Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Experimental Starting Date: 29 May 2014; Experimental Completion Date: 19 June 2014
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 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
UK GLP standards (Schedule 1, Good Laboratory Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004/0994)). The Department of Health of the Government of the United Kingdom.
Test type:
standard acute method
Limit test:
yes

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: liquid
Details on test material:
- Substance type: organic (alkyl pyrrolidone)
- Physical state: clear colourless liquid
- Analytical purity: 99.7%
- Composition of test material, percentage of components: N-Butylpyrrolidone: 99.7 % (GC); water: 0.18% (Coulometry)
- Purity test date: 2013-10-29
- Lot/batch No.: 01061301
- Expiration date of the lot/batch: 01 December 2016
- Storage condition of test material: room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Wistar (RccHan™:WIST) strain rats
- Source: Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: eight to twelve weeks
- Weight at study initiation: at least 200 g
- Fasting period before study: no
- Housing: individually during the 24-hour exposure period and in groups of up to four, by sex, for the remainder of the study.
- Diet (e.g. ad libitum): ad libitum (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK).
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: the back and flanks (shorn skin)
- % coverage: 10 % of of the total body surface area
- Type of wrap if used: A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with cotton wool moistened with distilled water to remove any residual test item
- Time after start of exposure: 24 hours

TEST MATERIAL
For the purpose of the study the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level. Specific gravity was 0.952
- Amount(s) applied (volume or weight with unit): 2.11 mL/kg
- Constant volume used: yes
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
- Other examinations performed: After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale:
Erythema and Eschar Formation:
No erythema: 0
Very slight erythema (barely perceptible): 1
Well-defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beef redness) to slight eschar formation (injuries in depth): 4

Edema Formation:
No edema: 0
Very slight edema (barely perceptible): 1
Slight edema (edges of area well-defined by definite raising): 2
Moderate edema (raised approximately 1 millimeter): 3
Severe edema (raised more than 1 millimeter and extending beyond the area of exposure): 4
Any other skin reactions, if present were also recorded.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no effects
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
Animals showed expected gains in body weight except for two females which showed no gain in body weight or body weight loss during the first week with expected gain in body weight during the second week.
Gross pathology:
No abnormalities were noted at necropsy.

Any other information on results incl. tables

Dermal Reactions

Very slight erythema was noted at the test sites of two females. Small superficial scattered scabs and glossy skin were also noted at the test site of one of these females. No signs of dermal irritation were noted at the test sites of all males and three females.

Table 1. Individual dermal reactions (males)

Dose Level mg/kg Animal Number and Sex Observation Effects Noted After Initiation of Exposure (Days)
1 2 3 4 5 6   8 9 10 11 12 13 14
  1-0 Male Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  3-0 Male Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  3-1 Male Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
2000 Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  3-2 Male Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  3-3 Male Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Table 2. Individual dermal reactions (females)

Dose Level mg/kg Animal Number and Sex Observation Effects Noted After Initiation of Exposure (Days)
1 2   4 5 6   8 9 10 11 12 13 14
  2-0 Female Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  4-0 Female Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  4-1 Female Erythema         0 0 0 0 0 0 0 0 0 0
2000 Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 SsG SsG SsG 0 0 0 0 0 0 0 0
  4-2 Female Erythema 1 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  4-3 Female Erythema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Edema 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  Other 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 - No reactions;

Ss - Small superficial scattered scabs;

G - Glossy skin

Table 3. Individual Body Weights and Body Weights Changes

Dose Level
(mg/kg bw)

Animal Number and Sex

Body Weight (g) at Day

Body Weight Change (g) during Week

0

7

14

1

2

2000

1-0 Male

229

245

263

16

18

3-0 Male

266

270

301

4

31

3-1 Male

257

272

298

15

26

3-2 Male

241

250

282

9

32

3-3 Male

264

285

306

21

21

2-0 Female

216

221

234

5

13

4-1 Female

233

230

243

-3

13

4-2 Female

218

218

230

0

12

4-3 Female

214

220

227

6

7

4-4 Female

226

227

244

1

17

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.
The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.
Executive summary:

The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat. Initially, two animals (one male and one female) were given a single, 24 hour, semi-occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg body weight. Based on the results of the initial test, a further group of eight animals (four males and four females) was similarly treated. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

There were no deaths and no signs of systemic toxicity in treated animals. Very slight erythema was noted at the test sites of two females. Small superficial scattered scabs and glossy skin were also noted at the test site of one female. No other signs of dermal irritation were noted. Animals showed expected gains in body weight except for two females which showed no gain in body weight or body weight loss during the first week with expected gain in body weight during the second week. No abnormalities were noted at necropsy. The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.