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Description of key information

Not irritating

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:
Between 15 March 1974 and 18 April 1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Valid and conclusive pre-GLP study comparable to guideline, basic data reported
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2002
Deviations:
yes
Remarks:
Only 2 gradings (24 and 72 h), test item not removed after 4 h, test end at 72 h before full effect reversibility, additionally abraded skin exposure
Qualifier:
equivalent or similar to guideline
Guideline:
other: U.S. 16 CFR 1500.41 Federal Hazardous Substances Act (Federal Register, Vol. 38, No. 187, P. 27019, 27 September 1973)
Deviations:
not specified
GLP compliance:
not specified
Remarks:
The experiment was performed before the first GLP standard was defined by FDA in 1976, therefore no formal GLP was possible. Nonetheless it can be assumed that comparable standards applied as the test was conducted in a specialized laboratory.
Species:
rabbit
Strain:
not specified
Details on test animals or test system and environmental conditions:
Test animals were albinos
Type of coverage:
occlusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount applied: A 0.5 g portion of the pure test item was applied to the intact and abraded skin
Duration of treatment / exposure:
Wrappings were removed after 24 h. Wiping of the skin to remove the test item is not mentioned in the report. Therefore it can be assumed that the exposure to the test item was maintained until the last reading at 72 h.
Observation period:
72 h; after 24 h the wrapping was removed and the treated areas were examined. Readings were also made at 72 h.
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: The test animals were clipped over a wide area. One side of the animals' backs was abraded at one site with a lancet sufficiently deep to penetrate the stratum corneum but not enter the derma to produce bleeding. The skin of the other side was allowed to remain intact.
- Type of wrap if used: The exposed skin was covered with gauze patched and wrapped with an impervious material.

REMOVAL OF TEST SUBSTANCE
The test item was not removed until the test end at 72 h.

SCORING SYSTEM: The Draize Score method was used for interpretation.
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
mean of 24 and 72 h
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
mean of 24 (weighted twice) and 72 h
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
other: score declined with time
Remarks on result:
other: patch removed after 24 h, no washing
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
mean of 24 and 72 h
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritation parameter:
erythema score
Basis:
animal #4
Remarks:
mean of 24 and 72 h
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritation parameter:
erythema score
Basis:
animal #5
Remarks:
mean of 24 (weighted twice) and 72 h
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
other: score declined with time
Remarks on result:
other: patch removed after 24 h, no washing
Irritation parameter:
erythema score
Basis:
animal #6
Remarks:
mean of 24 and 72 h
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
mean of 24 and 72 h
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effect, thus not applicable
Remarks on result:
other: patch removed after 24 h, no washing
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
mean of 24 and 72 h
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
mean of 24 and 72 h
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritation parameter:
edema score
Basis:
animal #4
Remarks:
24 and 72 h
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effect, thus not applicable
Remarks on result:
other: patch removed after 24 h, no washing
Irritation parameter:
edema score
Basis:
animal #5
Remarks:
24 and 72 h
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritation parameter:
edema score
Basis:
animal #6
Remarks:
24 and 72 h
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effect, thus not applicable
Remarks on result:
other: patch removed after 24 h, no washing, score unchanged with time
Irritant / corrosive response data:
None of the test animals showed a more severe grading at the second evaluation point after 72 h exposure. The mean erythema formation scores declined with time while the edema formation scores were unchanged.

Intact skin
Erythema and eschar formation scores
Mean 24 h score 2.00; individual scorings of the test animals no. 1 to 6: 2, 2, 2, 2, 2 and 2, respectively
Mean 72 h score 1.67; individual scorings of the test animals no. 1 to 6: 2, 1, 2, 2, 1 and 2, respectively
Edema formation scores
Mean 24 h score 0.50; individual scorings of the test animals no. 1 to 6: 0, 1, 1, 0, 1 and 0, respectively
Mean 72 h score 0.50; individual scorings of the test animals no. 1 to 6: 0, 1, 1, 0, 1 and 0, respectively

Abraded skin
Erythema and eschar formation scores
Mean 24 h score 2.00; individual scorings of the test animals no. 1 to 6: 2, 2, 2, 2, 2 and 2, respectively
Mean 72 h score 1.83; individual scorings of the test animals no. 1 to 6: 2, 2, 2, 2, 1 and 2, respectively
Edema formation scores
Mean 24 h score 0.67; individual scorings of the test animals no. 1 to 6: 0, 1, 1, 0, 2 and 0, respectively
Mean 72 h score 0.67; individual scorings of the test animals no. 1 to 6: 0, 1, 1, 0, 2 and 0, respectively

Primary Dermal Irritation Index (PDII) calculation
Subtotal of mean Erythema and eschar formation scores at 24 and 72 h (intact and abraded skin) = 2.00 + 1.67 + 2.00 + 1.83 = 7.50
Subtotal of mean Edema formation scores at 24 and 72 h (intact and abraded skin) = 0.50 + 0.50 + 0.67 + 0.67 = 2.34
Total of mean Erythema and eschar plus Edema formation = 9.84
PDII = 9.84 / 4 = 2.46
Based on the results the test item would not be classified as a primary irritant to albino rabbits within the definition of the Act-Reference: Section 1500.3 (c) (4) and requires no cautionary labelling with respect to that section (a value of 5 or greater would indicate a primary irritant).
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Exposure in excess of the OECD TG 404 (2002) requirements produced mild skin reactions insufficient for classification, which tended to decline with time.
Executive summary:

The irritation / corrosion properties of the test item were investigated in a pre-GLP study using clipped albino rabbit skin according to a protocol comparable to the OECD TG 404 (2002) standards. At variance to the guidance the test animal skin was still exposed to the test item at the test end after 72 h, which is a more severe test condition as foreseen in the OECD TG 404 (2002). Nonetheless some decline in the response was observed and the recorded effects never reached the classifiable level. Therefore this deviation and the lacking post-exposure observation period (as required in OECD TG 404, 2002) can be considered not impairing the conclusiveness of the study. The omitted 48 h reading can be replaced be double-weighting the 24 h reading. As at the earlier grading generally the effects are more severe, a higher overall grading results when the 48 h data lack and are replaced by the double-weighted 24 h gradings. Therefore this procedure applies again a worst case approach. As the test result was negative, it can be concluded that strictly following the OECD TG 404 (2002) protocol would reveal the same, non-irritating result. Consequently the study is considered acceptable for assessment. The experiment was performed before the first GLP standard was defined by FDA in 1976, therefore no formal GLP was possible. Nonetheless it can be assumed that comparable standards applied as the test was conducted in a specialized laboratory. The reporting is limited but sufficient information is given. The experiment is deemed valid, conclusive and thus suitable for assessment with minor restrictions, in that only a negative, non-irritating result is considered reliable.

A 0.5 g portion of the test item was applied to the intact and abraded skin of 6 rabbits and covered with gauze patched and wrapped with an impervious material. After 24 h the wrapping was removed and the treated areas were examined and graded according to the Draize method. No removal of the test item is reported. Readings were also made at 72 h. Mean 24 to 72 h scores for the intact skin were calculated for the individual test animals, whereat the generally higher 24 h value as weighted twice as no 48 h reading was performed. Abraded skin values are not meaningful according to OECD TG 404 (2002) and should be disregarded.

The individual erythema/eschar formation scores ranged between 1.67 and 2 and the edema formation scores between 0 and 1.

None of the individual scores and therefore none of the mean scores exceeded 2.

In summary exposure in excess of the OECD TG 404 (2002) requirements produced mild skin reactions insufficient for classification, which tended to decline with time. The test item was found not irritating in accordance with EU CLP Regulation No. 1272/2008, and no indication for classification is given on the basis of this study.

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:
Between 15 March 1974 and 18 April 1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Valid and conclusive pre-GLP study comparable to guideline, basic data reported
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
2002
Deviations:
yes
Remarks:
1 h grading omitted
Qualifier:
equivalent or similar to guideline
Guideline:
other: U.S. 16 CFR 1500.42 Federal Hazardous Substances Act (Federal Register, Vol . 38, No. 187, P. 27019, 27 September 1973)
GLP compliance:
not specified
Remarks:
The experiment was performed before the first GLP standard was defined by FDA in 1976, therefore no formal GLP was possible. Nonetheless it can be assumed that comparable standards applied as the test was conducted in a specialized laboratory.
Species:
rabbit
Strain:
other: Albino
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adults
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 g
- Concentration: Pure test item was used.
Duration of treatment / exposure:
3 d (72 h) from test start until test end (no washing)
Observation period (in vivo):
3 d (72 h); the treated eyes were examined at days 1, 2 and 3 following instillation of the test item.
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: No
- Time after start of exposure: The test animals were exposed until test end.

SCORING SYSTEM: Draize method, in accordance with the grading system outlined in the “illustrated Guide for Grading Eye Irritation by Hazardous Substances”.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 h (score 0 from this time on)
Remarks on result:
other: No 1 h reading performed
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 24 h (score 0 from this time on)
Remarks on result:
other: No 1 h reading performed
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 24 h (score 0 from this time on)
Remarks on result:
other: No 1 h reading performed; conjunctival redness and chemosis were not differentiated but were grouped as conjunctival scores. The maximum score for chemosis is 4.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Max. score:
4
Remarks on result:
not measured/tested
Irritant / corrosive response data:
None of the test animals showed any significant difference to the untreated control eye.
Other effects:
None
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Not irritating, no difference to control
Executive summary:

The eye irritation / corrosion properties of the test item was investigated in a pre-GLP study using albino rabbits according to a protocol comparable to the OECD TG 405 (2002) standards. At variance to the guideline the 1 h grading was omitted. As at the 24 h grading no difference to the control eyes was recorded, the study result is not impaired by this deviation. The experiment was performed before the first GLP standard was defined by FDA in 1976 therefore no formal GLP was possible. Nonetheless it can be assumed that comparable standards applied as the test was conducted in a specialized laboratory. The reporting is limited but sufficient information is given. The experiment is deemed valid, conclusive and suitable for assessment with minor restrictions.

A dose of 0.1 g of the test item was instilled in the right eyes of six healthy young adult albino rabbits. The untreated left eyes served as controls. The treated eyes were examined at days 1, 2 and 3 following instillation of the test item and graded in accordance with the Draize method.

No corneal opacity, iritis or conjunctival irritation was observed in any animal at any observation during the test period.

In summary the test item was found not eye irritating with no difference between treatments and control. No indication for classification is given and in accordance with EU CLP Regulation (EC) No. 1272/2008 no classification is required.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The irritation / corrosion properties were investigated in pre-GLP study (Gabriel 1974, Biosearch Report on Primary Skin Irritation Study - Rabbits) using clipped albino rabbit skin according to a protocol comparable to the OECD TG 404 (2002) standards. The experiment is deemed valid, conclusive and thus suitable for assessment with minor restrictions. The exposure was maintained during the whole test period (72 h) as residual submission item was not removed after 4 h. Therefore the test conditions were more severe as foreseen in the standards of OECD TG 404 (2002) and the reported mild effects will overestimate the irritation potential of the submission item however they are not sufficient for classification - even not on the basis of the abraded skin effects. These observations are in accordance with the report from the pre-experiments for the skin sensitisation study in guinea pigs (Rodabaugh 2004, Charles River Report no. LAS00004), where after 6 h exposure of pure submission item at 24 and 48 h slight, but confluent or moderate patchy erythema were reported in all 4 test animals (2 males, 2 females) and one female showed additionally a very slight edema (barely perceptible) at both observation times. Slight irritation below the classifiable level is therefore confirmed in two different studies in two species. Considering the mild, not classifiable reactions and the overexposure the submission item is deemed not irritating. This interpretation is supported by the absence of any effects in the eye irritation study (Gabriel 1974, Biosearch Report on Primary Eye Irritation Study - Rabbits), summarized below, and by the absence of hazard from empiric knowledge based on handling experience. Additionally in the study of Sanders (2012, Harlan Report no. 41103266) investigating the acute dermal toxicity to rats absence of any local effects such as erythema, edema, eschar formation or any other abnormalities was observed. In conclusion the submission item can be assessed not irritating to skin.

The eye irritation / corrosion properties were investigated in a pre-GLP study (Gabriel 1974, Biosearch Report on Primary Eye Irritation - Rabbits) using albino rabbits according to a protocol comparable to the OECD TG 405 (2002) standards. The experiment is deemed valid, conclusive and suitable for assessment with minor restrictions. A dose of 0.1 g of the submission item was instilled in the right eyes of six healthy young adult albino rabbits. The untreated left eyes served as controls. The treated eyes were examined at days 1, 2 and 3 following instillation of the submission item and graded in accordance with the Draize method. No corneal opacity, iritis or conjunctival irritation was observed in any animal at any observation during the test period.

No experimental data from a respiratory irritation study are available. No testing is required as inhalation exposure can be excluded in the supported uses. In absence of marked skin or eye irritating properties and considering its chemical structure the submission expected not irritating in the respiratory tract.


Justification for selection of skin irritation / corrosion endpoint:
The study of Gabriel (1974, Biosearch Report on Primary Skin Irritation Study - Rabbits) represents the only available experimental data.

Justification for selection of eye irritation endpoint:
The study of Gabriel (1974, Biosearch Report on Primary Eye Irritation - Rabbits) represents the only available experimental data.

Justification for classification or non-classification

Based on the available data, the submission item is not classified.