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Administrative data

Description of key information

Skin irritation/corrosion: Not irritating.
Eye irritation/corrosion: Severely irritating to the eye (67/548/EEC: R41; CLP 1272/2008; Serious eye damage Cat. 1)

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:
October 1-4, 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (GLP)
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Broekman Institute, Someren, The Netherlands
- Age at study initiation: Approx . 17 weeks
- Weight at study initiation: 2677 - 3077 g
- Housing: single housing in cages with perforated floors and equipped with an automatic drinking system (ITL, Bergen, The Netherlands)
- Diet: Standard laboratory rabbit diet (LKK-20, pellet diameter 4mm, Hope Farms, Woerden, The Netherlands) approx. 100 g/day.
- Water: Tap-water diluted with decalcified water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C (fluctuations were noted, but were considered not to have affected study integrity)
- Humidity (%): 55% (fluctuations were noted, but were considered not to have affected study integrity)
- Air changes (per hr): 15
- 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:
TEST MATERIAL
- Amount applied (volume or weight with unit): 0.5 ml
- Concentration: undiluted
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3 females
Details on study design:
TEST SITE
- Area of exposure: intact and ahved skin of the dorsal flank
- Type of wrap if used: Surgical gauze patch 2x3 cm mounted on Micropore tape (3M, St. Paul, USA); the dressing was wrapped around the abdomen and secured with an elastic bandage (Coban, 3M, St. Paul, USA)

REMOVAL OF TEST SUBSTANCE
- Washing: Remaining test substance was removed using a tissue moistened with tap-water and subsequently a dry tissue
- Time after start of exposure: 4 hours

SCORING SYSTEM:

ERYTHEMA AND ESCHAR 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)

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 mm)
4: Severe oedema (raised more than 1 mm and extending beyond area of exposure)

The test results were evaluated according to the EEC criteria for general classification and labelling requirements for dangerous substances and preparations (EEC Directive 91/325/EEC, Amendment to Annex VI of the Directive 67/548/EEC).
A primary irritation index (PII) was calculated by combining the average skin irritation scores for erythema and oedema after 24 and 72 hours. Using the following primary irritation index scheme, the degree of irritation can be obtained (Draize, JH, Woodard, G and Calvery, HO (1944)):

PII 0: non-irritating
PII 0.1 - 2.0: mildly irritating
PII 2.1 - 5.0: moderately irritating
PII 5.1 - 8.0: severely irritating

Note: Where the scoring procedure and the clinical judgement were not in agreement, the assessment of irritancy was based on the latter.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
0.4
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritant / corrosive response data:
The observed skin irritation consisted of very slight erythema and very slight oedema in all three animals. The skin irritation had resolved within 48 hours after exposure in two animals and within 72 hours in the third animal. There was no evidence of a corrosive effect on the skin.
Other effects:
No staining of the treated skin by the test substance was observed. No symptoms of systemic toxicity were observed in the animals during the test
period and no mortality occurred.

 Calculatiuons for EEC classification:

Reading Erythema/Edema in animal No.

1

2

3

24 h

1/1

1/0

1/1

48 h

0/0

0/0

1/0

72 h

0/0

0/0

0/0

mean

0.3/0.3

0.3/0

0.7/0.3

 

Interpretation of results:
not irritating
Remarks:
Migrated information EEC and GHS criteria
Conclusions:
The test substance is not irritating.
Executive summary:

The study was carried out in accordance with OECD Guideline 404 under GLP conditions.

The test substance was applied onto shaved skin of three female New Zealand White rabbits using semi-occlusive dressings for 4 hours, followed by four observations at approximately 1, 24, 48 and 72 hours after removal of the dressings and remaining test substance. Under the conditions of this study, the test substance resulted in slight erythema and slight oedema. The skin irritation had resolved within 48 to 72 hours after exposure in the three animals. No corrosive effect occurred on the skin in all three rabbits. In the area of application, no staining of the treated skin by the test substance was observed. No signs of systemic intoxication were observed during the study period.

Conclusions: The test substance is not irritating.

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:
October 7-21, 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (GLP)
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Broekman Institute, Someren, The Netherlands
- Age at study initiation: Approx. 12 weeks
- Weight at study initiation: 2561 - 2923 grams
- Housing: Individually in labelled cages with perforated floors and equipped with an automatic drinking system (ITL, Bergen, The Netherlands)
- Diet: Standard laboratory rabbit diet (LKK-20, pellet diameter 4 mm, Hope Farms, Woerden, The Netherlands) approx. 100 g per day
- Water: Tap-water diluted with decalcified water ad libitum
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C (Fluctuations were noted, but were considered not to have affected study integrity)
- Humidity (%): 55% (Fluctuations were noted, but were considered not to have affected study integrity)
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 / 12
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount applied (volume or weight with unit): 0.1 ml
- Concentration: undiluted
Duration of treatment / exposure:
unspecified
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
3 females
Details on study design:
NO REMOVAL OF TEST SUBSTANCE

SCORING SYSTEM:
Cornea
Opacity: degree of density (most dense area taken for reading)
0: No ulceration or opacity
1: Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris clearly visible
2: Easily discernible translucent area; details of iris slightly obscured
3: Nacrous area; no details of iris visible; size of pupil barely discernible
4: Opaque cornea; iris not discernible through the opacity

Iris
0: Normal
1: Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia; or injection; iris reactive to light (a sluggish reaction is considered to be an effect)
2: Hemorrhage, gross destruction, or no reaction to light

Conjunctivae
Redness (refers to palpebral and bulbar conjunctivae; excluding cornea and iris)
0: Normal
1: Some blood vessels hyperaemic (injected)
2: Diffuse, crimson colour; individual vessels not easily discernible
3: Diffuse beefy red

Chemosis
Swelling (refers to lids and/or nictating membranes)
0: Normal
1: Some swelling above normal
2: Obvious swelling, with partial eversion of lids
3: Swelling, with lids about half closed
4: Swelling, with lids more than half closed

Discharge
0: No discharge
1: Any amount different from normal (does not include small amounts observed in inner canthus of normal animals)
2: Discharge with moistening of the lids and hairs, just adjacent to lids
3: Discharge with moistening of the lids and hairs, in a considerable area around the eye

A Draize score was calculated for each day of observation, using the following formula (Draize et al., J. Pharmacol. Exp. Ther. 82, 1944):
(5x corneal opacity grade x area of opacity grade) + (5x iridial injury grade) + 2x (conjunctival redness grade + chemosis grade + discharge grade)

From the calculated maximum Draize score, a Kay and Calandra interpretation (J. Society of Cosmetic Chemists, Vol. 13 no. 6, 1962) was obtained, using the tables below. As can be seen in the second table, the Kay and Calandra interpretation takes into account the time required for the healing process.
0 - 0.5: Non-irritating (N)
0.5 - 2.5: Practically non-irritating (PN)
2.5 - 15: Minimally irritating (M1)
15 - 25: Mildly irritating (M2)
25 - 50: Moderately irritating (M3)
50 - 80: Severely irritating (S)
80 - 100: Extremely irritating (E)
100 - 110: Maximally irritating (Mx)
For borderline scores choose the higher rating.

Tentative Rating & Requirement for Maintenance:
N: MTS24 = 0; for MTS24 > 0, raise one level.
PN: As for N.
M1: MTS48 = 0; for MTS48 > 0, raise one level.
M2: MTS96 = 0; for MTS96 > 0, raise one level.
M3: (1) MTSf < 20 ; for MTSf > 20, raise one level, (2) ITSf < 10 (60%); if not true then no rabbit may show ITSf > 30; otherwise raise one level.
S: (1) As for M3 except use MTSf < 40, (2) As for M3 except use ITSf < 30 (60%) and 60 for high.
E: (1) As for M3 except use MTSf < 80, (2) As for M3 except use ITSf < 60 (60%) and 100 for high.
Mx: (1) MTSf > 80 (60%); for MTSf < 80, lower one level, (2) ITSf > 60 (60%); otherwise lower one level.
Symbols: MTS = Mean total score, ITS = Individual rabbit score. Subscripts denote scoring interval : 24, 48 or 96 hrs., f=final score (7 days).

TOOL USED TO ASSESS SCORE: hand-slit lamp & fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks:
within 21 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks:
within 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks:
within 21 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
2.7
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
2.3
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
2.7
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritant / corrosive response data:
Cornea, iris and conjunctivae affected. The injection of the iris had resolved within 7 days in all three animals. The opacity of the cornea and the irritation of the conjunctivae however, had not resolved within the study period (22 days). Grey/white discolouration of the conjunctivae as signs of necrosis was observed in all three animals during the study. Signs of necrosis were still noted on the nictating membrane in animals 3541 and 3542 on day 22. Pannus (neovascularisation of the cornea), corneal opacity (grade 2; animal 3540, grade 1; animals 3541 and 3542) and conjunctival redness and swelling were noted in all three animals on day 22. Corneal opacity was observed throughout the study and no significant decrease was noted on day 22, compared to the observations made earlier in the study. Treatment of the eyes with 2% fluorescein, 24 and 72 hours and 7, 14 and 22 days after test substance instillation revealed corneal epithelial damage in all of the animals. A slow rate of corneal epithelial healing was noted.
Other effects:
No staining of peri-ocular tissues by the test substance was observed. No toxic symptoms were observed in the animals during the test period and no mortality occurred.

 Calculations for EEC classification:

Animal No.

Reading time (h)

Corneal opacity

Iris lesion

Conjunctivae

Redness

Chemosis

3540 (1)

24

1

1

3

3

48

1

1

3

2

72

1

1

3

2

mean

1

1

3

2.3

3541 (2)

24

1

1

3

3

48

1

1

3

3

72

1

1

3

2

mean

1

1

3

2.7

3542 (3)

24

1

1

3

3

48

1

1

3

3

72

1

1

3

3

mean

1

1

3

3

Draize scores: 

Time after administration

1 h

24 h

48 h

72 h

7 d

14 d

21 d

Mean total score

22.3

34

42.3

41

38

25.3

27

 

Interpretation of results:
highly irritating
Remarks:
Migrated information Classification: risk of serious damage to eyes
Conclusions:
The test substance is severely irritating to the rabbit eye.
Executive summary:

The study was carried out in accordance with OECD Guideline 405 under GLP conditions.

The undiluted test substance (0.1 ml) was instilled into one eye of each of three female New Zealand White rabbits, followed by seven observations at approximately 1, 24, 48 and 72 hours and 7, 14 and 21 days after test substance administration. Under the conditions of this study, the test substance resulted in adverse effects on the cornea, iris and the conjunctivae. The injection of the iris had resolved within 7 days after instillation, but neither the opacity of the cornea nor the irritation of the conjunctivae had resolved within the study period in the three animals. Signs of necrosis on the conjunctivae were observed in all three animals and were still noted in two animals on day 22. The corneal opacity had been persistent throughout the study and had not decreased significantly on day 22. Neovascularisation of the cornea was noted in all three animal from day 8 onwards. No signs of systemic intoxication were observed during the study period.

Based on the Kay and Calandra interpretation of the calculated maximum Draize score (42.3), the test substance should be considered severely irritating (S) to the rabbit eye. The corneal opacity grades and persistency of the opacities to day 22 were considered to be corrosive effects caused by the test substance.

Conclusions: The test substance is severely irritating to the rabbit eye.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation:

In the key study according to OECD Guideline 404 undiluted N-Vinylformamide was not irritating to the skin of rabbits, when applied for 4 hours under semiocclusive conditions (Air Products and Chemicals, Inc. 1992). The observed skin findings consisted of very slight erythema and very slight oedema (grade 1 of Draize scoring system) in all three animals. The skin irritation had resolved within 48 hours after exposure in two animals and within 72 hours in the third animal. There was no evidence of a corrosive effect on the skin. No signs of systemic intoxication were observed during the study period.

In another study under occlusive conditions where the test substance remained in contact with the rabbit skin for 24 hours, i.e. under over-predictive conditions, no dermal irritation was observed at any test site during the study period (Air Products and Chemicals, Inc. 1989).

A third study is not reliable because it was performed with a batch of test substance, which caused extremely high toxic effects in a test for acute dermal toxicity (BASF AG, 1981). These effects were possibly caused by impurities of the test substance (formamide). Therefore, the results of the test substance in this study (5 of 6 animals died) have to be handled with care.

In conclusion, N-Vinylformamide was assessed to be not irritating to the skin.

Eye irritation:

In a study according to OECD Guideline 405, the instillation of 0.1 ml undiluted N-Vinylformamide into one eye of each of three female New Zealand White rabbits resulted in adverse effects on the cornea, iris and the conjunctivae. The injection of the iris had resolved within 7 days after instillation, but neither the opacity of the cornea nor the irritation of the conjunctivae had resolved within the 3-week study period. Signs of necrosis on the conjunctivae were observed in all three animals and were still noted in two animals on day 22. The corneal opacity had been persistent throughout the study and had not decreased significantly on day 22. Neovascularisation of the cornea was noted in all three animal from day 8 onwards. No signs of systemic intoxication were observed during the study period (Air Products and Chemicals Pura GmbH & Co. 1992).

This result is supported by an older Air Products and Chemicals, Inc. report. Instillation of 0.1 ml of the undliluted test substance into

one eye of each of three male and three female rabbits led to corneal, iridal and conjunctival irritations that were observed in all rabbits from hour 1 and persisted to day 7 in males and day 21 in females (Air Products and Chemicals, Inc. 1989).

A third eye irritation study in rabbits is not reliable because it was performed with a batch of test substance, which caused extremely high toxic effects in a test for acute dermal toxicity (BASF AG, 1981). These effects were possibly caused by impurities of the test substance (formamide). Therefore, the results of the test substance in this study have to be handled with care.

Based on the presented information it was concluded that N-Vinylformamide is severely irritating to the eye.

Respiratory irritation:

There exists no standard test method for the assessment of respiratory irritation. In a subchronic repeated dose inhalation study with rats, the high concentration (250 mg/m³ = 86 ppm) caused some clinical irritation of the upper respiratory tract in male animals with mild changes in the nasal cavity as histopathological correlate (BASF AG 1995). These findings were fully reversible within 5 days and no further irritation potential of N-Vinylformamide was observed.

Based on these data, there is no evidence that N-Ninylformamide causes respiratory irritation following repeated inhalation exposure.


Effects on eye irritation: highly irritating

Justification for classification or non-classification

GHS classification according to Annex I 1272/2008 CLP (EU GHS):

- Skin corrosion/irritation: No classification required

- Serious eye damage/eye irritation: Category 1

- Specific target organ toxicity, single exposure: No classification required