Registration Dossier

Administrative data

Description of key information

Skin: Notox B.V., 2003. Primary skin irritation /corrosion study with HC1161 in rabbits (4-hour semi-occlusive application). Report No. 379474. According to the OECD guideline 404, rabbits, New Zealand White, 4 h, semiocclusive, 0.5 g.
Eye: BASF AG, 1961. Results of the toxicological pretesting, Pyrrolidone distilled. Report No. IX/407. BASF Test, comparable to the OECD guideline 405, rabbits, Vienna White, 0.05 mL.
Respiratory system: no data available

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:
2003-05-13 to 2003-05-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study performed according to OECD 404; US EPA , OPPTS 870.2500; EU Method B.4 and JMAFF, Japanese test guideline without deviations.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Remarks:
The testing facilty indicated that the protocol was followed without deviation.
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Remarks:
The testing facilty indicated that the protocol was followed without deviation.
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
Remarks:
The testing facilty indicated that the protocol was followed without deviation.
Qualifier:
according to
Guideline:
other: JMAFF , Japanese guideline
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Kisslegg, Germany
- Age at study initiation: at least 6 weeks old
- Weight at study initiation: at least 1.0 kg
- Housing: individually in labelled cages with perforated floors
- Diet: approx. 100 g standard laboratory rabbit diet per day, pressed hay twice a week
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2 - 22.5 deg C
- Humidity (%): 38 - 77 %
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours artificial fluorescent light per day


IN-LIFE DATES: From: 2003-05-13 To:2003-05-30
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: not treated skin of treated animals
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 g
Duration of treatment / exposure:
4hr
Observation period:
at 1, 24 48, 72 hrs
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: dorsal area free of fur (150 square centimeters)
- % coverage: no data
- Type of wrap if used: metalline patch of 2x3 cm


REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: 4hr


SCORING SYSTEM:
Eyrthema and eschar formation:
0 No erythem
1 Very slight erythema (barely perceptible)
2 Well-defined erythema
3 Moderate to sever erythema
4 Severe erythema (beet redness)
Where signs of necrosis or corrosion (injuries in depth) prevent erythema scoring, the maximum grade for erythema (=4) is given.

Oedema formation:
0 No oedema
1 Very slight oedema (barely perceptible)
2 Slight oedema (edges of area well-defined by definite raising)
3 Moderate oedema (raised approximately 1 millimeter)
4 Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure)
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
312 (sentinel)
Time point:
other: 1 hr
Score:
1
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
312 (sentinel)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
338
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: After 1 hour the same observations were made.
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
348
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: After 1 hour the same observations were made.
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
312 (sentinel)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: After 1 hour the same observations were made.
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
338
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: After 1 hour the same observations were made.
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
348
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: After 1 hour the same observations were made.
Irritant / corrosive response data:
-Irritation: at 4 h exposure to 0.5 g of HC1161 resulted in very slight erythema in treated skin-area of 1/4 rabbit, which had resolved within 24 hours after exposure (see Remarks on results").
-Corrosion: There was no evidence of a corrosive effect on the skin.
Other effects:
-Colouration: No staining of the treated skin by the test substance was observed.
-Toxicity/Mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occured.

Table: Individual Skin Irritation Scores

Animal #

312 (sentinel)

338

348

Time after exposure

Erythema

Oedema

comments

Erythema

Oedema

comments

Erythema

Oedema

comments

1 hour

1

0

-

0

0

-

0

0

-

24 hours

0

0

-

0

0

-

0

0

-

48 hours

0

0

-

0

0

-

0

0

-

72 hours

0

0

-

0

0

-

0

0

-

 

Interpretation of results:
not irritating
Remarks:
Migrated information 1 rabbit reversible (within 24 h) slight irritation (after 4 h exposure) Criteria used for interpretation of results: other: EU GHS
Conclusions:
According to EC criteria for classification and labelling the HC1161 does not have to be classified and has no obligatory labelling requirement for skin irritation.
Executive summary:

The study was conducted in compliance with the OECD Guideline 404 and GLP.

The objective of this primary skin irritation study was to assess the irritation potential of a single dose of the test substance administered to the intact skin of rabbits.

Three rabbits were exposed to 0.5 gramm of HC1161, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observation were made 1, 24, 48 and 72 hours after axposure.

No skin irritation was observed after exposure. The test material is not irriating to the skin.

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:
1961
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable data which meets basic scientific principles, with acceptable restrictions (purity of the test substance not specified)
Qualifier:
according to
Guideline:
other: BASF Test comparable to OECD Guideline 405
Principles of method if other than guideline:
BASF-Test. 50 µL of the test substance were applied to the conjunctival sac of one eye in 2 animals. The animals were observed after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405.
GLP compliance:
no
Remarks:
The study was performed prior to the adoption of the GLP requirements
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
Body weight at test initiation: 2.46 and 3.2 kg, respectively
Vehicle:
unchanged (no vehicle)
Controls:
other: physiological saline was applied to the left eye, which served for control
Amount / concentration applied:
Amount applied: 0.05 mL
Duration of treatment / exposure:
unspecified (eyes were not washed)
Observation period (in vivo):
until complete reversibility of the effects was observed: 6 d (animal 1)/7 d (animal 2)
Number of animals or in vitro replicates:
2
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): not washed

SCORING SYSTEM: Draize (The original findings for both animals (referred to as 1 and 2) were converted into a numerical scoring system according to Draize)

TOOL USED TO ASSESS SCORE: fluorescein (at the final reading)
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24-72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: based on effects in two animals
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24-72 h
Score:
0
Max. score:
0
Reversibility:
other: no effects
Remarks on result:
other: based on effects in two animals
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: no effects
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: no effects
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24-72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: based on effects in two animals
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
24 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
48 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
swelling
Basis:
mean
Time point:
other: 24-72 h
Score:
0
Max. score:
0
Reversibility:
other: no effects
Remarks on result:
other: based on effects in two animals
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: no effects
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: no effects

Reading animal  cornea      iris  conjunctivae
         No.   opacity           redness  swelling
24 h    1 2 0 1 0
24 h    2 2 0 2 0
48 h    1 2 0 1 0
48 h    2 2 0 1 0
72 h    1 2 0 0 0
72 h    2 2 0 0 0
6 d     1 0 0 0 0
6 d     2 2 0 0 0
7 d     2 0 0 0 0
relevant for classification:          
mean    1 2 0 0.7 0
24-72h  2 2 0 1 0
         mean  2 0 0.8 0
Interpretation of results:
other: Cat 2 based on corneal opacity score of 2 in 2 animals.
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
2-pyrrolidone is considered to be irritating to the rabbit eyes (Category II).
Executive summary:

In the present eye irritation test, 2-pyrrolidone produced alterations at the cornea and conjunctivae. The iris was not affected. The observable effects were fully reversible until the end of the study.

Based on corneal opacity (24-72h score is 2 across 2 test animals), 2-pyrrolidone isclassified for its eye irritation potential as follows: Xi, R36: irritating to eyes (according to the criteria of Directive 2001/59/EC) and irritating to eyes Cat.2 (EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulations No. 1271/2008).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

In a GLP- and OECD-compliant irritation study, undiluted 2 -pyrrolidone at single dose was applied occlusive to the rabbits skin. No erythema or oedema were observed after 24, 48 and 72 hours after exposure (Notox B.V., 2003). No signs of systemic toxicity were observed in the animals during the study. The test material is considered to be not irritating if applied to the skin.

A Draize test was performed with six White Vienna rabbits (BASF AG 1981). A 24-hour occlusive exposure to 0.5 g of the unchanged test substance produced reversible minor erythema and no edema (overall erythema score of 1.06 for the readings 24, 48 and 72 h) and scaling in 2/6 animals persisting to the final reading on day 8.

In a second report, two rabbits were exposed to the unchanged test substance for 20 h under occlusive conditions (BASF AG 1961). Slight erythema (overall erythema score of 1.00 for the readings 24, 48 and 72 h) were reversible at least within 8 days, edema were not observed, while scaling was reported for the final reading on day 8.

Both results should be considered as overpredictive due to the harsh test conditions if compared to actual guideline recommendations (4 h under semiocclusive conditions).

Eye irritation

In the BASF eye irritation study (BASF, 1961), only two test animals were used. The mean corneal opacity score (24 -72h) was 2. The test material induced also conjunctivae alterations. The irirs was not affected. The observable effects were fully reversible until the end of the study.

Respiratory system

No data available

Justification for classification or non-classification

Skin irritation

Classification is not warranted according to the criteria of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008.

Eye irritation

Based on corneal opacity (24-72h score is 2 across 2 test animals), 2-pyrrolidone is classified for its eye irritation potential as follows: irritating to eyes Cat.2 (EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulations No. 1271/2008).

Respiratory system

Actually, there is no indication given for a classification according to this endpoint.