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Toxicological information

Skin irritation / corrosion

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Administrative data

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013-11-26 to 2013-12-27
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
1-butylpyrrolidin-2-one
EC Number:
222-437-8
EC Name:
1-butylpyrrolidin-2-one
Cas Number:
3470-98-2
Molecular formula:
C8H15NO
IUPAC Name:
1-butylpyrrolidin-2-one
Test material form:
other: Clear colourless liquid
Details on test material:
- Substance type: organic
- Physical state: clear colourless liquid
- Analytical purity: 99.7 %
- Lot/batch No.: 01061301
- Expiration date of the lot/batch: 31 Dec 2016
- Stability under test conditions: no details
- Storage condition of test material: Kept in a controlled temperature area

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Covance, Denver, PA
- Age at study initiation: 25 to 26 weeks
- Weight at study initiation: between 2.9 and 3.8 kg
- Housing: individually in suspended stainless steel cages
- Diet (e.g. ad libitum): PMI Nutrition International Certified Rabbit Chow No. 5322 was provided ad libitum throughout the study except during designated procedures. To avoid potential gastrointestinal disturbances, food was withheld for approximately 24 to 48 hours after receipt. Food was then gradually increased over a 3-day period.
- Water (e.g. ad libitum): Municipal tap water following treatment by reverse osmosis and ultraviolet irradiation was available ad libitum throughout the study.
- Acclimation period: at least 7 days before the first day of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 44-49
- Air changes (per hr): Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 26 Nov 2013 (day of arrival) To:

Test system

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
The test substance was administered as received (pure). Dose calculations were not corrected for purity.
Duration of treatment / exposure:
- animal 1: 3 min, 1h and 4hours
- animal 2: 4 hours
- animal 3: 4 hours
Observation period:
For the 3-minute exposure: Immediately after patch removal, 1 hour after patch removal, and 24, 48, and 72 hours after patch application.
For the 1-hour exposure: Immediately after patch removal, 1 hour after patch removal, and 24, 48, and 72 hours after patch application.
For the 4-hour exposure: 1 hour after patch removal, and 24, 48, and 72 hours after patch application.
If dermal irritation persisted at any test site, the observation period was extended for the affected animals up to 21 days.
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: approximately 1 inch x 1 inch
- Type of wrap if used: The gauze patches were held in contact with the skin at the cut edges with a nonirritating tape. Removal and ingestion of the test substance were prevented by placing an elastic wrap over the trunk and test area (semi-occlusive binding).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test substance was removed using gauze moistened with deionized water followed by dry gauze.
- Time after start of exposure: immediately after patch removal.

SCORING SYSTEM:
EPA-FIFRA Dermal Irritation Descriptive Classification:
The 1- (or initial observation), 24-, 48- and 72-hour erythema and oedema scores for all animals were added and the total divided by the number of test sites (5 (= animal 1(3 test sites: 3-min, 1-hour, 4-hour) + animal 2 (1) + animal 3(1))) x 4 (= number of observation time points: 1-hour, 24-hour, 48-hour and 72-hour) to yield the Primary Irritation Index (P.I.I.). The calculated Primary Irritation Index (P.I.I.) was classified according to the Dermal Irritation Descriptive Classification (1).

EEC Dermal Evaluation Criteria:
The 24-, 48- and 72-hour scores were added separately for erythema and oedema. For a group of three animals, the calculated mean scores were expressed individually. The resulting appropriate Primary Irritation Indices (P.I.I.) was classified according to the EEC Dermal Evaluation Criteria (2).

References:
1. Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation: Human and Domestic Animals-Addendum 3 on Data Reporting, U.S. Environmental Protection Agency, 1988.
2. Commission of European Communities, Official Journal of European Communities, Annex VI, General Classification and Labeling Requirements for Dangerous Substances and Preparations, No. L 225/263-314, August 2001.
 

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #1
Time point:
other: 3-min exposure
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 21 days
Remarks on result:
other: very slight erythema was noted on Day 14, which subsequently resolved completely by Day 21
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
animal #1
Time point:
other: 1-hour exposure
Score:
0.75
Max. score:
1
Reversibility:
fully reversible within: 21 days
Remarks on result:
other: The dermal irritation was not observed on Day 7, but was observed again on Day 14.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Remarks:
of 3 animals
Time point:
other: 4-hour exposure
Score:
1.33
Max. score:
2
Reversibility:
not fully reversible within: 14 days
Remarks on result:
other: The dermal irritation was not observed in 1/3 test sites on Day 7, but was again observed in that animal on Day 10. Dermal irritation did not resolve completely in the remaining 2 test sites.
Irritation parameter:
erythema score
Remarks:
mean from gradings at 24, 48 and 72-hour observation time points
Basis:
animal #1
Time point:
other: 4-hour exposure
Score:
2
Max. score:
2
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: the score of 1 for erythema was still present at day 21 post-exposure
Irritation parameter:
erythema score
Remarks:
mean from gradings at 24, 48 and 72-hour observation time points
Basis:
animal #2
Time point:
other: 4-hour exposure
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 21 days
Irritation parameter:
erythema score
Remarks:
mean from gradings at 24, 48 and 72-hour observation time points
Basis:
animal #3
Time point:
other: 4-hour exposure
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 21 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 1-hour observation time point
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
edema score
Remarks:
mean from gradings at 24, 48 and 72-hour observation time points
Basis:
animal #1
Time point:
other: 4-hour exposure
Score:
0
Max. score:
0
Remarks on result:
other: no irritation responses
Irritation parameter:
edema score
Remarks:
mean from gradings at 24, 48 and 72-hour observation time points
Basis:
animal #2
Time point:
other: 4-hour exposure
Score:
0
Max. score:
0
Remarks on result:
other: no irritation responses
Irritation parameter:
edema score
Remarks:
mean from gradings at 24, 48 and 72-hour observation time points
Basis:
animal #3
Time point:
other: 4-hour exposure
Score:
0
Max. score:
0
Remarks on result:
other: no irritation responses
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
1
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
3-Minute Exposure
Exposure to the test substance produced no erythema or oedema through 72 hours post-dose; however, very slight erythema was noted at the single test site on Day 14, which subsequently resolved completely by Day 21 (Table 1).
 
1-Hour Exposure
Exposure to the test substance produced very slight erythema at the single test site immediately after patch removal (Table 2). The dermal irritation was not present at the 1-hour scoring interval, but was present again at the 24-, 48-, and 72-hour scoring intervals. The dermal irritation was not observed on Day 7, but was observed again on Day 14. Day 21 scoring revealed no irritation. Additional dermal findings included desquamation.
 
4-Hour Exposure
Exposure to the test substance produced very slight erythema at 3/3 test sites and very slight oedema at 1/3 test sites by the 1-hour scoring interval (Table 3). Well-defined erythema was observed in 1/3 test sites at the 24-, 48-, and 72-hour scoring intervals. The dermal irritation was not observed in 1/3 test sites on Day 7, but was again observed in that animal on Day 10. Dermal irritation did not resolve completely in the remaining 2 test sites. Additional dermal findings included blanching (focal and/or pinpoint areas up to 10% of the test site) in 1/3 test sites and desquamation in 3/3 test sites.
Other effects:
No other effects were reported in treated animals.

Any other information on results incl. tables

Table 1. Individual dermal irritation scores (3 -min exposure; animal 1)

Animal No. /Sex/ Body weight (kg)

Scoring Interval

Erythema

Oedema

5810/M

2.903

Patch removal

0

0

1 hour

0

0

24 hours

0

0

48 hours

0

0

72 hours

0

0

7 days

-

-

10 days

-

-

14 days

1

0

21 days

0

0

Primary Irritation Index = 0.00 (Non-irritant)

Table 2. Individual dermal irritation scores (1-hour exposure; animal 1)

Animal No. /Sex

Scoring Interval

Erythema

Oedema

Comments

5810/M

Patch removal

1

0

 

1 hour

0

0

 

24 hours

1

0

 

48 hours

1

0

 

72 hours

1

0

 

7 days

0

0

DES

10 days

0

0

DES

14 days

1

0

DES

21 days

0

0

 

DES - desquamation

Primary Irritation Index = 0.75 (Slight irritant)

PII = ((Summe of erythema and oedema scores at 1, 24, 48 and 72 hours) / ( 1 (Number of test sites) x 4 (Number of scoring intervals))

Table 3. Individual dermal irritation scores (4-hour exposure; animal 1, 2 and 3)

Animal No. /Sex/ Body weight (kg)

Scoring Interval

Erythema

Oedema

Comments

5810/M

Patch removal

1

0

 

1 hour

1

1

 

24 hours

2

0

BLA-1

48 hours

2

0

BLA-1

72 hours

2

0

BLA-1

7 days

1

0

DES

10 days

1

0

DES

14 days

1

0

DES

21 days

1

0

DES

 

 

 

 

5811/M
3.784

Patch removal

1

0

 

1 hour

1

0

 

24 hours

1

0

 

48 hours

1

0

 

72 hours

1

0

 

7 days

1

0

 

10 days

1

0

DES

14 days

1

0

DES

 

 

 

 

5812/M
3.133

Patch removal

1

0

 

1 hour

1

0

 

24 hours

1

0

 

48 hours

1

0

DES

72 hours

1

0

 

7 days

0

0

 

10 days

1

0

DES

14 days

1

0

DES

DES: desquamation

BLA-1: blanching

Primary Irritation Index = 1.33 (Slight irritant)

PII = ((Sum of erythema and oedema scores at 1, 24, 48 and 72 hours) / ( 3 (Number of test sites) x 4 (Number of scoring intervals))

Applicant's summary and conclusion

Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: other: according to Primary Irritation Index
Conclusions:
Under the conditions of the test (4 hour exposure), the test substance is considered to be a slight irritant to the skin of the rabbit. The calculated Primary Irritation Index for the test substance was 1.33.
According to the EEC Dermal Evaluation Criteria, the test substance is considered to be a nonirritant for erythema and oedema
Executive summary:

The objective of this study was to assess the corrosive effects of the test substance when given as a single dermal administration to rabbits. Each of 3 rabbits received a 0.5 mL dose of the test substance as a single dermal application. The dose was held in contact with the skin under a semi-occlusive binder for exposure periods of 3 minutes, 1 hour, and 4 hours for 1 animal and exposure periods of 4 hours for 2 animals. Following the completion of each exposure period, the binder was removed and the remaining test substance was wiped from the skin using gauze moistened with deionized water followed by dry gauze. Test sites were subsequently examined and scored for dermal irritation for up to 21 days following patch removal.

 

3-Minute Exposure

Exposure to the test substance produced no erythema or oedema through 72 hours post-dose; however, very slight erythema was noted at the single test site on Day 14, which subsequently resolved completely by Day 21.

 

1-Hour Exposure

Exposure to the test substance produced very slight erythema at the single test site immediately after patch removal. The dermal irritation was not observed at the 1-hour scoring interval, but was present again at the 24-, 48-, and 72-hour scoring intervals. The dermal irritation was not observed on Day 7, but was observed again on Day 14. Day 21 scoring revealed no irritation. Additional dermal findings included desquamation.

 

4-Hour Exposure

Exposure to the test substance produced very slight erythema at 3/3 test sites and very slight oedema at 1/3 test sites by the 1-hour scoring interval. Well-defined erythema was observed in 1/3 test sites at the 24-, 48-, and 72-hour scoring intervals. The dermal irritation was not observed in 1/3 test sites on Day 7, but was again observed in that animal on Day 10. Dermal irritation did not resolve completely in the remaining 2 test sites. Additional dermal findings included blanching (focal and/or pinpoint areas up to 10% of the test site) in 1/3 test sites and desquamation in 3/3 test sites.´

 

Conclusion

Under the conditions of the test (4 hour exposure), the test substance is considered to be a slight irritant to the skin of the rabbit. The calculated Primary Irritation Index (P.I.I) for the test substance was 1.33.

According to the EEC Dermal Evaluation Criteria, the test item is considered to be a nonirritant for erythema and oedema as listed below:.

Animal No./Sex

Erythema

Edema

P.I.I.

3-Minute Exposure

5810/M

0.00

0.00

0.00 - Nonirritant

Irritation Rating

Nonirritant

Nonirritant

1-Hour Exposure

5810/M

1.00

0.00

0.75 - Slight irritant

Irritation Rating

Nonirritant

Nonirritant

4-Hour Exposure

5810/M

2.00

0.00

1.33 - Slight irritant

5811/M

1.00

0.00

5812/M

1.00

0.00

Irritation Rating

Nonirritant

Nonirritant