Registration Dossier

Administrative data

Description of key information

Several studies are available to evaluate the skin and eye irritation potential of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid. The substance is not irritating for skin, but irritating for eyes.

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:
From 18 to 21 January 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study (B4 Method)
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Froxfield (U.K.) Ltd., Petersfield, Hampshire, England.
- Age at study initiation: 11-14 weeks old
- Weight at study initiation: 2.4 to 3.2 kg
- Housing: individually in plastic cages with perforated floors
- Diet (e.g. ad libitum): standard Iaboratory diet SDS Stanrab (P) Rabbit Diet, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: yes but no detail

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 19°C
- Humidity (%): 30-70%
- Air changes (per hr): 19 air changes per hour
- Photoperiod (hrs dark / hrs light): lighting was controlled by means of a time switch to give 12 hours of artificial Iight (0700 - 1900 hours) in each 24 hours period.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
A 0.5 ml amount of the test substance was applied under a 25 mm x 25 mm gauze pad to one intact skin site on each animal.
Each treatment site was covered with "Elastoplast" elastic adhesive dressing for four hours. The animals were not restrained during the exposure period and were returned to their cages immediately after treatment.
At the end of the exposure period, the semi-occlusive dressing and gauze pad were removed and the treatment site was washed with warm water (30° to 40°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.
Duration of treatment / exposure:
4 hours
Observation period:
Examination of the treated skin was made on Day 1 (i.e. approximately 60 minutes after removal of the dressings) and on Days 2, 3 and 4 (equivalent to 24, 48 and 72 hours after exposure).
Number of animals:
3 rabbits
Details on study design:
Approximately 24 hours prior to application of the test substance, hair was removed with electric clippers from the dorso-Iumbar region of each rabbit exposing an area of skin approximately 100 mm x 100 mm.
All animals were observed daily for signs of ill health or toxicity.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
other: No erythema was observed
Irritation parameter:
edema score
Basis:
mean
Remarks:
3 rabbits
Time point:
other: 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
other: No oedema was observed
Irritant / corrosive response data:
No dermal irritation was observed.
Other effects:
There were no signs of toxicity or ill health in any rabbit during the observation period.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
A single semi-occlusive application of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid to intact rabbit skin for four hours elicited no dermal irritation. According to these study, 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid is not irritating for skin in rabbits.
Executive summary:

A study was performed to assess the skin irritation potential of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid to the rabbit (Method B.4.). Three rabbits were each administered a single dermal dose of 0.5 ml of the test substance and observed for four days. There were no signs of toxicity or ill health in any rabbit during the observation period. No dermal reactions were observed following a single semi-occlusive dermal application of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid to intact rabbit skin for four hours. 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid does not require labelling as lrritating to skin.

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:
From 07 February 2006 to 01 March 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study (OECD 405)
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Grimaud frères selection S.A.S., La Corbière, Roussay, France
- Age at study initiation: 2-4 months old
- Weight at study initiation: 3.0 ± 0.2 kg.
- Housing:individually in Techniplast (49 cm x 62 cm x 30 cm) or Pajon (50 cm x 57 cm x 75 cm) cages.
- Diet (e.g. ad libitum): free access to 110C pelleted diet
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: 5 days at least

ENVIRONMENTAL CONDITIONS
• temperature: 18 ± 3°C
• relative humidity: 30 to 70%
• light/dark cycle: 12 h/12 h
• ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
Vehicle:
unchanged (no vehicle)
Controls:
other: The right eye was not treated and served as control.
Amount / concentration applied:
A single dose of 0.1 mL of the undiluted test item was instilled into the conjunctival sac of the left eye after gently pulling the lower lid away from the eyeball.
Duration of treatment / exposure:
one exposure
Observation period (in vivo):
The eyes were examined approximately 1 hour, 24, 48 and 72 hours after administration of the test item.
Since there were persistent ocular reactions at 72 hours, the observation period was extended up to their complete reversibility (day 15).
Number of animals or in vitro replicates:
3 rabbits
Details on study design:
REMOVAL OF TEST SUBSTANCE: no

SCORING SYSTEM:
Conjunctival reactions, iritis and corneal opacification were evaluated daily for each animal.
For the evaluation of corneal opacification (presence or absence, affected area), the eyes were examined under a UV lamp after instillation of one or two drops of 0.5% sodium fluorescein solution (a clear fluorescence is visible in the areas of opacification). This evaluation was performed on day 2 and repeated thereafter whenever necessary.

Ocular reactions were scored according to the following numerical scale:
Conjunctival lesions and discharge
Chemosis (lids and/or nictitating membranes)
. no swelling ...............................................................................................................................0
. any swelling above normal (includes nictitating membranes) .................................................1
. obvious swelling with partial eversion of lids..........................................................................2
. swelling with lids about half-closed.........................................................................................3
. swelling with lids more than half-closed .................................................................................4
Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)
. blood vessels normal ................................................................................................................0
. a number of blood vessels definitely hyperemic (injected)......................................................1
. diffuse, crimson colour, individual vessels not easily discernible ...........................................2
. diffuse, beefy red......................................................................................................................3
Discharge
. absence of discharge ................................................................................................................0
. slight discharge (does not include small amounts normally found in
inner canthus) ...........................................................................................................................1
. discharge with moistening of lids and hairs adjacent to lids....................................................2
. discharge with moistening of lids and hairs on wide area around the eye...............................3
Iris lesions
. normal .....................................................................................................................................0
. markedly deepened rugae, congestion, swelling, moderate circum-corneal
hyperemia, or injection, any of these or combination of any thereof, iris still
reacting to light (sluggish reaction is positive) ........................................................................1
. no reaction to light, haemorrhage, gross destruction (any or all of these) ...............................2

Corneal lesions
Degree of opacity (area most dense taken for reading)
. no ulceration or opacity............................................................................................................0
. scattered or diffuse areas of opacity (other than slight dulling or normal lustre),
details of iris clearly visible .....................................................................................................1
. easily discernible translucent area, details of iris slightly obscured ........................................2
. nacreous areas, no details of iris visible, size of pupil barely discernible ...............................3
. opaque cornea, iris not discernible through the opacity...........................................................4
Area of opacity
. one quarter (or less) but not zero..............................................................................................1
. greater than one quarter but less than a half.............................................................................2
. greater than one half but less than three quarters.....................................................................3
. greater than three quarters up to whole area. ...........................................................................4
Any other lesions observed were noted.

Irritation parameter:
cornea opacity score
Remarks:
(opacity)
Basis:
mean
Remarks:
(3 rabbits)
Time point:
other: 24-48-72 hours
Score:
1.1
Max. score:
4
Reversibility:
fully reversible within: 9 days
Remarks on result:
other: Individual scores: 1.3-1.0-1.0
Irritation parameter:
conjunctivae score
Remarks:
(chemosis)
Basis:
mean
Remarks:
(3 rabbits)
Time point:
other: 24-48-72 hours
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 15 days
Remarks on result:
other: Individual scores: 3.0-3.0-3.0
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
(3 rabbits)
Time point:
other: 24-48-72 hours
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 15 days
Remarks on result:
other: Individual scores: 3.0-3.0-3.0
Irritation parameter:
iris score
Basis:
mean
Remarks:
(3 rabbits)
Time point:
other: 24-48-72 hours
Score:
0.8
Max. score:
2
Reversibility:
fully reversible within: 6 days
Remarks on result:
other: Individual scores: 0.3-1.0-1.0
Irritant / corrosive response data:
Slight to severe conjunctival reactions including, slight to marked chemosis (grades 1 to 3), slight to severe redness of the conjunctiva (grades 1 to 3) and clear and/or whitish purulent discharge, were observed in all animals from day 1. Some of these reactions persisted up to day 13 (1/3 animals) or 14 (2/3 animals).
An iritis (grade 1) was noted in all animals on day 2; it persisted up to day 4 (1/3 animals) or 5 (1/3 animals).
A slight or moderate corneal opacity (grade 1 or 2), which sometimes covered the whole area of the eye, was recorded in all animals on day 2; it persisted up to day 6 (1/3 animals) or 8 (2/3 animals).
A neovascularisation was noted in 2/3 animals between day 9 and day 14.
Mean scores calculated for each animal over 24, 48 and 72 hours were 3.0, 3.0 and 3.0 for chemosis, 3.0, 3.0 and 3.0 for redness of the conjunctiva, 0.3, 1.0 and 1.0 for iris lesions and 1.3, 1.0 and 1.0 for corneal opacity.
Other effects:
No reported data in the report.
Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under these experimental conditions, 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid was irritant when administered by ocular route to rabbits.
Executive summary:

2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid was administered to three male New Zealand White rabbit. A single dose of 0.1 mL of the undiluted test item was instilled into the left conjunctival sac. The eyes were not rinsed after administration of the test item. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration and then daily until reversibility of the ocular reactions.

The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal.

Slight to severe conjunctival reactions (slight to marked chemosis, slight to severe redness of the conjunctiva and clear and/or whitish purulent discharge) were observed in all animals from day 1. Some of these reactions persisted up to day 13 (1/3 animals) or 14 (2/3 animals). An iritis was noted in all animals on day 2; it persisted up to day 4 (1/3 animals) or 5 (1/3 animals).

A slight or moderate corneal opacity, which sometimes covered the whole area of the eye, was recorded in all animals on day 2; it persisted up to day 6 (1/3 animals) or 8 (2/3 animals). A neovascularisation was noted in 2/3 animals between day 9 and day 14.

Mean scores calculated for each animal over 24, 48 and 72 hours were 3.0, 3.0 and 3.0 for chemosis, 3.0, 3.0 and 3.0 for redness of the conjunctiva, 0.3, 1.0 and 1.0 for iris lesions and 1.3, 1.0 and 1.0 for corneal opacity.

Under these experimental conditions, 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid was irritant when administered by ocular route to rabbits.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

Three studies were performed to assess the skin irritation potential of the test item to the rabbit. All the studies showed the same results : 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid is not irritating for skin.

In the Parcell's and Liggett's studies, three rabbits were each administered a single dermal dose of 0.5 ml of the test substance and observed for four days. There were no signs of toxicity or ill health in any rabbit during the observation period. No dermal reactions were observed following a single semi-occlusive dermal application of test item to intact rabbit skin for four hours.

In the Janssen's study, three rabbits were exposed to 0.5 ml of test substance, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48, 69 and/or 72 hours after exposure. Exposure to test item resulted in very slight erythema in the treated skin-areas of two rabbits, which had resilved within 24 or 69 hours after exposure. No erythema was noted in the remaining animal. No oedema was noted in all animals. The primary irritation index was calculated to be 0.2.

Eye irritation

Three studies were performed to assess the eye irritation potential of the test item to the rabbit. All the studies showed the same results : 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid is irritating for eyes.

In the Sire's study (2006), the test item was administered to three male New Zealand White rabbit. A single dose of 0.1 mL of the undiluted test item was instilled into the left conjunctival sac. The eyes were not rinsed after administration of the test item.

Slight to severe conjunctival reactions were observed in all animals from day 1. Some of these reactions persisted up to day 13/14. An iritis was noted in all animals on day 2 and persisted up to day 4/5. A slight or moderate corneal opacity, which sometimes covered the whole area of the eye, was recorded in all animals on day 2, and persisted up to day 6/8. A neovascularisation was noted in 2/3 animals between day 9 and day 14. Mean scores calculated for each animal over 24, 48 and 72 hours were 3.0, 3.0 and 3.0 for chemosis, 3.0, 3.0 and 3.0 for redness of the conjunctiva, 0.3, 1.0 and 1.0 for iris lesions and 1.3, 1.0 and 1.0 for corneal opacity. Under these experimental conditions, the test item SR494 was irritant for eyes when administered by ocular route to rabbits.

In the Janssen's study, single samples of 0.1 ml of test item were instilled into the left eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours and 7, 14 and 21 days after instillation. Instillation of the test substance resulted in effects on the cornea, iris and conjunctivae. The corneal injury consisted of opacity (maximum grade 1) and epithelial damage (maximum 35% , 50% and 50% of the corneal area). As a result of the corneal injury, pannus (neovascularisation of the cornea) was apparent in two animals 7 days after instillation. lridial irritation grade 1 was observed had resolved within 7 days. All the effects had completely resolved within 21 days. A bald area was noted around the left eye in all animals at 7 and 14 days after treatment. Mean scores calculated for each animal over 24, 48 and 72 hours were 3.7, 3.7 and 3.7 for chemosis, 3.0, 3.0 and 3.0 for redness of the conjunctiva, 0.7, 0.3 and 0.0 for iris lesions and 1.0, 1.0 and 1.0 for corneal opacity. Based on these results, the test substance is considered to be irritating for eyes in rabbit.

In the Parcell's study, three rabbits were each administered a single ocular dose of 0.1 ml of the test substance and observed for a maximum of 14 days after instillation. A single instillation of test item into the eye of the rabbit elicited comeal opacification, iridial inflammation and moderate to severe conjunctival irritation. Based on these results, test item is considered to be irritating for eyes in rabbit.


Justification for selection of skin irritation / corrosion endpoint:
Three reliable studies are available to evaluate the skin irritation potential of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid.
All the studies showed the same results. The study performed on the real registered substance is chosen (UVCB substance).

Justification for selection of eye irritation endpoint:
Three reliable studies are available to evaluate the eye irritation potential of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid.
All the studies showed the same results. The study the most recent and performed on the real registered substance is chosen (UVCB substance).

Effects on eye irritation: irritating

Justification for classification or non-classification

No damage or irritation on the skin was observed in the rabbit study, 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid is not irritating for skin. No classification is expected for skin irritation endpoint.

In all three studies available, instillation of the test substance resulted in effects on the cornea, iris and conjunctivae in rabbits. Based on these results, 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid considered to be irritating for eyes, and classified as "Eye irritating" in the Category 2 of CLP classification (Regulation EC 1272/2008) and as "irritating" (R36) according to the DSD classification.

Criteria of classification (CLP) as corrosive or severely irritant for eye are not completed, because the effects on the eyes are fully reversible in 21 days, and the effects on cornea or iris are not severe (score smaller than1.5). However, the criteria of classification for reversible eye effects are completed : the score of corneal opacity and iris is equal to 1 in 2/3 animals in the key study, the score of redness is higher than 2 for all three animals.

No study by inhalation is available to evaluate the irritant potential of 2,2-bis(hydroxymethyl)-1,3-propanediol, ethoxylated and propoxylated, esters with acrylic acid on the respiratory tract.

But, as the substance is not skin or eye irritant, no irritation on the respiratory tract is expected. No classification is proposed.