1-butylpyrrolidin-2-one

Skin irritation / corrosion

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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

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
- 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

Results

Results 1

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

Results 2

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.

Results 3

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.

Results 4

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

Results 5

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

Results 6

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

Results 7

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

Results 8

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

Results 9

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

Results 10

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

Results 11

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

Results 12

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:

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