Reaction mass of 3-({[2,2-dimethyl-3-({[2-(2-{[(prop-2-en-1-yloxy)carbonyl]oxy}ethoxy)ethoxy]carbonyl}oxy)propoxy]carbonyl}oxy)prop-1-ene and 3-{[(2,2-dimethyl-3-{[(prop-2-en-1-yloxy)carbonyl]oxy}propoxy)carbonyl]oxy}prop-1-ene and diallyl 2,2'-oxydiethyl dicarbonate

Endpoint summary

Description of key information

Skin irritation: Category 2 (irritant) based on GHS criteria; eye irritation: not irritating (GHS criteria not met). 

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:

August- September 1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on supporting substance

Justification for type of information:

RAV 7MC (EC 700-742-1)
Reaction mass of diallyl oxydiethane-2,1-diyl biscarbonate, diallyl 2,2-dimethylpropane-1,3-diyl biscarbonate and allyl 2-(2-{[(allyloxy)carbonyl]oxy}ethoxy)ethyl 2,2-dimethylpropane-1,3-diyl biscarbonate

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The rational for the analogue approach is the high structural similarity between the source substance RAV 7AT (# 1; CAS 142-22-3; EC 205-528-7) and the target substance RAV 7MC (EC 700-742-1). Both substances, RAV 7MC and RAV 7AT belong to a class of chemicals that is comprised of carbonate esters with a terminal allyl chain on both sides and that is only variable in carbon chain length. Thereby, RAV 7AT acts as a monomer with the smallest chain length and consequently the lowest molecular size compared to the other allyl carbonates. The main functional groups in the reaction mixture are allyl groups and ester functions. Due to the similarities in structure, composition and functional groups, similar physico-chemical properties of the substances are to be expected, which would result in similar toxicokinetic behaviour and most likely also in very similar physico-chemical, toxicodynamic and toxicological behaviour. Due to their overlapping constituent profile, using data from this related substance is reasonable.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The target chemical RAV 7MC is a UVCB of which the main constituent is the source chemical RAV 7AT (# 1; CAS 142-22-3; EC 205-528-7) including the same impurities # 2 (8 %), # 3 (2 %), # 7 (5 %) and # 8 (4 %). Besides RAV 7AT, RAV 7MC consists of further diallyl carbonates such as the constituents # 4 (23 %) and # 5 (11 %), which contain instead of an oxygen atom a quaternary carbon atom. It can be assumed that the hazard potential will not be enhanced by the quaternary carbon atom. The same applies for the impurities # 6 (3 %), # 9 (3 %), # 10 (2 %) and # 11 (4 %).

3. ANALOGUE APPROACH JUSTIFICATION

Due to the above-mentioned similarities of source and target chemical, with regard to their structure, functional groups and composition, it can be reasonably concluded that a similar physico-chemical, toxicokinetic and toxicological behaviour can be expected.
Thus, the common basic structure of the reaction mixture RAV 7MC consists of terminal allyl carbonates, whereby RAV 7AT can be regarded as a monomer, while the other constituents can be regarded as oligomers. In summary, the main difference between these molecules is the chain length and consequently the molecular size. Based on a worst case approach the toxicological and ecotoxicological properties of the target substance, RAV 7MC, are expected to be lower than the effects observed for the source substance RAV 7AT due to the molecular size. Additionally, from comparing the similar production processes of these substances it is apparent that RAV 7AT and RAV 7MC are closely related to each other. Finally, it can be assumed that the physico-chemical, toxicological and ecotoxicological properties of RAV 7MC and RAV 7AT will be very similar and as a result, read across is justified.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

The observation period should be up to 14 days after administration (in the present study the last observation was done at 72 hours after administration).

GLP compliance:

no

Remarks:

The sudy was performed prior to the adoption of the GLP compliance

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: data not available
- Age at study initiation: data not available
- Weight at study initiation: data not available
- Housing:data not available
- Diet (e.g. ad libitum): data not available
- Water (e.g. ad libitum):data not available
- Acclimation period:data not available


ENVIRONMENTAL CONDITIONS
data not available

Type of coverage:

occlusive

Preparation of test site:

other: one test site was abraded, the other one remained intact

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL undiluted

Duration of treatment / exposure:

24 hours

Observation period:

24 and 72 hours after administration

Number of animals:

4

Details on study design:

The test procedure was modeled after that of Draize et al. Prior to the application of the test material, the hair was clipped from the back and flanks of each rabbit.

TEST SITE
- Area of exposure: Two test sites located lateral to the midline of the back approximately ten centimeters apart were selected.
- % coverage: no data

The test material was applied to each of the test sites on each rabbit.
- Type of wrap if used: The test sites were immediately occluded with two-inch square gauze patches. The patches were placed directly over the test sites and secured with masking tape. The trunk' of each animal was then wrapped with impervious plastic sheeting. The wrap held the patches in position and retarded evaporation of the test material during the 24-hour exposure period. To prevent ingestion, a light-weight collar was placed on each animal.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): No
- Time after start of exposure: 24 hours

The intact and abraded test sites were examined and scored separately for erythema and edema on a graded scale of 0 to 4. After 72 hours, the sites were reexamined and rescored. In evaluating the average irritation present, the mean scores for erythema and edema of the intact lest sites after 24 and 72 hours were added. Similarly, the mean scores for erythema and edema of the abraded test sites after 24 and 72 hours were added. These two values were totaled and divided by four to obtain the mean primary irritation score.

Irritation parameter:

erythema score

Basis:

mean

Remarks:

3.5

Time point:

other: 24 hours

Score:

2 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: abraded skin sites

Irritation parameter:

erythema score

Basis:

mean

Remarks:

3.5

Time point:

other: 72 hours

Score:

2 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: abraded skin sites

Irritation parameter:

edema score

Basis:

mean

Remarks:

3.5

Time point:

other: 24 hours

Score:

2 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: abraded skin sites

Irritation parameter:

edema score

Basis:

mean

Remarks:

3.2

Time point:

other: 72 hours

Score:

1 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: abraded skin sites

Irritation parameter:

erythema score

Basis:

mean

Remarks:

3.5

Time point:

other: 24 hours

Score:

2 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: intact skin sites

Irritation parameter:

erythema score

Basis:

mean

Remarks:

3.5

Time point:

other: 72 hours

Score:

2 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: intact skin sites

Irritation parameter:

edema score

Basis:

mean

Remarks:

3.5

Time point:

other: 24 hours

Score:

2 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: intact skin sites

Irritation parameter:

edema score

Basis:

mean

Remarks:

3.2

Time point:

other: 72 hours

Score:

1 - 4

Max. score:

4

Reversibility:

no data

Remarks on result:

other: intact skin sites

Irritant / corrosive response data:

no data

Other effects:

not known

Table 3: Results of Primary Skin Irritation Test (Report Date: 10 September 1971)

TEST MATERIAL: 'diallyl 2,2'oxydiethyl dicarbonate'
Primary Skin Irritation Test - Albino Rabbits
Results
Animal Number	Irritation Scores for Abraded Skin Sites At:				Irritation Scores for Intact Skin Sites At:
	24 Hours		72 Hours		24 Hours		72 Hours
	Er.	Ed.	Er.	Ed.	Er.	Ed.	Er.	Ed.
1	4	4*	4	4*	4	4*	4	4*
2	2	2	2	1	2	2	2	1
3	4	4**	4	4**	4	4**	4	4**
4	4	4**	4	4**	4	4**	4	4**
Mean	3.5	3. 5	3. 5	3. 2	3.5	3. 5	3. 5	3. 2
Subtotal	13. 7				13. 7
Primary Irritation Score = 6.8

Key: Er. = Erythema Ed, = Edema * Subdermal hemorrhage ** Superficial burns

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

In 3/4 rabbits, both abraded and non-abraded sites had scores of 4 for both erythema and edema at 24 and 72 hours (beet or crimson red erythema and swelling of more than 1 mm). Superficial burns were noted in 2 of these animals at both time points. Erythema and edema were not as severe in one animal (scores of 2 and 1). The average primary irritation score was 6.8 (extremely irritating).

Executive summary:

Undiluted test material (0.5 mL) was applied to one intact and one abraded skin site on four rabbits under occluded conditions for 24 hours and assessed for up to 72 hours after exposure. In three of the four rabbits, both abraded and non-abraded sites showed severe erythema and edema at 24 and 72 hours. Carbonic acid, oxydiethylene diallyl ester was highly irritating to rabbit skin. Since the multi-constituent to be registered (EC 700 -742 -1) contains as a main ingredient diallyl 2,2'-oxydiethyl dicarbonate (CAS 142-22-3; EC 205-528-7), the experimental data from this substance were used in a read-across approach.

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:

December 1979 - March 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on supporting substance

Justification for type of information:

RAV 7MC (EC 700-742-1)
Reaction mass of diallyl oxydiethane-2,1-diyl biscarbonate, diallyl 2,2-dimethylpropane-1,3-diyl biscarbonate and allyl 2-(2-{[(allyloxy)carbonyl]oxy}ethoxy)ethyl 2,2-dimethylpropane-1,3-diyl biscarbonate

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

The rational for the analogue approach is the high structural similarity between the source substance RAV 7AT (# 1; CAS 142-22-3; EC 205-528-7) and the target substance RAV 7MC (EC 700-742-1). Both substances, RAV 7MC and RAV 7AT belong to a class of chemicals that is comprised of carbonate esters with a terminal allyl chain on both sides and that is only variable in carbon chain length. Thereby, RAV 7AT acts as a monomer with the smallest chain length and consequently the lowest molecular size compared to the other allyl carbonates. The main functional groups in the reaction mixture are allyl groups and ester functions. Due to the similarities in structure, composition and functional groups, similar physico-chemical properties of the substances are to be expected, which would result in similar toxicokinetic behaviour and most likely also in very similar physico-chemical, toxicodynamic and toxicological behaviour. Due to their overlapping constituent profile, using data from this related substance is reasonable.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The target chemical RAV 7MC is a UVCB of which the main constituent is the source chemical RAV 7AT (# 1; CAS 142-22-3; EC 205-528-7) including the same impurities # 2 (8 %), # 3 (2 %), # 7 (5 %) and # 8 (4 %). Besides RAV 7AT, RAV 7MC consists of further diallyl carbonates such as the constituents # 4 (23 %) and # 5 (11 %), which contain instead of an oxygen atom a quaternary carbon atom. It can be assumed that the hazard potential will not be enhanced by the quaternary carbon atom. The same applies for the impurities # 6 (3 %), # 9 (3 %), # 10 (2 %) and # 11 (4 %).

3. ANALOGUE APPROACH JUSTIFICATION

Due to the above-mentioned similarities of source and target chemical, with regard to their structure, functional groups and composition, it can be reasonably concluded that a similar physico-chemical, toxicokinetic and toxicological behaviour can be expected.
Thus, the common basic structure of the reaction mixture RAV 7MC consists of terminal allyl carbonates, whereby RAV 7AT can be regarded as a monomer, while the other constituents can be regarded as oligomers. In summary, the main difference between these molecules is the chain length and consequently the molecular size. Based on a worst case approach the toxicological and ecotoxicological properties of the target substance, RAV 7MC, are expected to be lower than the effects observed for the source substance RAV 7AT due to the molecular size. Additionally, from comparing the similar production processes of these substances it is apparent that RAV 7AT and RAV 7MC are closely related to each other. Finally, it can be assumed that the physico-chemical, toxicological and ecotoxicological properties of RAV 7MC and RAV 7AT will be very similar and as a result, read across is justified.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Vehicle:

unchanged (no vehicle)

Controls:

other: the left eye served as the untreated control

Duration of treatment / exposure:

a single exposure in one eye of albino rabbits

Observation period (in vivo):

All animals were observed closely for gross signs of systemic toxicity and mortality at frequent intervals during the day of dosing and at least twice daily thereafter for a ( total of 14 days. Room conditions as well as availability of adequate food and water were checked and any noteworthy conditions recorded.

Number of animals or in vitro replicates:

A total of nine rabbits (6 not rinsed and 3 rinsed) were used.

Irritation parameter:

overall irritation score

Basis:

mean

Remarks:

of six animals

Time point:

other: 1 h

Max. score:

8

Reversibility:

fully reversible within: 24 h

Remarks on result:

other: not rinsed

Irritation parameter:

overall irritation score

Basis:

mean

Remarks:

of three animals

Time point:

other: 1 h

Max. score:

3

Reversibility:

fully reversible within: 48 h

Remarks on result:

other: rinsed

Other effects:

no

Body Weights

Body weights at the termination of the study ranged from 2.15 to 2.75 kilograms. Body weight changes appear to be normal.

Observations and Mortality

No animal exhibited signs of systemic toxicity and no deaths occurred during the investigation.

Necropsy

Evaluation of the test animals at necropsy by the pathologist revealed no significant gross pathologic findings.

Primary Eye Irritation Index

Means of individual irritation scores used to calculate the primary irritation index presented in Table 3 and 4.

Table 3: Primary Eye Irritation Index in Rabbits (not rinsed)

Tissue	Examination Intervals
	1 h	6 h	24 h	48 h	72 h	4 Days	7 Days
Cornea	0	0	0	0	0	0	0
Iris	0	0	0	0	0	0	0
Comjunctiva	48	4	0	0	0	0	0
Total	48	4	0	0	0	0	0
Mean	8.0	0.67	0	0	0	0	0

Table 4: Primary Eye Irritation Index in Rabbits (rinsed)

Tissue	Examination Intervals
	1 h	6 h	24 h	48 h	72 h	4 Days	7 Days
Cornea	0	0	0	0	0	0	0
Iris	0	0	0	0	0	0	0
Comjunctiva	18	4	2	0	0	0	0
Total	18	4	2	0	0	0	0
Mean	3.0	0.67	0.33	0	0	0	0

Positive scores only noted in the conjunctiva lasted through the 24-hour examination interval. No positive findings were noted upon further examination with fluorescein dye.

Interpretation of results:

GHS criteria not met

Conclusions:

When 100% DDC (diallyl diglycol carbonate) was instilled into one eye of each of nine albino rabbits (6 not rinsed and 3 rinsed) the primary eye irritation index was determined to be 8.0 and was classified as minimally irritating. Instillation of water into the treated eyes of three rabbits did not change the classification but decreased the score to 3.0.

Executive summary:

The objective of this study was to determine the irritative potential of the test material following a single exposure in one eye of albino rabbits. Nine rabbits (6 not rinsed and 3 rinsed) were used.

0.1 mL of undiluted test material was instilled in the right eye of each animal. All animals were observed for signs of systemic toxicity and mortality until sacrifice on day 14. Body weights on the day of exposure and the termination were recorded. A gross necropsy were performed on the visceral and thoracic cavities. Primary Eye Irritation Index was calculated using the standard scoring system of Draize.

No positive findings were noted in two ocular tissues: cornea and iris. Positive scores were only noted in the conjunctiva lasted through 24 -hour interval. The one-hour interval provided the highest mean score (8.0) for 100% DDC (diallyl diglycol carbonate) and was therefore used as the primary irritation index and classified the test compound as minimally irritating using the method of Draize. Instillation of water into the treated eyes of three rabbits did not change the classification but decreased the mean score to 3.0.

Since the multi-constituent to be registered (EC 700 -742 -1) contains as a main ingredient diallyl 2,2'-oxydiethyl dicarbonate (CAS 142-22-3; EC 205-528-7), the experimental data from this substance were used in a read-across approach.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation

In the "Primary Skin Irritation Test" (Acute Toxicity Studies IBT No. A254, 1971 -09 -10) with 'diallyl 2,2'oxydiethyl dicarbonate' the exposure period was 24 hours. In accordance with the OECD Guideline 404 Acute Dermal Irritation-Corrosion the exposure period should be normally 4 hours. After 24 hour exposure period in three of the four rabbits, both abraded and non-abraded sites showed severe erythema and edema at 24 and 72 hour reading. Carbonic acid was found to be highly irritating to rabbit skin. Contradictive results were obtained in the irritation tests on the skin of rabbits (data published M.Lacroix et al., 1976, endpoint 7.3.1.003). Here 'diallyl 2,2'oxydiethyl dicarbonate provoked only minimal changes in the skin after 24 hours (slight erythema in certain animals). The exposure period of 24 hours is not realistic to humans. Therefore, the skin irritation studies of 'diallyl 2,2'oxydiethyl dicarbonate' (report dated 1976 -06 -04) was taken forward for risk characterization. In this study undiluted test material (0.5 mL) was applied to one intact and one abraded skin site on rabbits (3/sex) under occluded conditions for 6 hours and assessed for up to 13 days after exposure. At 48 hours, moderate to severe erythema were noted on all sites and by 72 hours, irritation progressed to necrosis with severe erythema and very slight edema. Reddened and blackened skin at all sites was noted. By 13 days, edema, but not erythema, resolved. "...there is no dose relationship between the reaction that occurred in the first treatment and the third treatment and the pattern of reaction inconsistent and not reproducible... The reaction seems not to depend upon the animal that is being tested or the amount of solution or site selection and thus, one can conclude that there certainly is reaction taking place but being not reproducible and one must consider this is a spurious result." (from the conversation letter of Dr. M. Vinegar, Toxicologist and P.T. Breen, Dermatologist, dated 1979- 03 -12). Carbonic acid, oxydiethylene diallyl ester irritating to rabbit skin.

Eye irritation

In the earlier study "Eye Irritation Test" [(Acute Toxicity Studies IBT No. A254, 1971 -09 -10) Endpoint 7.3.2.002] undiluted 'diallyl 2,2'oxydiethyl dicarbonate' (0.1 mL) was instilled in the conjunctival sac of the right eye of five rabbits. Test eyes were not washed. Irritation was scored at 1 minute, 1, 24 and 72 hours and 7 days after administration. Conjunctival redness and slight discharge was seen which resolved after 24 – 72 hours. In this study the test material was slightly irritating to rabbit eyes. In the Acute Eye Irritation Study in Rabbits with 100% DDC (report date 1981 -03 -24) the principle of test design was the same as in the previous one except the number of animals. 6 not rinsed and 3 rinsed animals were tested. The cornea and the iris were not affected, the conjunctiva was affected by one- and six-hour examination and the lesions were fully reversible within 24 hours. The one-hour interval provided the highest mean score (8.0) for 100% DDC (diallyl diglycol carbonate) and was therefore used as the primary irritation index and classified the test compound as minimally irritating using the method of Draize. Instillation of water into the treated eyes of three rabbits did not change the classification but decreased the mean score to 3.0. The test material is considered to be slightly irritating to eyes.

Justification for read-across from supporting substance RAV 7AT (diallyl 2,2'-oxydiethyl dicarbonate; CAS 142-22-3; EC 205-528-7): About 53 % of RAV 7MC (EC 700-742-1) consists of components that can be found in RAV 7NG (EC 700-483-4). About 60 % of RAV 7NG (EC 700-483-4) in turn consists of components that can be found in the commercial ADC grades known as RAV 7AT, Nouryset 200 and CR39. Merely from comparing the similar production processes of these substances it is apparent that RAV 7AT, RAV 7NG and RAV 7MC are closely related to each other. Finally, it can be assumed that the physical-chemical, toxicological and ecotoxicological properties of RAV 7MC and RAV 7AT will be very similar and as a result, read across is justified.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: slightly irritating (but GHS criteria not met)

Justification for classification or non-classification

GHS: Skin irritation Cat 2.

The classification is warranted according to the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulations No 1272/2008.