 6 rabbits still had slight erythema. Very slight to severe edema was noted in all rabbits at 1 hr through 72 hrs. On day 7, moderate to severe edema was present in 2 rabbits and very slight edema was still evident in one rabbit on day 14.

At the 3 min. site, very slight erythema was noted at 1 and 24 hrs in a single rabbit. Erythema was no longer evident by 48 hrs. Very slight edema was observed in 3 of 6 rabbits at 1 hr only.

OXEMA exposure resulted in full thickness destruction on intact skin tissue within an observation period up to 14 days starting after an exposure time of more than 60 minutes, but not more than 4 hours.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation

In a key study, male New Zealand white rabbits were exposed to 0.5 ml undiluted OXEMA to the shaved, intact skin under semi-occlusive conditions for 4 hours. Skin irritation was evaluated according to Draize criteria at 1, 24, 48, and 72 hours, and 7 and 14 days after patch removal. No mortality or clinical signs of systemic toxicity were observed during the study. Average erythema scores over 24, 48, and 72 hours were 4 for all animals, while average edema scores ranged from 3.33 to 3.67. Skin effects indicative of corrosivity (i.e., concave eschar, scar formation and/or lack of hair growth) were evident on day 14. Based on the finding of corrosivity, an additional 6 animals were similarly exposed for 1 hour (semi-occluded) and 3 minutes (unoccluded) at two separate sites. At the 1 hour site, very slight to severe erythema and edema were observed in most rabbits from 1 hour to 7 days from exposure. On day 14, 1 of 6 rabbits had slight erythema and very slight edema with evidence of desiccation and thickened skin. At the 3 minutes site, very slight erythema was observed at 1 and 24 hours in one rabbit, which resolved by 48 hours. Very slight edema was observed in 3 of 6 rabbits at 1 hour only. Based on these data, OXEMA is corrosive to the skin.

A supporting study showed well-defined to severe erythema and slight to severe edema in six rabbits at 24 and 72 hours following a 4 hour occluded exposure to 0.5 ml undiluted OXEMA. Scabs were observed in all animals at 14 days, following by slight smooth scars at 30 days.

Eye Irritation

No specific studies were avilable to assess the eye irritation potential of OXEMA. Based on the corrosive effects to the skin observed in the rabbit dermal irritation study, it is suggested that OXEMA will be corrosive to the eyes.

Justification for classification or non-classification

According to GLP criteria, OXEMA is corrosive (Category 1) to the skin. Based on the corrosive effects to the skin, it is suggested that OXEMA will be corrosive to the eyes.