Poly(oxy-1,2-ethanediyl), α-[2-(dide- cylmethylammonio)ethyl]- .omega.- hydroxy-, propanoate (salt) (Bardap 26)

Endpoint summary

Description of key information

Data indicate that the substance is corrosive to skin and a severe eye irritant.

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:

July - September 1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

Principles of method if other than guideline:

Not applicable.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

The animals were 3-5 month old New Zealand White rabbits obtained from Hoechst AG, Kastengrund, Germany. The rabbits weighed 2.2-3.6 kg. The animals were housed individually, temperature was maintained at 20 ± 3°C and relative humidity was maintained at 50 ± 20% with a 12 hour light/dark cycle. The rabbits were fed Altromin 2123 Haltungsdiat - Kaninchen ad libitum, and provided with deionised chlorinated water ad libitum.

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.5 ml undiluted test substance/site

Duration of treatment / exposure:

3 minutes, 1 hour and 4 hours

Observation period:

14 days

Number of animals:

3 per exposure period

Details on study design:

On the day prior to administration, the dorsal area and the trunk of each animal was clipped free of fur. Only animals with intact skin were selected for the test.
On the day of dosing, a wound plaster with a 2.5 x 2.5 cm pulp patch (Beiersdorf AG, Hamburg) was fixed on the prepared skin site of each animal. 0.5 ml of the undiluted test substance was administered under the plaster. For animals with 1- and 4-hour exposures the test area was covered with a semi-occlusive bandage. The exposure period was 3 minutes, 1 hour or 4 hours. Residual test material was gently removed from the test sites with lukewarm water.
Skin reactions were recorded 30-60 minutes, 24, 48 and 72 hours after removal of the dressings, and at 7 and 14 days. Reactions were scored according to the scoring system set out in OECD 404. Rabbits were observed for mortality daily.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2.22

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: 3 minute exposure

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: 3 minute exposure

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

3.56

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: 1 hour exposure

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.56

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

other: 1 hour exposure

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: 4 hour exposure

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

other: 4 hour exposure

Irritant / corrosive response data:

Very slight to moderate erythema and barely perceptible to slight oedema was observed following the 3-minute exposure, persisting for up to 7 days. 14 days after patch removal the skin showed very slight, barely perceptible erythema. The test site was observed to be dry, chapped and discoloured light brown. One animal had hardened skin 72 hours after patch removal, and 7 days after patch removal fine and rough desquamation partially occurred.
Moderate to severe erythema was observed up to 7 days after exposure for 1 hour. Barely perceptible to slight oedema was observed up to 24 hours after the 1 hour exposure. In addition, the skin was discoloured light brown, hardened and arched. Rough desquamation was observed from day 7 onwards. Eschar formation was observed in 2 animals after termination, and swelling of the treated skin was observed in one animal.
Following 4 hours exposure, the skin showed well defined to moderate erythema and very slight to moderate oedema up to 72 hours after patch removal. Very slight, barely perceptible erythema and oedema were observed 7 days after patch removal. The test sites were hardened, discoloured red-brown and the patch site framed white. The skin showed well defined to severe erythema 14 days after patch removal. One animal showed a defined oedema; oedema formation could not be observed in the other 2 animals due to hardening of the test site skin. The skin was roughly and finely desquamated, hardened, arched and discoloured red-brown. One animal was observed to have an open wound, and eschar formation was observed in all animals.

Other effects:

No other effects reported.

Table 1. Mean skin irritation scores after 3 minutes of exposure

If 3 animals or less	^*Mean score animal number			Maximum value	Maximum duration of any effect	Maximum value at the end of the observation period
	1	2	3
erythema/eschar	2.33	2	2.33	3	14 days	1
oedema	1.33	0	1.67	2	7 days	0
^*calculated on the basis of the scores at 24, 48, 72 hours for each animal

 

Table 2. Mean skin irritation scores after 1 hour of exposure

If 3 animals or less	^*Mean score animal number			Maximum value	Maximum duration of any effect	Maximum value at the end of the observation period
	1	2	3
erythema/eschar	4	4	2.67	4	7 days	0
oedema	0.67	0.33	0.67	2	1 day	0
^*calculated on the basis of the scores at 24, 48, 72 hours for each animal

 

Table 3. Mean skin irritation scores after 4 hours of exposure

If 3 animals or less	^*Mean score animal number			Maximum value	Maximum duration of any effect	Maximum value at the end of the observation period
	1	2	3
erythema/eschar	2	2	2	4	14 days	4
oedema	1.67	1.67	1.67	3	14 days	2
^*calculated on the basis of the scores at 24, 48, 72 hours for each animal

Interpretation of results:

Category 1B (corrosive)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

It was concluded that the test substance is corrosive to rabbit skin after 1 and 4 hours exposure.

Executive summary:

The acute skin irritant potential of Bardap 26 was investigated in nine New Zealand White rabbits. The rabbits were given a single topical application of 0.5 ml undiluted test substance/site under a semiocclusive dressing for either 3 minutes, 1 hour or 4 hours (3 rabbits per exposure period). The rabbits were observed for up to 14 days post-application.

Moderate skin irritation was observed after 3 minutes of exposure. The test substance was corrosive after 1 and 4 hours of exposure with necrosis, desquamation and scars observed at 14 days after both exposure periods. It was concluded that the test substance is corrosive to rabbit skin following 1 and 4 hours exposure, and should therefore be classified as Corrosive Category 1B according to Regulation (EC) No. 1272.

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:

key study

Study period:

July 1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Principles of method if other than guideline:

Not applicable.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

The animals were 3-5 month old New Zealand White rabbits obtained from Hoechst AG, Kastengrund, Germany. The rabbits weighed 2.8-3.7 kg. The animals were housed individually, temperature was maintained at 20 ± 3°C and relative humidity was maintained at 50 ± 20% with a 12 hour light/dark cycle. The rabbits were fed Altromin 2123 Haltungsdiat - Kaninchen ad libitum, and provided with deionised chlorinated water ad libitum.
In-life date was 2 July 1985.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 ml undiluted test substance/eye

Duration of treatment / exposure:

Single instillation

Observation period (in vivo):

6 hours

Number of animals or in vitro replicates:

3

Details on study design:

24 hours prior to administration, the eyes were examined under a UV-light for potential damage of the cornea after instillation of a drop of sodium fluorescein solution (0.01%). Only animals with normal eyes were used for the study.
A single dose of 0.1 ml of test substance was instilled into the conjunctival sac of the left eye of 3 rabbits. The untreated eyes served as a control.
Eye reactions were evaluated at 1 and 6 hours post-instillation. The study was terminated at 6 hours due to the severity of the effects observed. Reactions were scored according to the system set out in EU Method B.5.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

probability of severe irritation

Remarks:

1 hour post-instillation

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

probability of severe irritation

Remarks:

6 hours post-instillation

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: a clear discharge was observed

Remarks:

1 hour post-instillation

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: a clear discharge was observed

Remarks:

6 hours post-instillation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Max. score:

2

Reversibility:

other: tent of conjunctival swelling

Remarks on result:

other: Effects on the iris could not be assessed due to the extent of conjunctival swelling

Remarks:

1 and 6 hours post-instillation

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Max. score:

3

Reversibility:

other: Conjunctival redness could not be assessed due to the extent of conjunctival swelling

Remarks on result:

other: Conjunctival redness could not be assessed due to the extent of conjunctival swelling

Remarks:

1 and 6 hours post-instillation

Irritant / corrosive response data:

At 1 and 6 hours post-instillation, the eyes were half closed due to swelling. Corneal opacities (grade 4), conjunctival swelling (grade 3 at 1 hour and grade 4 at 6 hours) and a clear discharge were seen in all animals. Effects on the iris and conjunctival redness could not be assessed because of the extent of the swelling.

Other effects:

No other effects reported.

Table 1. Individual eye irritation scores

Time after application	1 hour			6 hours
Animal No.	1	2	3	1	2	3
Chemosis	3	3	3	4	4	4
Redness	D	D	D	D	D	D
Iris	S	S	S	S	S	S
Opacity	4	4	4	4	4	4
Discharge
- clear	x	x	x	x	x	x
Conjunctivae
- discoloured white	x	x	x	x	x	x

D = evaluation impossible due to severe chemosis and white discolouration

S = evaluation impossible due to severe opacity

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

It was concluded that the test substance is severely irritating to rabbit eyes.

Executive summary:

The eye irritant potential of Bardap 26 was evaluated in 3 New Zealand White rabbits. The rabbits received a single intraocular application of 0.1 ml of the test substance, reactions were evaluated at 1 and 6 hours post-instillation.

At 1 and 6 hours post-instillation, the eyes were half closed, corneal opacity, conjunctival swelling (chemosis) and a clear discharge were seen in all rabbits. Swelling precluded assessment of the iris and conjunctival redness. It was concluded that the test substance is severely irritating to rabbit eyes, and meets the classification criteria for Irreversible Effects on the Eye (Category 1) according to Regulation (EC) No. 1272/2008. The substance is already classified as Skin Corrosion Category 1B with hazard statement H314: Causes severe skin burns and eye damage, therefore additional classification as Irreversible Effects on the Eye (Category 1) with hazard statement H318 is already covered.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Exposure to the test substance resulted in full skin thickness eschar in two out of three rabbits exposed for 4 hours (Merkel, 2001). Severe erythema, desquamation and corrosive eschar were observed in both rabbits until study termination (Day 14). The test substance was corrosive in three rabbits, following 1 and 4 hours dermal exposure with necrosis, desquamation and scars observed at 14 days (Hofmann and Weigand, 1985). Therefore the test substance is classified as corrosive to skin.

The test substance was also severely irritating to the eye (Hofmann and Hollander, 1985).

Justification for selection of skin irritation / corrosion endpoint:
Two high quality, guideline- and GLP-compliant studies are available for this endpoint. The study with the more severe effects is selected as key.

Justification for selection of eye irritation endpoint:
Only one study is available for this endpoint.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: irritating

Justification for classification or non-classification

Bardap 26 was found to be corrosive to skin, and severely irritating to the eye therefore the substance should be classified as Skin Corrosion Category 1B and Eye Damage Category 1 with corresponding hazard statements H314: Causes severe skin burns and eye damage and H318: Causes serious eye damage, according to Regulation (EC) No. 1272/2008.