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Description of key information

Skin irritation in vivo

This substance is not a skin irritant.

 

Eye irritation in vivo

The substance is an eye irritant at 100%, but not an eye irritant at a 50% concentration.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 March 1990 - 20 April 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study protocol was not in accordance with modern guidelines, which for example would have required fewer animals, but the scientific basis of the method followed is nevertheless robust.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Denver, PA.
- Age at study initiation: Approximately 11 weeks.
- Weight at study initiation: Approximately 2-3 kg.
- Housing: Individually housed in suspended steel cages.
- Diet (e.g. ad libitum): Restricted feeding regimen.
- Water (e.g. ad libitum): Ad libitum.
- Acclimation period: 15 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65-70ºF (18.3-21.1ºC).
- Humidity (%): Target himudity range was 40-60%. Measured humidity exceeded 60% once during the acclimation period and twice during the study; however, the study authors concluded that these deviations did not adversely affect the study results.
- Air changes (per hr): NDA.
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark.


IN-LIFE DATES: From: 20 March 1990 To: 27 March 1990
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
7 days
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: Not stated.
- % coverage: Not stated.
- Type of wrap if used: The test material was introduced under a gauze patch which was secured with tape. The patch was loosely held in contact with the skin by means of a semi-occlusive dressing.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test material was removed, where possible, using reverse osmosis water and paper towels.
- Time after start of exposure: Four hours.


SCORING SYSTEM: Dermal responses were scored according to the Draize method (see below).
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.89
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Other effects:
There were no supplemental dermal observations noted during the study.

Mean erythema and oedema scores at each time interval

35 min

24 hour

48 hour

72 hour

7 day

Erythema

1.00

0.83

0.83

1.00

0.00

Oedema

0.00

0.00

0.00

0.00

0.00

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the findings and the primary irritation index of 0.92, the test material may be considered a mild irritant to rabbit skin.
Executive summary:

The dermal irritancy potential of the test material was tested in a GLP study in rabbits. 0.5 mL of neat liquid test material was applied under a gauze patch to the shaved dorsal skin of six male New Zealand White rabbits and held in place using a semi-occlusive dressing. After approximately four hours of exposure, the dressing and gauze patch were removed, residual test material washed away using water and paper towels, and the dermal responses scored periodically over the next seven days according to the Draize method.

Erythema responses of 0 (no erythema), 1 (very slight erythema - barely perceptible), or 2 (well-defined erythema) was seen in all animals during the initial 72 hours post-administration. The mean erythema score for the 24 -, 48- and 72 -hour observations was 0.89. By Day 7, there was no erythema in any animal. No oedema was observed at any time and no supplemental dermal observations were noted. A primary dermal irritation index (PII) of 0.92 was calculated. Based on the findings and the PII, the test material may be considered a mild irritant to rabbit skin.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Between March 9th, 1997 and March 30th, 1977
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study; well-documented study report.
Qualifier:
according to guideline
Guideline:
other: FHSA 16 CFR 1500.41
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or test system and environmental conditions:
Albino rabbits were used in the test.
Type of coverage:
occlusive
Preparation of test site:
other: abraded and intact
Vehicle:
unchanged (no vehicle)
Controls:
other: Intact skin site was used as a control
Amount / concentration applied:
0.5 ml unchanged test substance
Duration of treatment / exposure:
Wrappings were removed at the end of 24 hours.
Observation period:
Wrappings were removed at the end of 24 hours.
Number of animals:
6
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 72 h
Score:
1.75
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 72 h
Score:
0.5
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: intact skin
Other effects:
No data.

The mean score for the test substance is shown in the following table:

                              Mean Scores

Intact Skin

Abraded Skin

Mean Erythema Score (24, 72 hrs)

1.75

1.75

Mean Edema Score (24, 72 hrs)

0.5

0.5

Based on these scores, the primary irritation score was calculated to be 2.25.

Interpretation of results:
Category 3 (mild irritant) based on GHS criteria
Remarks:
Migrated information
Conclusions:
The test substance is not a skin irritant.
Executive summary:

A skin irritation study was performed using male albino rabbits according to the definition of the FHSA 16 CFR 1500.41. Groups of 6 male rabbits were administered single doses of 0.5 ml test material to abraded or intact skin, and observed post-dose for 72 h. Mortality was not observed, scores for erythema and eschar formation, and edema formation were recorded using the Draize method of scoring. Based on these results the test article would not be classified as a primary irritant to albino rabbits within the definition of the Act-Reference: Section 15000. 3. (c) (4) and required no cautionary labeling with respect to that section.

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

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Between June 1st, 1992 and June 18th, 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A dose response was examined, well documented study. Restrictions due to it was not a GLP study, and there was no observations beyond 72 hours to assess reversibility.
Qualifier:
according to guideline
Guideline:
other: FHSA 16CFR1500
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Vehicle:
other: Mineral oil
Controls:
yes, concurrent no treatment
Duration of treatment / exposure:
24 h
Observation period (in vivo):
24, 48 and 72 hours following treatment
Number of animals or in vitro replicates:
3 male and 3 female/group (2 groups)
Irritation parameter:
cornea opacity score
Remarks:
undiluted test substance
Basis:
mean
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
not specified
Irritation parameter:
iris score
Remarks:
undiluted test substance
Basis:
mean
Time point:
24/48/72 h
Score:
0.8
Max. score:
2
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Remarks:
undiluted test substance
Basis:
mean
Time point:
24/48/72 h
Score:
1.5
Max. score:
3
Reversibility:
not specified
Irritation parameter:
chemosis score
Remarks:
undiluted test substance
Basis:
mean
Time point:
24/48/72 h
Score:
2.1
Max. score:
4
Reversibility:
not specified
Other effects:
In groups treated with undiluted test substance:
Blistered appearance to the conjunctiva were observed in 6/6, 4/6, and 1/6 animals at 24, 48 and 72 h, respectively;
Blistered appearance to the nictitating membrane were observed in 2/6, 0/6, and 0/6 animals at 24, 48 and 72 h, respectively;

6/6 animals treated showed evidence of positive corneal, iritic, or conjunctival changes in response to undiluted (100%) test substance.                   

      Table 1: Mean Scores (24,48 and 72 hours) for 100% Test Substance

Corneal Opacity

Iris

Conjunctival Erythema

Conjuctival Edema

1.3

0.8

1.5

2.1

 

1/6 animals tested showed evidence of positive corneal, iritic, or conjuctival changes in response to 50% w/w test substance.

   Table 2: Mean Scores (24,48 and 72 hours) for 50% w/w Test Substance

Corneal Opacity

Iris

Conjunctival Erythema

Conjuctival Edema

0.0

0.0

0.3

0.2

No evidence of corrosion was noted in response to the test substance at 100% or 50%w/w concentrations.

No observations were made beyond 72 hours, therefore, the reversibility of the effects could not be assessed.

The mineral oil vehicle used as the dilute was determined to be a non-irritant in a separate study. 

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
The undiluted (100%) test substance is classified as an irritant, whereas the test substance at 50% w/w is classified as a nonirritant.
Executive summary:

An eye irritation study was performed using male New Zealand White rabbits according to the definition of the FHSA 16CFR1500. Two groups of 6 rabbits (3 male and 3 female) were administered with a single dose of 0.1 ml test material to one eye of each animal, and eyes were examined and graded for ocular reaction at approximately 24, 48 and 72 h following dose administration using the Draize method. Following the 24 h reading the eyes were rinsed with physiological saline. Based on these scores, the undiluted (100%) test substance is classified as an irritant, whereas the test substance at 50% w/w is classified as a nonirritant.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Between March 9th, 1997 and March 30th, 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study; well-documented study report, restriction due to it is an old study predated GLP.
Qualifier:
according to guideline
Guideline:
other: Section 1500.42- Hazardous Substances and Articles, Administration and Enforcement Regulations, Federal Register, Vol. 38, No. 187 (1973).
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
Albino rabbit
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Duration of treatment / exposure:
The test material was not washed from the eyes.
Observation period (in vivo):
Treated eyes were examined at 1, 2, 3 and 5 days following installation of the test substance.
Number of animals or in vitro replicates:
6
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24, 48, and 72h
Score:
ca. 6.3
Reversibility:
fully reversible within: 5 d

Table 1: Grades for Ocular Lesions (Mean Value)

1 day

2 day

3 day

5 day

Cornea

5.0

0

0

0

Iris

0

0

0

0

Conjunctivae

8.3

4.0

1.7

0

Daily Primary Eye Irritation Index

13.3

4.0

1.7

0

Overall primary eye irritation index

6.3

The effects of the treatment were reversed on day 5.

Table 2: Mean Scores (24, 48 and 72 h)

Cornea

Iris

Conjunctivae

1.7

0

4.7

Interpretation of results:
Category 2B (mildly irritating to eyes) based on GHS criteria
Remarks:
Migrated information
Conclusions:
The test substance is a mild ocular irritant
Executive summary:

An eye irritation study was performed using albino rabbits according to the definition of the Section 1500.42- Hazardous Substances and Articles, Administration and Enforcement Regulations, Federal Register, Vol. 38, No. 187 (1973). 6 rabbits were administered with a single dose of 0.1 ml test material to one eye of each animal, and eyes were examined and graded for ocular reaction at approximately 1, 2, 3 and 5 days following dose administration using the grading system outlined in the “Illustrated Guide for Grading Eye Irritation By Hazardous Substances”.  Based on these scores, the undiluted test substance is classified as an mild ocular irritant.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Between March 09th, 1987 and March 30th, 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study; well-documented study report.
Qualifier:
according to guideline
Guideline:
other: 40CFR158 Series 81-4, EPA Pesticide Assessment Guidelines-Subdivision F-Hazard Evaluation – Human & Domestic Animals, November 1984
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Duration of treatment / exposure:
The treated eye was not washed out.
Observation period (in vivo):
Treated eyes were examined after 1 hour and 1, 2, 3, 4 and 7 days following treatment. Eyes exhibiting ocular irritation at 7 days were also examined at 14 days. If ocular irritation persisted at 14 days, eyes were re-examined at 21 days.
Number of animals or in vitro replicates:
6
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.28
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: observation period 21 d
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.11
Max. score:
2
Reversibility:
not specified
Remarks on result:
other: observation period 21 d
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
24/48/72 h
Score:
1.22
Max. score:
3
Reversibility:
not specified
Remarks on result:
other: observation period 21 d
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.83
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: observation period 21 d
Other effects:
None.

Conjunctival irritation was noted in 6/6 animals on day 1, 5/6 animals on day 3, 3/6 animals on day 7, the remining 3/6 animals exhibited conjunctival irritation through day 21.

Corneal opacity was noted for 3/6 animals on day 2, and in 1/6 animals after day 3 and day 7.  0/6 animals showed corneal opacity on days 14 and 21.

Iritis was noted for 1/6 animals at 24 and 48 hours and 0/6 animals on day 3.

Table 1: Average Ocular Irritation Scores

Time

1 h

 1 d

2 d

 3 d

4 d

7 d

14 d

21 d

Ocular Irritation Scores

14.3

12.5

17.2

9.3

8.0

5.0

1.3

1.3

Table 2:  Mean Scores (24,48,72 hours)

Corneal Opacity

Iris

Conjunctival Erythema

Conjunctival Edema

0.28

0.11

1.22

1.83

Interpretation of results:
GHS criteria not met
Remarks:
Migrated information
Conclusions:
The test substance is an eye irritant.
Executive summary:

An eye irritation study was performed using male New Zealand White rabbits according to the definition of the 40 CFR158 Series 81-4, EPA Pesticide Assessment Guidelines-Subdivision F-Hazard Evaluation. 6 rabbits were administered with a single dose of 0.1 ml test material to one eye of each animal, and eyes were examined and graded for ocular reaction following dose administration using the Draize method. Conjunctival irritation was noted in 6/6 animals on day 1, 5/6 animals on day 3, 3/6 animals on day 7, the remining 3/6 animals exhibited conjunctival irritation through day 21. Corneal opacity was noted for 3/6 animals on day 2, and in 1/6 animals after day 3 and day 7. 0/6 animals showed corneal opacity on days 14 and 21. Iritis was noted for 1/6 animals at 24 and 48 hours and 0/6 animals on day 3. Based on these scores, the test substance is not classified as an eye irritant.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data on respiratory irritation are available for the test material.

No skin irritation was observed in an animal study in which the test substance was administered as supplied and held in place under semi-occlusive wrap for 4 hours.

Using a weight of evidence approach, 100% test material had irritant effects on the mucous membranes of the eyes but at 50% concentration, no ocular irritation was observed. The studies are found to be adequate to fulfill the purposes of this endpoint.

The following information is taken into account for any hazard / risk assessment:

This substance is not a skin irritant, is an eye irritant at 100%, but not an eye irritant at a 50% concentration.


Effects on eye irritation: irritating

Justification for classification or non-classification

Skin irritation

There are conclusive but not sufficient data for classification of the test material with regard to skin irritation / corrosion, so the test material is not classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008.

 

Eye irritation

In a weight of evidence approach for the 100 % test material, three in vivo eye irritation studies have been assessed. In the first study (Hershman, 1987) the 24/48/72 hour mean scores for corneal opacity, iritis, conjunctival redness and chemosis did not meet CLP criteria and lack of reversibility based on overall ocular irritation score at 21 days was not relevant to classification. The second study (Buehler, 1992) observed animals for only 72 hours and did not demonstrate reversibility. However, results indicated that the 100 % substance should be classified as an eye irritant (category 2) because the mean 24/48/72 hour chemosis score was ≥ 2. In the third study (Gabriel, 1977) reversibility of irritant effects was demonstrated within 5 days even though data did not permit CLP classification based on corneal opacity, iritis, conjunctival redness and chemosis. It is therefore concluded that the pure test substance meets criteria for classification as an eye irritant (category 2) under the terms of regulation (EC) No 1272/2008. The test material was not determined to meet the criteria for classification as an eye irritant at a concentration of 50 %.