N-(n-octyl)-2-pyrrolidinone

Endpoint summary

Description of key information

- corrosive to the skin (1992, OECD guideline 404) 
- severe damage to the eye (1986, method described by Draize; HET-CAM, 2006)

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Principles of method if other than guideline:

As the irritant/corrosive potential of the test substance was unknown one animal has been tested in a first step. As no severe skin damage has been noted in this animal, another two animals were tested. The results of the three animals were pooled for evaluation.

GLP compliance:

yes

Species:

rabbit

Strain:

Vienna White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Gaukler; D-W6050 Offenbach, FRG
- Age at study initiation: Young adult animais
- Weight at study initiation: 2.52-3.07 kg
- Housing: Single housing
- Diet: KLIBA Labordiät 341, 4 mm; Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland (about 130 g per animal per day)
- Water: About 250 ml tap water per animal per day
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

The test patch (2.5 cm x 2.5 cm) was moistened with a dose of 0.5 ml of the unchanged liquid test substance.

Duration of treatment / exposure:

4 hour(s)

Observation period:

15 days

Number of animals:

3

Details on study design:

The test substance was applied in a single dose to the intact untreated skin. The test patch was secured in position with a semiocclusive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Lutrol concentrated and Lutrol diluted 1:1 with warm water
- Time after start of exposure: 4 hours

SCORING SYSTEM: (according to the OECD Draize system)
Erythema formation:
0: No erythema
1: Very slight erythema (barely perceptible)
2: Well defined erythema
3: Moderate to severe erythema
4: Severe erythema (beet-redness) to slight, eschar formation (injuries in depth)

Edema formation:
0: No edema
1: Very slight edema (barely perceptible)
2: Slight edema (edges of area well defined by definite rising)
3: Moderate edema (raised approx. 1 mm)
4: Severe edema (raised more than 1 mm and extending beyond the area of exposure)

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 15 days

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 8 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

other: Animal was sacrificed ahead of schedule due to severe irritation / full thickness necrosis.

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

other: Animal was sacrificed ahead of schedule due to severe irritation / full thickness necrosis.

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.67

Max. score:

4

Reversibility:

fully reversible within: 15 days

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 8 days

Irritant / corrosive response data:

Haemorrhagia, spreading full-thickness necrosis (1 animal), scaling, highly superficial formation of eschar, spreading oedema.

 

Readings	Animal	Exposure period: 4 h
		Erythema	Edema	Additional findings
1 h	1	1	0
	2	2	2	HE+, ED+
	3	2	1	HE
24 h	1	3	1
	2	4	1	N+, ED+
	3	2	1	HE
48 h	1	3	1
	2	4	1	N+, ED+
	3	3	2	HE
72 h	1	3	1
	2	4	1	N+, *, ED+, SI
	3	3	2	HE
8 d	1	1	0	SS
	2	-	-
	3	2	0	HE, SU
15 d	1	0	0	S
	2	-	-
	3	0	0	SU
Mean 24, 48, 72 h	1	3	1
	2	4	1
	3	2.7	1.7
Mean 24, 48, 72 h	1-3	3.2	1.2

Calculation of the mean according to 83/467/E EC Criteria of July 29th, 1983 (for calculation of the means of erythema and edema only the readings of 24, 48 and 72 hours are used).

 

HE: hemorrhage

HE+: hemorrhage extending beyond the area of exposure

ED+: edema extending beyond the area of exposure

N+: visual necrosis extending beyond the area of exposure

S: Scaling

SS: severe scaling

SU: superficial scabbing

*: Pathological evaluation (Dr. Freisberg): full thickness necrosis

SI: study already discontinued because of severe irritation

Visual necrosis was observed in one animal 72 hours after application. Thus, the observation period for this animal was terminated. The necrotic change of the skin was assessed by macroscopic pathology indicating full thickness necrosis. Such necroses are relevant for classification representing a chemical being corrosive to the skin.

Interpretation of results:

Category 1B (corrosive) based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

From 12 to 23 June 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines

Qualifier:

according to guideline

Guideline:

other: modification of that described by J.H. Draize.

Deviations:

no

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: a suitable licensed dealer
- Age at study initiation: 3 months
- Weight at study initiation: approximately 2 kilograms
- Housing: housed in galvanized or stainless steel cages, in a temperature controlled room
- Diet (e.g. ad libitum): consisted of a growth and maintenance ration from a commercial producer. ad libitum
- Water (e.g. ad libitum): consisted of a growth and maintenance ration from a commercial producer. ad libitum
- Acclimation period: at least 3 days

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit):0.1ml

Duration of treatment / exposure:

the first six rabbits 24 hours, the remaining three 30 seconds

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

9

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done):with sufficient lukewarm water at room temperature
- Time after start of exposure:The eyes of the first six animals remained unwashed for 24 hours. The eyes of the remaining three rabbits were irrigated 30 seconds following instillation of the test article.

SCORING SYSTEM:Draize scale

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 1.56

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: After 21 days all animals has a score of 4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 0.83

Max. score:

1

Reversibility:

not reversible

Remarks on result:

other: The score of 1 persisited after 21 days in 5 of 6 animals.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 2.11

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: The score of 1 persisted after 21 days in 5 of 6 animals.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 3.17

Max. score:

4

Reversibility:

not fully reversible within: 21

Remarks on result:

other: Signs persisted after 21 days in 5 of 6 animals

Irritant / corrosive response data:

The results presented above relate to the 6 animals treated for 24 hours and exclude those exposure only for 30 seconds. Severe corneal opacity, iritis and conjunctivitis were observed.

Other effects:

Blanching, bloody discharge, fibrovascular connective tissue and nodular mass subjacent to meibomian gland were also evident throughout the observation period.

0.1mL, neat

Draize  Scores
Group	Hours			Days
	24	48	72	4	7	14	21
Unwashed	37.7	36.3	37.2	38.3	60.7	83.3	72.2
30” Wash	32.3	31.0	32.3	30.7	32.7	18.0	13.3

Interpretation of results:

Category 1 (irreversible effects on the eye)

Conclusions:

This test substance is a severe ocular irritant to rabbits under conditions of this test. The wash procedure reduced the severity of the irritation observed.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In vitro skin irritation studies do not need to be conducted because adequate data from in vivo skin irritation studies are available.

Skin irritation / corrosion

The potential of N-(n-Octyl)pyrrolidone to cause acute dermal irritation or corrosion was assessed by a single topical application of 0.5 ml to the intact skin of 3 White Vienna rabbits for 4 hours under semiocclusive dressing (1992: GLP, OECD guideline 404_RL1). The average score (24 to 72 hours) for irritation was calculated to be 3.2 for erythema and 1.2 for edema. Visual necrosis was observed in one animal 72 hours after application. The necrotic change of the skin was assessed by macroscopic pathology indicating full thickness necrosis. The skin findings of the other animals were reversible after 15 days. They only showed scaling or superficial scabbing. Under the test conditions chosen and considering the findings described above N-(n-Octyl)pyrrolidone gives indication for severe skin damage after an exposure period of 4 hours.

In one supporting study, a single topical administration of 0.5 ml to the intact rabbit skin for 3 min or 1 h under semioclusive dressing lead to irritation, but no necrosis was observerd (1992_RL1).

The other 4 supporting studies confirmed the findings for N-(n-Octyl)pyrrolidone: In a skin corrosion study run according to DOT requirements (1986_RL1), the substance was administered neat to unabraded skin for 4 hours and clear signs of corrosion were shown in all animals. In another skin irritation study (1986_RL1), the substance was administered neat to both abraded and unabraded skin for 24 hours. The substance was clearly a dermal irritant and showed signs indicating skin corrosion. In a comodogenic assay (1986_RL1), a 2% suspension of the substance in water was administered 5 days/week for 4 weeks and resulted in dermal irritation being observed. In a dermal irritation study (1988_RL2), the substance was administered as a 2% suspension in water to unabraded skin for 24 hours.The substance was not dermally irritating. This study indicates that at concentrations of up to 2% the substance is not an irritant.

Eye irritation

The potential of the test substance N-(n-Octyl)pyrrolidone to cause serious damage was assessed in an occular irritation study (1986_RL1). The substance was administered neat to 6 animals for 24 hours and a further 3 animals for 30 seconds. The animals exposed for 24 hours had observations related to corneal opacity, iritis and conjunctiva which persisted in at least 5 of 6 animals after 21 days, demonstrating potential for severe ocular irritation.

In a supporting occular irritation study (1986_RL1), a 2% aqueous suspension of the substance was administered neat to 6 animals for 24 hours and a further 3 animals for 30 seconds. No animals exhibited signs of irritation, indicating the substance is not irritating to eyes at concentrations of up to 2%.

Furthermore, there is an in vitro test available (HET-CAM, 2006_RL1) showing that the test substance causes serious eye damage.

Justification for classification or non-classification

The data justify a classification as Eye Dam 1,H318 and Skin Corr 1C, H314. However, according to Annex VI of EC/1272/2008, the test substance is to be classified as Skin Corr 1B; H314 (EU-GHS).

According to the ECHA Guidance für CLP Criteria, section 3.1.4.2., labelling NOP additionally with EUH071 may be appropriate due to its skin corrosivity and the possibility of exposure to aerosols, although there are no acute inhalation data for NOP and its vapour pressure is low (0.08 Pa).