Registration Dossier

Administrative data

Description of key information

C14 Alkyl polyethoxy glycidylether was found to be a mild skin irritant when tested in vivo on rabbit skin. In an in vivo study in rabbits for eye irritation it caused mild irritation but did not reach positive criteria for classification according to GHS criteria.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
between 21 April 1999 and 11 May 1999.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
HYPOTHESIS FOR THE ANALOGUE APPROACH
Read across is done from C14-Alkyl polyethoxy glycidylether (C14-GEE) to C12-14 Alkyl polyethoxy glycidylether (C12-14-GEE)

The production of both substances is identical: Alkyl alcohol ethoxylate (2EO) oligomers are reacted with epichlorohydrin (in slight molar excess) in the presence of a catalyst to form the corresponding epoxides. The substances are in principle UVCB because of variation in alkyl chain, number of EO (range 0 to 4, average 2) and possibility of 0 to two glycidyl (most 1) and all possible combinations.

However, the only difference between the two substances is the alkyl chain lengths distribution of the Alkyl alcohol (2EO) starting material, being either a (predominantly) 14-carbon chain length or a mixture of 12 and 14-carbon chain length in the ratio of 3:1 (C12:C14).
As consequence, these products are for 25% completely identical, whereas for the other 75% the C12-14-GEE has a slightly shorter alkyl chain compared to the C14-GEE.
For all other aspects, the substances are identical. As both have the same chemical structure they both have identical functional groups, show the same chemical reactivity and have very comparable physicochemical properties as can be seen in the comparative profiling included to the endpoint summary of chapter 7.1 on toxicokinetics. Consequently, they share the same mechanism of action. This is similarly applicable to all constituents of these UVCBs.

Related to the (small) difference in average alkyl chain-lengths between the two substances, the C12-14-GEE with on average a slightly shorter chain-length than the C14-GEE, is expected to be slightly better bioavailable (slightly smaller molecule also leading to more moles per unit of weight, slightly higher solubility, slightly lower Kow, and slightly higher vp) and is expected to have (a slightly) higher toxicity profile compared to C14-GEE.

Specifically for dermal irritation, substances with relative shorter chains show higher effects. (As shown by BfR profiling rules for dermal irritation). In the current read-across for dermal irritation, the C14-GEE might slightly underpredict the effects for C12-14-GEE. As C14-GEE was only mildly irritating, and only was classified Cat.2 skin irritant based on some effects still visible at the end of the observation period, it has no bearing on the validity of read-across to C12-14-GEE.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted 17 July 1992
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: twelve to sixteen weeks
- Weight at study initiation: 2.57 to 2.74 kg
- Housing: individually housed in suspended metal cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 30 to 70%
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: between 21 April 1999 and 11 May 1999.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 ml of the test material was introduced under a 2.5 cm x 2.5 cm cotton gauze patch
Duration of treatment / exposure:
Initial animal, three suitable test sites were selected on the back of the rabbit: 3 minutes, 1 hour and 4 hours
Two additional animals: 1 site, 4 hours
Observation period:
up to 14 days
Number of animals:
Total 3.
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- Type of wrap if used: Each patch was secured in position with a strip of surgical adhesive tape (BLENDERM: approximate size 2.5 cm x 4.0 cm). To prevent the animal interfering with the patches, the trunk of the rabbit was wrapped in an elasticated corset (TUBIGRIP)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Any residual test material was removed by gentle swabbing with cotton wool soaked in 74% Industrial Methylated Spirits.
- Time after start of exposure: Initial animal: One patch was removed at each of three time points: 3 minutes, 1 hour and 4 hours after application.
Two additional animals: 4 hours

OBSERVATION TIME POINTS
(indicate if minutes, hours or days) : one hour following the removal of the patches, and 24, 48 and 72 hours later, and on Days 7 and 14

SCORING SYSTEM:
- Method of calculation: scored according to the following scale from Draize J H, (1977) for Erythema and Eschar Formation and Oedema Formation.
Additionally the Primary Irritation Index was calculated and Grading of the Irritancy Potential Using the Draize Scheme:
The scores for erythema and oedema at the 24 and 72-hour readings (4-hour exposure) were totalled for the three test rabbits (12 values) and this total was divided by six to give the primary irritation index of the test material. The test material was classified according to the following scheme devised by Draize J H (1959) "Dermal Toxicity" In: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Association of Food and Drug Officials of the United States, Austin, Texas, p.47:
Primary Irritation Index - Classification of Irritancy
0 - Non-irritant
> 0 to 2 - Mild irritant
> 2 to 5 - Moderate irritant
> 5 to 8 - Severe irritant
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible
Remarks:
Moderate desquamation observed after 14 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible
Remarks:
Moderate desquamation observed after 14 days.
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible
Irritant / corrosive response data:
After 3 min. exposure: Only Grade 1 (Very slight erythema (barely perceptible) ) erythema observed 1 hour and 24 hour after exposure.

After 1 hr. exposure: Grade 2 (Well-defined erythema) erythema observed at 1 hour and 24 hours after exposure, Grade 1 (Very slight erythema (barely perceptible) ) erythema at 48 and 72 hours, accompanied by oedema grade 1 (Very slight oedema (barely perceptible) ) at these time points. Erythema and oedema was cleared at day 7 (with moderate desquamation) and 14

After 4 hrs: See table.
PII score: (Sum all scores at 24 & 72 hrs / no. of animals) = 23/6 = 3.8
This classifies as 'Moderate irritant'
Other effects:
- Other adverse local effects: See table
Loss of skin flexibility and/or elasticity was noted at two treated skin sites at the 72-hour observation. Crust formation was noted at two treated skin sites with moderate desquamation at the remaining treated skin site at the 7-day observation.
Moderate desquamation was noted at two treated skin sites at the 14-day observation.
- Other adverse systemic effects: No systemic effects observed

Table: Individual Scores - Rabbit Number and Sex

Skin Reaction

Observation time

male 1

male 2

male 3

Total

Erythema/Eschar Formation

1 hour

2

2

2

(6)

24 hour

2

2

2

6

48 hour

2

2

2

(6)

72 hour

2

2 Le

2 LeLf

6

7 days

0 D

0 Cf

0 CfLf

(0)

14 days

0

0 D

0 D

(0)

Oedema Formation

1 hour

2

1

1

(4)

24 hour

2

2

2

6

48 hour

1

2

2

(5)

72 hour

1

2

2

5

7 days

0

0

0

(0)

14 days

0

0

0

(0)

 ( ) = Total values not used for calculation of primary irritation index

Cf = crust formation

D = moderate desquamation

Le = loss of skin elasticity

Lf - loss of skin flexibility

Sum of 24 and 72-hour Readings (S): 23

Primary Irritation Index (S/6): 23/6 = 3.8

Classification: Moderate irritant

Interpretation of results:
Category 3 (mild irritant) based on GHS criteria
Conclusions:
The test material produced a primary irritation index of 3.8 and was classified as a MODERATE lRRlTANT to rabbit skin according to the Draize classification scheme. No corrosive effects were noted.
Executive summary:

A study was performed to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. The method used followed the recommendations of the OECD Guidelines for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion" (adopted 17 July 1992) and Method B4 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

 

A single 4-hour, semi-occluded application of the test material to the intact skin of three rabbits produced well-defined erythema (grade 2) and slight oedema (grade 2). Loss of skin elasticity and flexibility, crust formation and moderate desquamation were also noted.

Erythema and oedema were resolved by observation after 7 days. Two animals still showed moderate desquamation at the end of the observation period of 14 days, but in view of the continuous diminishing effects, full recovery is expected.

 

In conclusion:

The test material produced a primary irritation index of 3.8 and was classified as a moderate irritant to rabbit skin according to the Draize classification scheme.

 

For GHS: Mean value of ≥ l.5 - ≤ 2.3 for erythema/eschar or for oedema in at least 2 of 3 tested animals from grades at 24,48 and 72 hours or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions when not included in the irritant category above.

As all animals have a 2 for erythema, this results to GHS Cat.3 "Mild irritant"

 

For CLP: Mean value of ≥ 2.3 - ≤ 4.0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from grades at 24,48 and 72 hours or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions when not included in the irritant category above.

There are no mean scores above ≥ 2.3. This result to "No classification".

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
between 6 May 1999 and 13 May 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
HYPOTHESIS FOR THE ANALOGUE APPROACH
Read across is done from C14-Alkyl polyethoxy glycidylether (C14-GEE) to C12-14 Alkyl polyethoxy glycidylether (C12-14-GEE)

The production of both substances is identical: Alkyl alcohol ethoxylate (2EO) oligomers are reacted with epichlorohydrin (in slight molar excess) in the presence of a catalyst to form the corresponding epoxides. The substances are in principle UVCB because of variation in alkyl chain, number of EO (range 0 to 4, average 2) and possibility of 0 to two glycidyl (most 1) and all possible combinations.

However, the only difference between the two substances is the alkyl chain lengths distribution of the Alkyl alcohol (2EO) starting material, being either a (predominantly) 14-carbon chain length or a mixture of 12 and 14-carbon chain length in the ratio of 3:1 (C12:C14).
As consequence, these products are for 25% completely identical, whereas for the other 75% the C12-14-GEE has a slightly shorter alkyl chain compared to the C14-GEE.
For all other aspects, the substances are identical. As both have the same chemical structure they both have identical functional groups, show the same chemical reactivity and have very comparable physicochemical properties as can be seen in the comparative profiling included to the endpoint summary of chapter 7.1 on toxicokinetics. Consequently, they share the same mechanism of action. This is similarly applicable to all constituents of these UVCBs.

Related to the (small) difference in average alkyl chain-lengths between the two substances, the C12-14-GEE with on average a slightly shorter chain-length than the C14-GEE, is expected to be slightly better bioavailable (slightly smaller molecule also leading to more moles per unit of weight, slightly higher solubility, slightly lower Kow, and slightly higher vp) and is expected to have (a slightly) higher toxicity profile compared to C14-GEE.

Specifically for eye irritation, substances with relative shorter chains generally show higher effects. In the current read-across for eye irritation, the C14-GEE might slightly underpredict the effects for C12-14-GEE. As C14-GEE was only very mildly irritating, without a need for classification, this could potentially be an issue. However, when looking at the individual scores, none of the average scores 24/48/72 hours for conjunctivae and chemosis (the only eye effects observed) came above 1. The slight difference between C12-14-GEE and C14-GEE cannot be expected to lead to a twice as high scoring, which would be needed to come to a positive result for classification.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted 24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: twelve to sixteen weeks old.
- Weight at study initiation: 2.75 to 3.00 kg
- Housing: individually housed in suspended metal cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 30 to 70%
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 6 May 1999 and 13 May 1999
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): undiluted
Duration of treatment / exposure:
No flushing of eyes after instillation
Observation period (in vivo):
72 hours
Duration of post- treatment incubation (in vitro):
n.a.
Number of animals or in vitro replicates:
One initial and two additional animals
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing

SCORING SYSTEM: According to Draize scale for
1. CONJUNCTIVAE: A. Redness (0-30); B. Chemosis (0-4); C. Discharge (0-3)
THE TOTAL SCORE = (A + B + C) x 2 MAXIMUM TOTAL = 20
2. IRIS: D. Iris values (0-2)
THE TOTAL SCORE = D x 5 MAXIMUM TOTAL = 10
3. CORNEA: E. Degree of Opacity (0-4); F. Area of Cornea Involved (0-4)
THE TOTAL SCORE = (E x F) x 5 MAXIMUM TOTAL = 80
Maximum total score (1 + 2 +3 ) = 110

Additional scoring: MODIFIED KAY AND CALANDRA INTERPRETATION OF EYE IRRITATION TEST

TOOL USED TO ASSESS SCORE: standard ophthalmoscope
Irritation parameter:
cornea opacity score
Basis:
animal: All
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
iris score
Basis:
animal: All
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 h
Irritant / corrosive response data:
No corneal or iridial effects were noted during the study.
Moderate conjunctival irritation was noted in all treated eyes one hour after treatment.
Moderate conjunctival irritation persisted in two treated eyes with minimal conjunctival irritation in the remaining treated eye at the 24-hour observation.
Minimal conjunctival redness was noted in two treated eyes at the 48-hour observation.
One treated eye appeared normal at the 48-hour observation and the two remaining treated eyes appeared normal at the 72-hour observation.

Table: Individual scores and individual total scores for occular irritation

Rabbit number and sex

#1 male

#2 male

#3 male

Time after treatment

1 hr

24 hr

48 hr

72 hr

1 hr

24 hr

48 hr

72 hr

1 hr

24 hr

48 hr

72 hr

Cornea

E=degree opacity

0

0

0

0

0

0

0

0

0

0

0

0

F=Area opacity

0

0

0

0

0

0

0

0

0

0

0

0

Score (ExF) x 5

0

0

0

0

0

0

0

0

0

0

0

0

IRIS

D

0

0

0

0

0

0

0

0

0

0

0

0

Score (D x 5)

0

0

0

0

0

0

0

0

0

0

0

0

CONJUNCTIVA

A=Redness

2

2

1

0

2

2

1

0

2

1

0

0

B=Chemosis

1

1

0

0

2

1

0

0

1

1

0

0

C=Discharge

2

1

0

0

2

1

0

0

2

1

0

0

Score (A+B+C) x 2

10

8

2

0

12

8

2

0

10

6

0

0

Total Score

10

8

2

0

12

8

2

0

10

6

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
The test material did not produce positive criteria in any rabbit according to GHS criteria.
Executive summary:

A study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit. The method used followed that described in the OECD Guidelines for Testing of Chemicals No. 405 "Acute Eye Irritation/Corrosion" (adopted 24 February 1987) and Method 85 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

 

A single instillation of the test material to the non-irrigated eye of three rabbits produced moderate conjunctival irritation. One treated eye appeared normal at the 48-hour observation and the remaining treated eyes appeared normal at the 72-hour observation.

No corneal or iridial effects were noted during the study.

Mean score at 24/48/72 hr for Conjunctival redness for the 3 animals were 1, 1 and 0.3, and for chemosis 0.3, 0.3 and 0.3 respectively.

As none of the mean scores were ≥ 2, the test material did not produce positive criteria for eye irritation in any of the rabbit according to GHS criteria.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No in vitro testing for skin or eye irritation has been performed, as adequate in vivo data were already available.

 

A GLP compliant study was performed to assess the irritancy potential of C14 Glycidyl ether to the skin of the New Zealand White rabbit (OECD 404). A single 4-hour, semi-occluded application of the test material to the intact skin of three rabbits produced well-defined erythema (grade 2) and slight oedema (grade 2). Loss of skin elasticity and flexibility, crust formation and moderate desquamation were also noted. Erythema and oedema were resolved by observation after 7 days. Two animals still showed moderate desquamation at the end of the observation period of 14 days, but in view of the continuous diminishing effects, full recovery is to be expected. This agrees with the results of the in vivo eye irritation study in rabbits, which showed complete clearing of effects on the conjunctiva within 48 to 72 hours (see below). It is possible that the lingering effects are local reactions to modified proteins caused by the reactivity of the epoxide.

In conclusion: The test material produced a primary irritation index of 3.8 and was considered a moderate irritant to rabbit skin according to the Draize classification scheme. Based on the result of scoring for erythema and oedema at 24/48/72 hours, no classification for CLP would be needed.

 

C14 Glycidyl etherwas evaluated for eye irritation in a GLP-compliant in vivo eye irritation study in rabbit (OECD 405). A single instillation of the test material to the non-irrigated eye of three rabbits produced moderate conjunctival irritation. Complete recovery was observed at 48 hours after exposure in one animal, and at the 72-hour observation also for the other two animals.

No corneal or iridial effects were noted during the study.

Mean score at 24/48/72 hr for Conjunctival redness for the 3 animals were 1, 1 and 0.3, and for chemosis 0.3, 0.3 and 0.3 respectively. As none of the mean scores were ≥ 2, the test material did not produce positive criteria for eye irritation in any of the rabbit according to GHS criteria.

Justification for classification or non-classification

Classification for dermal irritation: GHS Cat. 2; H315: Causes skin irritation.

Although there are no mean (24/48/72 hr) scores above 2.3 for erythema/eschar or for oedema, cat. 2 is still applicable based on moderate desquamation that was visible at the end of the observation period of 14 days in two animals.

 

Classification for eye irritation: No classification

The test material did not produce positive criteria according to GHS for eye irritation in any of the rabbit eyes tested in an OECD 405 study. Therefore, no classification for eye irritation is required.