Registration Dossier

Based on the availabla data, Ethyl 4-dimethylaminobenzoate is not skin or eye irritating.

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 July 1987 to 24 July 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

not precised

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

not precised

Deviations:

no

GLP compliance:

not specified

Remarks:

The study was conducted in accordance with quality assurance procedures.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 10 to 13 weeks
- Weight at study initiation: 2.2 to 3.0 kg
- Housing: individually housed in metal cages with perforated floors
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Yes; the report states that all rabbits were acclimated to the laboratory environment

ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 19 °C
- Humidity: 30 to 70 % (relative)
- Air changes: Approximately 19 per hour
- Photoperiod:12 hours of artificial light in each 24 hour period (from 07.00 to 19.00 hours)

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 0.5 g moistened with 0.5 mL distilled water

Duration of treatment / exposure:

4 hours

Observation period:

4 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: Dorso-lumbar region. Approximately 24 hours prior to application of the test substance, hair was removed with electric clippers exposing an area of skin approximately 10 cm square.
- Coverage: 2.5 cm square; the test material was applied under a 2.5 cm square gauze pad
- Type of wrap if used: The test site was occluded with elastic adhesive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the exposure period, the semi-occlusive dressing and gauze pad were removed and the treatment site washed with water
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
- Examinations: Days 1 (30 minutes after patch removal), 2, 3 and 4

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 the area well defined by definite raising)
3 = Moderate oedema (area raised approximately 1 mm)
4 = Severe oedema (area raised more than 1 mm and extending beyond the area of exposure)

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

There was no response to treatment in any of the animals throughout the observation period. All scores for erythema and oedema were 0 for all animals at all time points.

Interpretation of results:

GHS criteria not met

Remarks:

Not skin irritating

Conclusions:

Under the conditions of this study the test material was determined to be non-irritating to the skin.

Executive summary:

A study was performed to investigate the potential of the test material to cause skin irritation in accordance with the standardised guidelines OECD 404 and EU Method B.4.

Three New Zealand White rabbits were exposed to the test material in a semi-occlusive manner for 4 hours. The hair was clipped to expose skin on the dorso-lumbar region and 0.5 g of the test material was applied under a 2.5 cm² gauze pad, moistened with 0.5 mL of distilled water. The gauze pads were secured with an elastic adhesive dressing for a four-hour exposure period. After the four-hour exposure, the wraps were removed and the test sites were washed with water to remove any residual test material. The test sites were examined for dermal irritation at approximately 30 minutes and at 24, 48 and 72 hours following removal of the patches.

There were no signs of erythema or oedema during the course of the study. The mean erythema and oedema scores were 0.0 and 0.0, respectively. All rabbits scored 0 for both erythema and oedema at each evaluation.

Under the conditions of this study the test material was determined to be non-irritating to the skin.

Endpoint conclusion:

no adverse effect observed (not irritating)

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 August 1987 to 17 August 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

not precised

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

not precised

Deviations:

no

GLP compliance:

not specified

Remarks:

The study was conducted in accordance with quality assurance procedures.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: 10 to 13 weeks
- Weight at study initiation: 2.3 to 3.0 kg
- Housing: Rabbits were individually housed in metal cages with perforated floors
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Yes; the report states that all rabbits were acclimated to the laboratory environment

ENVIRONMENTAL CONDITIONS
- Temperature: Approximately 19 °C
- Humidity: 30 to 70 % (relative)
- Air changes: Approximately 19 per hour
- Photoperiod: 12 hours of artificial light (07.00- 19.00) in each 24 hour period

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent negative control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 33 mg (occupying a volume of 0.1 mL)

Duration of treatment / exposure:

After the test material was placed into the eye, the eyelids were gently held together for one second before releasing.

Observation period (in vivo):

7 days
Examination of the eyes was carried out 1 hour and 1, 2, 3, 4 and 7 days after installation.

Number of animals or in vitro replicates:

3 animals

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Eyes were not washed

SCORING SYSTEM: Grading and scoring of the ocular lesions were performed using the prescribed numerical scoring system as follows:

- Cornea (opacity; degree of density (area most dense taken for reading))
0 = No ulcerations 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 areas, details of iris slightly obscured*
3 = Nacreous areas, no details of iris visible, size of pupils 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, any of these or a combination of any thereof, iris still reacting to light (sluggish reaction is positive)*
2 = No reaction to light, haemorrhage, gross destruction (any or all of these)*

- Redness (refers to palpebral and bulbar conjunctivae cornea and iris)
0 = Blood vessels normal
1 = Some blood vessels definitely hyperaemic (injected)
2 = Diffuse, crimson colour, individual vessels not easily discernible*
3 = Diffuse, beefy red *

- Chemosis (lids and/or nictitating membranes)
0 = No swelling
1 = Any swelling above normal (includes nictitating membranes)
2 = Obvious swelling with partial eversion of lids*
3 = Swelling with lids about half-closed*
4 = Swelling with lids more than half-closed*

* Interpreted as a positive effect

TOOL USED TO ASSESS SCORE: A handheld torch was used to aid observations

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.11

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritant / corrosive response data:

No corneal damage or iridial inflammation was observed in any of the animals. Obvious swelling with partial eversion of the eyelids was seen in one animal one hour after instillation only. Transient, mild conjunctival irritation was seen in the two remaining animals. The eyes were normal two days after instillation.
The numerical scores awarded to the ocular reactions elicited by the test material can be seen in Table 1.

Table 1: Ocular reactions elicited by the test material

Rabbit number and sex	Region of eye		One hour	Day after instillation
Rabbit number and sex	Region of eye		One hour	1	2	3	4	7
587 Male	Cornea		0	0	0	0	0	0
	Iris		0	0	0	0	0	0
	Conjunctivae	Redness	1	1	0	0	0	0
	Conjunctivae	Chemosis	1	0	0	0	0	0
608 Male	Cornea		0	0	0	0	0	0
	Iris		0	0	0	0	0	0
	Conjunctivae	Redness	1	1	0	0	0	0
	Conjunctivae	Chemosis	2	1	0	0	0	0
610 Male	Cornea		0	0	0	0	0	0
	Iris		0	0	0	0	0	0
	Conjunctivae	Redness	1	1	0	0	0	0
	Conjunctivae	Chemosis	1	0	0	0	0	0

Interpretation of results:

GHS criteria not met

Remarks:

Not eye irritating

Conclusions:

Under the conditions of this study, the test material has been determined to be not irritating to the eye.

Executive summary:

A study was conducted to investigate the potential of the test material to cause eye irritation in accordance with the standardised guidelines OECD 405 and EU Test Method B.5.

Three male albino rabbits (New Zealand White strain) were treated with the instillation of 33 mg of the test material, equivalent to a volume of 0.1 mL, into the lower everted lid of one eye. The eyelids were held together for one second before releasing; the contralateral eye remained untreated and served as a control. Eyes of the test animals were examined after 1 hour and 1, 2, 3, 4 and 7 days post treatment.

No corneal damage or iridial inflammation was observed in any of the animals. Obvious swelling with partial eversion of the eyelids was seen in one animal one hour after instillation only. Transient, mild conjunctival irritation was seen in the two remaining animals. The eyes were normal two days after instillation.

The overall mean scores for the three animals from the 24, 48 and 72 hour observations for the cornea, iris, redness and chemosis parameters were 0, 0, 0.33 and 0.11, respectively.

Under the conditions of this study, the test material has been determined to be not irritating.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin Irritation

The key study was performed to investigate the potential of the test material to cause skin irritation in accordance with the standardised guidelines OECD 404 and EU Method B.4. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Three New Zealand White rabbits were exposed to the test material in a semi-occlusive manner for 4 hours. The hair was clipped to expose skin on the dorso-lumbar region and 0.5 g of the test material was applied under a 2.5 cm² gauze pad, moistened with 0.5 mL of distilled water. The gauze pads were secured with an elastic adhesive dressing for a four-hour exposure period. After the four-hour exposure, the wraps were removed and the test sites were washed with water to remove any residual test material. The test sites were examined for dermal irritation at approximately 30 minutes and at 24, 48 and 72 hours following removal of the patches.

There were no signs of erythema or oedema during the course of the study. The mean erythema and oedema scores were 0.0 and 0.0, respectively. All rabbits scored 0 for both erythema and oedema at each evaluation.

Under the conditions of this study the test material was determined to be non-irritating to the skin.

In a supporting study, the potential of the test material to cause skin irritation was investigated using three different batches of the test material on 10 human volunteers. Three batches of the test material were investigated. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

An occlusive application of 0.2 g of the test material in its pure form was applied to the upper outer left arm of the test participants for a 23 hour period. After this period the patch was removed, the area was washed with water and 1 hour later was observed for any reactions regarding erythema and dryness. An identical patch was then applied to the area for a further period of 23 hours and skin reactions were once again assessed 1 hour after patch removal. .

The overall mean irritation scores (erythema and dryness) for the three batches of material were 0.15, 0.30 and 0.15. Skin sensations were noted in one or two of the volunteers but very little irritation was caused by the patches.

Under the conditions of this study the test material was determined to be non-irritating to the skin.

Eye Irritation

A study was conducted to investigate the potential of the test material to cause eye irritation in accordance with the standardised guidelines OECD 405 and EU Test Method B.5. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

Three male albino rabbits (New Zealand White strain) were treated with the instillation of 33 mg of the test material, equivalent to a volume of 0.1 mL, into the lower everted lid of one eye. The eyelids were held together for one second before releasing; the contralateral eye remained untreated and served as a control. Eyes of the test animals were examined after 1 hour and 1, 2, 3, 4 and 7 days post treatment.

No corneal damage or iridial inflammation was observed in any of the animals. Obvious swelling with partial eversion of the eyelids was seen in one animal one hour after instillation only. Transient, mild conjunctival irritation was seen in the two remaining animals. The eyes were normal two days after instillation.

The overall mean scores for the three animals from the 24, 48 and 72 hour observations for the cornea, iris, redness and chemosis parameters were 0, 0, 0.33 and 0.11, respectively.

Under the conditions of this study, the test material has been determined to be not irritating.

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the substance does not require classification with respect to irritation or corrosion to the skin and eye.