Registration Dossier

Administrative data

Description of key information

not sensitising

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
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 406 (Skin Sensitisation)
Deviations:
not applicable
Principles of method if other than guideline:
The animals were acclimated to the laboratory for at least four days before they were used (five days in OECD 406).The test animals are initially exposed to the test substance by epidermal application (induction exposure). The test material was applied to the same site of test animal once each week for a total of three applications. The control animals were maintained without treatment until primary challenge application (following OECD 406 control animals should be treated sham and then receive the challenge exposure). Following a rest period of 10 to 14 days (induction) the animals were exposed to a challenge dose.
GLP compliance:
no
Remarks:
The study was performed prior to the adoption of the test guideline specified
Type of study:
Buehler test
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Murphy Breeding Laboratories, Inc., R. R. 3, Box 445, Plainfield, Indiana 46168.
- Age at study initiation: data not available
- Weight at study initiation: 300 - 400 gm at the time of delivery (determined by the supplier, seven days prior to study initiation).
- Housing:singly in wire mesh cages suspended above the droppings throughout the study.
- Diet (e.g. ad libitum): Purina Guinea Pig Chow was available ad libitum throughout the study.
- Water (e.g. ad libitum): The animals were maintained on medicated water containing 4% of sulfaethoxypyridazine (6.25% S.E.Z.R, American Cyanamid) for four days. At the end of this period they were furnished with non-medicated water ad libitum
- Acclimation period: at least four days
The animals were of a size that would easily fit into the restrainers used throughout the study.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): data not available
- Humidity (%): data not available
- Air changes (per hr): data not available
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To: data not available
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
0.4 mL (undiluted) was used in the group of test animals. Based on specific density 1.143 of test material the concentration used was 0.4572 mg/mL. In pilot study the test substance was tested as undiluted, and as 50%, 25%, and 10% v/v solution in acetone.
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
0.4 mL (undiluted) was used in the group of test animals. Based on specific density 1.143 of test material the concentration used was 0.4572 mg/mL. In pilot study the test substance was tested as undiluted, and as 50%, 25%, and 10% v/v solution in acetone.
No. of animals per dose:
20 test animals;
10 control animals (were maintained without treatment until primary challenge application).
4 pilot study animals (one animal per dose)
Details on study design:
RANGE FINDING TESTS:

Four additional guinea pigs were used for a pilot study to determine the highest non-irritating concentration which could be applied for the primary challenge : For this purpose the test substance was tested as undiluted, and as 50%, 25%, and 10% v/v solution in acetone.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 hours
- Test groups: test material 0.4 mL (undiluted)
- Control group: without treatment
- Site: The upper left quadrant of the backs of the test guinea pigs was clipped using electric clippers. On the following day the patches were applied using a Parke-Davis Readi Bandage coverlet with a 20 x 20 mm Webril swatch moistened with test material. The guinea pigs were placed in restrainers and rubber dental damming was placed over the animals' backs and secured to the restrainers with clips. After an exposure period of six hours, the patches were removed and the animals were returned to their cages.

The patches were reapplied to the same site once each week for a total of three applications. The same site was shaved the day before each application was made. A new vial of the test substance was used for each application.

On the day following application, the clipped areas were depilated with Neet Cream Hair Remover (Whitehall Laboratories, Inc., New York, N.Y. 10017). The depilatory was allowed to remain on the sites for 15 to 30 minutes and was then washed off with warm (ca. 37°C) tap water.

- Frequency of applications: once each week
- Duration: three weeks
- Concentrations: 0.4 mL
The patch sites were scored for irritation four to five hours later.
After an exposure period (three week) followed two-week rest period

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: after two-week rest period (day 28 approx.)
- Exposure period: 6 hours
- Test groups: test material 0.4 mL (undiluted)
- Control group: test material0.4 mL (undiluted)
- Site: After a two-week rest period a fresh application site for primary challenge was prepared by clipping the lov/er left quadrant of the backs of the test and control guinea pigs.
- Concentrations: 0.4 mL
- Evaluation (hr after challenge): On the next day the sites were depilated and scored within two to three hours (24-hour reading). The sites were scored again for a 48-hour reading without additional depilation.
Challenge controls:
were treated in the same manner as test animals during challenge exposure
Positive control substance(s):
no
Concentration:
Not applicable
No. of animals per dose:
Not applicable
Details on study design:
Not applicable
Statistics:
Not applicable
Positive control results:
no
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.4 mL
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no reaction
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.4 mL. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: no reaction.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.4 mL
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no reaction
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.4 mL. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: no reaction.
Reading:
1st reading
Hours after challenge:
24
Group:
other: untreated controls
Dose level:
0.4 mL
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no reaction (only 9 animals were evaluated due to a death during the study
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: other: untreated controls. Dose level: 0.4 mL. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no reaction (only 9 animals were evaluated due to a death during the study.
Reading:
2nd reading
Hours after challenge:
48
Group:
other: untreated controls
Dose level:
0.4 ml
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no reaction (only 9 animals were evaluated due to a death during the study)
Remarks on result:
other: see Remark
Remarks:
Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: untreated controls. Dose level: 0.4 ml. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no reaction (only 9 animals were evaluated due to a death during the study).
Parameter:
SI
Remarks on result:
other: Not applicable
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: Not applicable

Irritative effects noted during the pilot test of the test substance included one grade of ± and three grades of 0 as undiluted; four grades of 0 as a 50% v/v solution in acetone; four grades of 0 as a 25% v/v solution in acetone; and four grades of 0 as a 10% v/v solution in acetone. During the primary challenge of the test substance as undiluted in the main study, reactions noted in the test animals at the 24-hour reading included twenty grades of 0. At the 48-hour reading twenty grades of 0 were noted in the test animals. For the control animals nine grades of 0 were noted at the 24-hour and 48-hour readings. One control guinea pig was found dead in the restrainer during the challenge application.

"The death of one animal in the study may not necessarily be indicative of test material toxicity. Occasionally an animal on this type of test may die due to trauma related to the restraint procedure. While additional veterinary medical and toxicological information would be necessary to absolutely confirm the cause of death of this particular animal, the fact that no mortalities were noted in the test animals (which received four doses of 0.4 mL of the test substance), and the mortality was in a control animal (which received only one dose of 0.4 mL of the material) during restraint suggests the death was probably due to the restraint procedure." (from a conversation letter between M.B. Vinegar and Dr. A. Plilip Leber from 1979 -02 -27, included in the present study )

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
When tested according to the method of Buehler, CR-39 Monomer produced no positive responses at the 24 or 48-hour readings in any of the test or control animals.
Executive summary:
The study was conducted to evaluate the potential of 'diallyl 2,2'oxydiethyl dicarbonate' to induce delayed contact hypersensitivity in guinea pigs. The sample used in this study was received from PPG Industries, Inc. on January 2, 1979. The substance is a clear liquid, the procedure used was based on that of Buehler.

The test included three phases: induction phase, when test material is applied to hair free skin of test animals for 6 hours occlusive each week for a total of three application; two-week rest period during which an immune response may develop and challenge phase during which the immune system if sensitized react hypersensitive.

20 test animals and 10 control animals were used in the study. 0.4 mL of test material undiluted was used in the induction phase and in the challenge phase. Treated skin sites were scored according scale as described in the Buehler test method. 24 and 48 -hour readings were performed after the challenge applications.

No positive responses were found at the 24 or 48 -hour reading in any of the test or control animals. 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 sensitising)
Additional information:
In the delayed contact hypersensitivity study in guinea pigs of 'diallyl 2,2'oxydiethyl dicarbonate' (dated 1979-02-15) guinea pigs (10/sex) were dosed with 0.4 mL of the test substance to shaved intact skin under occluded conditions for 6 hours. Patches were reapplied to the same site of test animals once a week for a total of three applications. After a 2-week rest period, a fresh application site was challenged with 0.4 mL of the test substance as described previously. During the primary challenge, all 20 animals did not show any irritation at the 24- and 48-hour readings. The test substance was not a skin sensitiser in guinea pigs. 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.

Migrated from Short description of key information:
The "Delayed Contact Hypersensitivity Study In Guinea Pigs" (dated 1979-02-15) was performed prior to the adoption of the GLP regulations as well as OECD Guidelines.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

- Skin sensitisation: the test substance was not a skin sensitizer in guinea pigs and rabbits; the classification is not 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.

- Respiratory sensitisation: no data