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Toxicological information

Eye irritation

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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August-September 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP lab following OECD guideline

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
GLP compliance:
yes

Test material

Constituent 1
Reference substance name:
glycerol formal
IUPAC Name:
glycerol formal
Test material form:
other: liquid
Details on test material:
Name : Glycerol formal
Other name : Glycerol Formal Ultra Pure Grade
Both denominations correspond to the same test item.
CAS number : 4740-78-7 + 5464-28-8 (ratio ~ 50/50)
Batch number : 1206191600R
Supplier : LAMBIOTTE & CIE S.A.
Description : colorless liquid
Container : brown glass flask
Purity : 99.9840%
pH : 6.22 (10% in water)
Storage condition : at room temperature
Date of receipt : 12 July 2012
Expiry date : 19 June 2015.

Test animals / tissue source

Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Number: two males. These animals were previously used in CiToxLAB France/Study No. 39308 TAL for the evaluation of the dermal irritation potential of the same test item before being allocated to the present study.
Strain and species: New Zealand White rabbits.
Reason for selection of species: rabbit is a non-rodent species accepted by Regulatory Authorities for this type of study and background data from previous studies are available at CiToxLAB France.
Breeder: CEGAV, Argenvilliers, France
Age/weight: at the beginning of the study, the animals were 5 to 6 months old and had a mean body weight of 4370 g (range: 4275 g to 4465 g) (see § Study plan adherence).
Receipt: on arrival, the animals were given a clinical examination to ensure that they are in good condition.
Acclimation: the animals were acclimated for a period of at least 5 days before treatment of the dermal irritation study (CiToxLAB France/Study No. 39308 TAL).
Selection: before treatment, the eyes of each animal were examined in order to use only animals without any signs of ocular irritation or lesions.
Identification: the animals were individually identified by a plastic ear tag at the breeder's facility. After
allocation to groups, each animal received a unique CiToxLAB France identity number.

Environmental conditions
From arrival at CiToxLAB France, the animals were housed in a barriered non-rodent unit.
The animal room conditions were set as follows:
. temperature : 18 ± 3°C, (see § Study plan adherence),
. relative humidity : 50 ± 20%,
. light/dark cycle : 12h/12h,
. ventilation : approximately 12 cycles/hour of filtered, non-recycled air.
The corresponding instrumentation and equipment are checked and calibrated at regular intervals. The
temperature and relative humidity are recorded continuously and the records checked daily and filed.

Housing
The animals were individually housed in inox cages (Pajon, 75 cm x 57 cm x 50 cm). The cages were suspended in batteries over trays with absorbant paper and each cage contained a platform and enrichment (dumbbell).

Food and water
All animals had free access to pelleted breeding diet "type 110C", batch Nos. 12044 and 12102, (SAFE, Augy, France) and tap water (filtered using a 0.22 μm filter) contained in bottles.

Contaminant analyses
The batches of diet were analyzed by the supplier for composition and contaminant levels. Bacterial and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides and heavy metals). No contaminants that could have interfered with or prejudiced the outcome of the study were found in the diet or drinking water.

Test system

Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
A dosage-volume of 0.1 mL/animal was used.
Duration of treatment / exposure:
The test item was administered in the conjunctival sac of the left eye after gently pulling the lower lid away
from the eyeball. The lids were then gently held together for about one second in order to prevent loss of
the test item.
The right eye remained untreated and served as control.
A dosage-volume of 0.1 mL/animal was used.
Before 24-hour reading, residual test item was removed by means of a rinsing in animal Y30811. Both eyes
were rinsed with sterile isotonic saline solution (0.9% NaCl), under a volume and velocity of flow which will
not cause injury to the eyes.
The eyes of animal Y30812 were not rinsed before 24-hour reading.
Observation period (in vivo):
The eyes were examined approximately 1 hour, 24, 48 and 72 hours after administration of the test item.
Since both animals showed persistent ocular reactions at the 72-hour reading, the evaluation of ocular reactions was extended up to the complete reversibility (at the latest day 8).
Number of animals or in vitro replicates:
2
Details on study design:
Rationale for design selection
The sequential study design was as follows:
The test item was administered in the left eye of a single animal (No. Y30811):
. as mean value from grading at 24, 48 and 72 hours after instillation was ≥ 2 for conjunctival edema (chemosis) or for conjunctival redness and/or ≥ 1 for iris lesions or for corneal opacity, the test item was administered in the left eye of a second animal (No. Y30812).

After administration to the second animal:
. as mean value from grading at 24, 48 and 72 hours after instillation was ≥ 2 for conjunctival edema (chemosis) or for conjunctival redness and/or ≥ 1 for iris lesions or for corneal opacity, no other animal was treated.

For each animal, the day of dose application was recorded as day 1 of its observation period.

Ocular reactions were graded in each animal according to the following scoring scale:

A) Conjunctival lesions and discharge
Chemosis (lids and/or nictitating membranes)
. no swelling ............................................................................................................................................ 0
. any swelling above normal ................................................................................................................. 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 the most severe reading for the palpebral
and bulbar conjunctivae, excluding the cornea and iris)
. blood vessels normal ........................................................................................................................... 0
. some blood vessels hyperemic (injected).......................................................................................... 1
. diffuse, crimson color, individual vessels not easily discernible .................................................. 2
. diffuse, beefy red .................................................................................................................................. 3
B) Iris lesions
. normal ................................................................................................................................................... 0
. markedly deepened rugae, congestion, swelling, moderate circum-corneal
hyperemia or injection; any or a combination of any there findings, but iris still
reacting to light (a sluggish reaction being considered positive) ................................................. 1
. no reaction to light, haemorrhage, gross destruction (any or all of these) ............................... 2

C) Corneal lesions
From the 24-hour scoring, the presence of corneal opacification was 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). As findings were noted at 24 hours, a fluoresceine examination was conducted at each subsequent scoring time-point until a negative response was obtained.

Opacity (degree of intensity: 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

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
scores of animal Y30811
Time point:
24/48/72 h
Score:
2
Max. score:
4
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
scores of animal Y30811
Time point:
24/48/72 h
Score:
1.7
Max. score:
3
Irritation parameter:
iris score
Basis:
mean
Remarks:
scores of animal Y30811
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Irritation parameter:
cornea opacity score
Remarks:
(opacy intensity)
Basis:
mean
Remarks:
scores of animal Y30811
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Irritation parameter:
cornea opacity score
Remarks:
(opacy area)
Basis:
mean
Remarks:
scores of animal Y30811
Time point:
24/48/72 h
Score:
1
Max. score:
4
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
scores of animal Y30812
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
scores of animal Y30812
Time point:
24/48/72 h
Score:
2
Max. score:
3
Irritation parameter:
iris score
Basis:
mean
Remarks:
scores of animal Y30812
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Remarks:
(opacy intensity)
Basis:
mean
Remarks:
scores of animal Y30812
Time point:
24/48/72 h
Score:
1
Max. score:
4
Irritation parameter:
cornea opacity score
Remarks:
(opacy area)
Basis:
mean
Remarks:
scores of animal Y30812
Time point:
24/48/72 h
Score:
1
Max. score:
4
Irritant / corrosive response data:
The results obtained were evaluated in conjunction with the nature and the reversibility of the findings observed, whilst taking into account all the reactions of the treated animals.
The test item was classified according to the criteria laid down in Regulation (EC) No. 1272/2008 (CLP) of the European parliament and of the council of 16 December 2008 on classification, labelling and packaging of substances and mixtures.

No ocular reactions were observed in the right untreated control eye.

In the left treated eye of animal Y30811, marked chemosis of the conjunctiva (grade 3) was noted on days 1 and 2 then moderate or slight chemosis (grade 1 or 2) persisted until day 4. Moderate redness of the conjunctiva (grade 2) was observed from day 1 until day 3, then slight conjunctiva reactions (grade 1)
was noted until day 5. Iris lesions (grade 1) were noted on day 2, only. Slight or moderate corneal opacity (grade 1 or 2) was recorded from day 2 to day 4.

In the left treated eye of animal Y30812, moderate chemosis of the conjunctiva (grade 2) was noted on days 1 and 2 then slight chemosis (grade 1) persisted up to day 5. Slight or moderate redness of the conjunctiva (grade 1 or 2) was observed from day 1 until day 7. Slight corneal opacity (grade 1) was
recorded from day 2 to day 5. In addition, lacrimation was recorded on days 1 and 2.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:
. chemosis : 2.0 and 1.3; showing eye irritation in 1/2 animals,
. redness of the conjunctiva: 1.7 and 2.0; showing eye irritation in 1/2 animals,
. iris lesions: 0.3 and 0.0; showing no significant eye irritation,
. corneal opacity: 1.3 and 1.0; showing eye irritation in both animals.
Other effects:
MORTALITY
No unscheduled deaths occurred during the study.

CLINICAL SIGNS
No clinical signs of systemic toxicity were noted in any animals.

BODY WEIGHT
The body weight of the animals was unaffected by the test item treatment.

Applicant's summary and conclusion

Interpretation of results:
Category II
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the experimental conditions of this study, the test item, Glycerol formal, was irritant when administered by ocular route to rabbits.
According to the criteria of CLP Regulation, the test item should be classified category 2 and assigned the signal word "warning" and the hazard statement "H319: causes serious eye irritation".
Executive summary:

SUMMARY

The objective of this study was to evaluate the potential irritant properties of the test item for the eye, Glycerol formal, following a single administration to rabbits.

Methods

The test item, Glycerol formal (batch No. 1206191600R), was first administered to a single male New Zealand White rabbit.

As mean value from grading at 24, 48 and 72 hours after instillation was ≥ 2 for conjunctival edema (chemosis) and/or ≥ 1 for corneal opacity, the test item was administered in the left eye of a second animal.

After administration to the second animal, as mean value from grading at 24, 48 and 72 hours after instillation was ≥ 2 for conjunctival redness and/or ≥ 1 for corneal opacity, no other animal was treated. The test item was administered in the conjunctival sac of the left eye. The right eye remained untreated and served as control. A dosage-volume of 0.1 mL/animal was used.

Before 24-hour reading, both eyes of animal Y30811 were rinsed with a sterile isotonic saline solution (0.9% NaCl).

Each animal was observed at least once a day for mortality and clinical signs. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration and then daily until the 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. Body weight was recorded on the day of treatment and the end of the observation period. On completion of the observation period, the animals were sacrificed then discarded without macroscopic post-mortem examination.

Results

No unscheduled deaths occurred during the study and no clinical signs of systemic toxicity were noted in any animals.

The body weight of the animals was unaffected by the test item treatment.

In the left treated eye of both animals, slight to marked chemosis and slight to moderate redness of the conjunctiva were noted from day 1 until day 4, 5 or 7. Iris lesions were noted in one of them on day 2, only. Slight or moderate corneal opacity was recorded in both animals from day 2 to day 4 or 5. In addition, lacrimation was recorded in 1/2 animals on days 1 and 2.

Mean scores calculated for each animal over 24, 48 and 72 hours were as follows:

. chemosis : 2.0 and 1.3; showing eye irritation in 1/2 animals,

. redness of the conjunctiva: 1.7 and 2.0; showing eye irritation in 1/2 animals,

. iris lesions: 0.3 and 0.0; showing no significant eye irritation,

. corneal opacity: 1.3 and 1.0; showing eye irritation in both animals.

Conclusion

Under the experimental conditions of this study, the test item, Glycerol formal, was irritant when administered by ocular route to rabbits. According to the criteria of CLP Regulation, the test item should be classified category 2 and assigned the signal word "warning" and the hazard statement "H319: causes serious eye irritation".