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Administrative data

Description of key information

2 guideline, reliability 1 studies are available for skin and eye irritation. a disregarded eye and skin irritation study is also available but not considered.
No data are available for respiratory inhalation.
Supporting data from the read across analogue phenoxy ethanol are available for reference only.

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:
May 30, 2008 - February 20, 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to OECD TG 404 and in accordance with the principles of GLP.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
U.S. EPA Health Effects Test Guidelines, OPPTS 870.2500 (1998), JMAFF 12-Nouan-8147, November 2000, Official Journal of the European Communities. Methods for the Determination of Toxicity, Part B.4 (Skin Irritation), Directive 2004/73/EC, 29 April 2004.
Deviations:
no
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: Toxicology, Department of Safety Assessment, Advinus Therapeutics Private Limited, Bangalore 560 058, INDIA
- Age at study initiation: 4-5 months
- Weight at study initiation: 2.21 to 2.31 kg
- Housing: The rabbits were housed individually in rabbit cages (approx. size: L 65 x B 65 X H 45 cm) with Noryl shallow cage body and noryl perforated raised shelf for enrichment and facilities for pelleted food (Stainless steel feed hopper) and drinking water (750 ml markrolon bottle fitted with sipper tube). The litter collection tray (noryl waste tray) were washed daily with water (except on sundays).
- Diet (e.g. ad libitum): The animals were offered rabbit feed (Nutrilab® ) manufactured by Tetragon Chemie Pvt. Ltd, KHB Industrial Area, Yelahanka New Town, Bangalore-560 064.
- Water (e.g. ad libitum): The animals were provided deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd., Mumbai - 400 001, INDIA.
- Acclimation period: One rabbit (RB6923) was acclimatized for fourteen days while the other two (RB6924 and RB6925) rabbits were acclimatized for fifteen days under laboratory conditions after physical examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22°C
- Humidity (%): 30-70%
- Air changes (per hr): 12-15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hour light and 12 hour dark cycle
Type of coverage:
occlusive
Preparation of test site:
other: Clipped with an electric clipper
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml


Duration of treatment / exposure:
4 hours
Observation period:
Rabbit used for the single animal test was observed for a period of 96 hours (skin reaction scores were recorded only through 72 hours post application) and the additional two rabbits used in the confirmatory test were observed up to 72 hours post removal of the test patch.
Number of animals:
3 female rabbits
Details on study design:
TEST SITE
Five-tenths of a milliliter (0.5 ml) of liquid test material was placed on the dose site and covered with a gauze pad of size approximately 6 cm2 (2 x 3 cm -6ply). A control patch blank gauze pad was applied 3 – 4 cm anterior to the 4 hour test patch. All the patches were secured to the body of the animal by an adhesive tape and the entire trunk of each animal was then wrapped with non-irritating crepe elastic tape to avoid dislocation of the patch. Animals were exposed to thetest substance for a period of 4 hours. Elizabethan collars were placed on each rabbit for the designated exposure period.

REMOVAL OF TEST SUBSTANCE
The patches were removed after four hours and the applied area was wiped with water. The skin was assessed immediately after removal of the 4 hours test patch for severe irritation / corrosion. The results indicated that the test item was not irritant or corrosive to the skin. The rabbit was restrained using Elizabethan collar for 28 hours post application of the test patch.

SCORING SYSTEM:
Following the exposure period, the patches were removed and the application sites were wiped with water to remove any residual test substance. The 4 hour dose sites was examined for signs of erythema and edema within 30-60 minutes and at intervals of approximately 24, 48 and 72 hours after patch removal according to the "Primary Skin Irritation Scoring System" developed by Draize. Individual scores were recorded for each rabbit.
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritant / corrosive response data:
There were no skin reactions observed at 1, 24, 48 and 72 hours post removal of the test patch.
Other effects:
There were no toxic signs and pre-terminal deaths during the course of the experiment. The body weights of all the rabbits increased slightly through the observation period.

None

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the results, there was no evidence of dermal irritation as evidenced by erythema and edema score of ‘0’ was observed at all the observation time points, hence classified as not irritating to skin.
Executive summary:

The acute dermal irritation/corrosion study in New Zealand White Rabbits was conducted to evaluate the skin irritation potential of Diethylene glycol mono phenyl ether.

Five-tenths of a milliliter (0.5 ml) of the undiluted test item was applied to the dose site and covered with a gauze pad of size approximately 6 cm2 (2 x 3 cm -6ply). A control patch blank gauze pad was applied 3 – 4 cm anterior to the 4-hour test patch. All patches were secured to the body of the animal by an adhesive tape and a crepe bandage wrapped around the torso of the animal. After 4 hours contact period the bandage was removed and the dose sites were wiped with water.

The degree of irritation was evaluated and scored by Draize’s evaluation method at 1, 24, 48 and 72 hour post removal of the test patch. There was no evidence of dermal irritation as evidenced by erythema and edema score of ‘0’ was observed at all the observation time points.

There were no toxic signs, pre-terminal deaths and no skin reactions observed. There were no abnormalities detected at necropsy.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted in according to OECD TG 405 and in accordance with the principles of GLP.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
U.S. EPA Health Effects Test Guidelines, OPPTS 870.2400 (1998), JMAFF 12-Nouan-8147, November 2000 and Official Journal of the European Communities. Methods for the Determination of Toxicity, Part B.5 (Eye Irritation), Directive 2004/73/EC, 29 April 2004.
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:
TEST ANIMALS
- Source: Toxicology, Department of Safety Assessment, Advinus Therapeutics Private Limited, Bangalore 560 058, INDIA
- Age at study initiation: 5-6 months
- Weight at study initiation: 2.20 to 2.39 kg
- Housing: The rabbits were housed individually in rabbit cages (approx. size: L 65 x B 65 X H 45 cm) with Noryl shallow cage body and noryl perforated raised shelf for enrichment and facilities for pelleted food (Stainless steel feed hopper) and drinking water (750 ml markrolon bottle fitted with sipper tube). The litter collection tray (noryl waste tray) were washed daily with water (except on sundays). The water bottle and feed hopper were changed once a week.
- Diet (e.g. ad libitum): The animals were offered rabbit feed (Nutrilab®) manufactured by Tetragon Chemie Pvt.Ltd., KHB Industrial Area, Yelahanka, New
Town, Bangalore - 64, India.
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum
purifier, manufactured by Eureka Forbes Ltd., Mumbai- 400001, was provided to animals in Markrolon bottles with stainless steel sipper tubes.
- Acclimation period: One rabbit RB6926 was acclimatized for 14 days while the other two (RB6927 and RB6928) rabbits were acclimatized for 15 days
under laboratory conditions after physical examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22°C,(except on one day the maximum temperature was 23°C)
- Humidity (%): 30-70%
- Air changes (per hr): 12-15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hour light and 12 hour dark cycle

Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
Prior to instillation, both eyes of each rabbit were examined with the aid of a pen light for irritation and ocular defects. The eyes were then checked for opacity using ophthalmic fluorescein sodium. One drop was instilled into each eye and the eyes were then irrigated with enough physiological saline (0.9% NaCl) to
remove any excess fluorescein (approximately 30 seconds). Using an ultraviolet lamp, the eyes were checked and evaluated for preexisting corneal damage.
One tenth of a milliliter of the test item (undiluted) was placed in the everted lower lid (conjunctival sac) of the left eye of each rabbit. The eye lids were gently held together for about one second, in order to minimize loss of the test item.
Duration of treatment / exposure:
72 hrs
Observation period (in vivo):
A single rabbit was initially exposed to the test item. Since the test item was not corrosive or severely irritating at 24 hours observation, hence, the test was conducted using two additional animals.
Number of animals or in vitro replicates:
Three female rabbits
Details on study design:
Ocular lesions were evaluated with the illumination of a white light source at intervals of approximately 1, 24, 48 and 72 hours post-instillation of the test substance according to the "Scale for Scoring Ocular Lesions".

In addition, all treated eyes were examined using ophthalmic fluorescein sodium at the 24-hour interval. Corneal opacity exists at 24 hours, hence, fluorescein was used as needed, at subsequent scoring intervals, to aid in evaluating the extent of corneal damage.

Irritation persisted in all rabbits at 72 hours, hence, scoring was continued for all rabbits at 4, 7, 10, 14, 17 and 21 days post instillation.

Individual scores were recorded for each rabbit. All scores were calculated as described in the "Scale for Scoring Ocular lesions",and the total possible points (out of 110) were tallied. In addition to the observation of the cornea, iris and conjunctivae, any other lesions that are observed were noted. To aid in the interpretation of data, the average score for all rabbits at each scoring period was calculated.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 hrs
Score:
1
Max. score:
1
Reversibility:
not reversible
Remarks:
See Attachment 1
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 hrs
Score:
0
Max. score:
0
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 hrs
Score:
2
Max. score:
2
Reversibility:
not reversible
Remarks:
See Attachment 1
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 hrs
Score:
1.7
Max. score:
2
Reversibility:
not reversible
Remarks:
See Attachment 1
Irritant / corrosive response data:
The conjunctival redness, chemosis and discharge were observed in all the animals till termination. The corneal opacity was observed in all the animals till termination. There were no iris reactions. Mild circumcorneal injection was observed in one rabbit from day 10 onwards and in the other two rabbits from day 14 onwards till termination of observation on day 21.
Other effects:
The body weights of all rabbits increased slightly through the observation period.

Irritation scores calculated

Cornea opacity
Animal Observation time Mean value Mean value (over all animals)
24 hours 48 hours 72 hours
1 1 1 1 1 1.0
2 1 1 1 1
3 1 1 1 1
Iris lesion
Animal Observation time Mean value Mean value (over all animals)
24 hours 48 hours 72 hours
1 0 0 0 0.0 0.0
2 0 0 0 0
3 0 0 0 0.0
Conjunctivae (redness)
Animal  Observation time Mean value  Mean value (over all animals)
24 hours 48 hours 72 hours
1 2 2 2 2 2.0
2 2 2 2 2.0
3 2 2 2 2
Conjunctivae (chemosis)
Animal  Observation time Mean value Mean value (over all animals)
24 hours 48 hours 72 hours
1 1 1 1 1 1.7
2 2 2 2 2
3 2 2 2 2
Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material was irritating to the eyes with conjuctival chemosis and redness and cornea opacity scores meeting the criteria for CLP category 2a. However the cornea opacity effects persisted until the end of the observation period of 21 days. This therefore meets the criteria for a 'serious effect' and as such category 1 eye irritant is appropriate.
Executive summary:

The acute eye irritation/corrosion study in New Zealand White rabbits was conducted to evaluate the eye irritation potential of Diethylene glycol mono phenyl ether. One-tenth of a milliliter (0.1 ml) of the undiluted test item was instilled into the conjunctival sac of the left eye of the animal after gently pulling the lower lid away from the eyeball. The eyelids were held together gently for about one second to minimize loss of test item. The right eye remained untreated and served as the reference control. All the rabbits were treated in a similar manner. The ocular lesions were evaluated at 1, 24, 48, 72 hours, 4, 7, 10, 14, 17 and 21 days post instillation according to the scale for scoring ocular lesions. In addition, the treated eyes were examined using ophthalmic fluorescein sodium at 24, 72 hours, at 7 and 14 days post instillation. The total mean scores were 18, 27.34, 27.34, 27.34, 25.34, 22.06, 34.67, 27.33, 27.33 and 18.67 at 1, 24, 48, 72 hours, 4, 7, 10, 14, 17 and 21 days, respectively. Mild circumcorneal injection was observed in one rabbit from day 10 onwards and in the other two rabbits from day 14 onwards till termination of observation (day 21). There were no toxic signs and pre-terminal deaths.

Based on the evidence of irritation and the persistence of effects until the end of the observation period, the test material meets the criteria for Category 1 A according to CLP.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a well conducted skin irritation test (GLP and Guideline) there was no evidence of irritation in any animal at 1, 24, 48, or 72 hours post exposure. This substance was therefore not considered to be irritating to the skin.

In a well conducted eye irritation test (GLP and Guideline) the scores for conjunctival redness and chemosis and the scores for corneal opacity were 2, 2, and 1 (respectively) in at least 2 out of the 3 animals tested. In addition, the corneal effect was still evident in all animals at observation day 21. As such this substance is considered to be irritating to the eyes.

No data on respiratory irritation are available, however given the low vapour pressure of this substance and the absence of skin irritation it is concluded that this substance will have a low potential for respiratory irritation.


Justification for selection of skin irritation / corrosion endpoint:
Reliability 1 OECD guideline study

Justification for selection of eye irritation endpoint:
Reliability 1 OECD guideline study

Effects on eye irritation: highly irritating

Justification for classification or non-classification

The test material did not meet the criteria as irritating to the skin. However in the eye irritation assay, the scores in 2 out of 3 animals were sufficient to classify as Category 2a, irritating to the eyes. In addition to this, the effects persisted (corneal effects) to the end of the observation period (day 21) and so must be considered as severe, or irreversible. Therefore this substance should be classified as Category 1 for eye irritation.