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Administrative data

Description of key information

Skin sensitisation (OECD 406, GPMT): not skin sensitising

Data read-across from the source substance bis(2-(2-butoxyethoxy)ethyl)adipate (CAS No. 141-17-3)

Respiratory sensitisation: no data available

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24 Oct - 27 Dec 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
(1992)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Version / remarks:
(2003)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
A non-LLNA test is available that was performed prior to the current data requirements, stipulated in Regulation (EC) No. 1907/2006. In accordance with the same Regulation, the data was included to avoid unnecessary testing.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Crl:HA
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: approximately 4 weeks old
- Weight at study initiation: 315 - 366 g
- Housing: The animals were kept in groups in Terluran - cages on Altromin saw fibre bedding (preliminary test: lot no. 190612, main study: lot no. 290912) in a semi barrier in an air-conditioned room.
- Diet: autoclaved hay and Altromin 3122 maintenance diet for guinea pigs (preliminary test: lot no. 1114, main study: lot no. 0807), rich in crude fibre; ad libitum
- Water: tap water (drinking water, municipal residue control, microbiological controls at regular intervals); ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
Route:
intradermal and epicutaneous
Vehicle:
other: physiological saline 0.9% NaCl (B. Braun Melsungen, lot no. 121678081, expiry date: 03/2015) for intradermal induction
Concentration / amount:
intradermal: 5%
epicutaneous: 100%
Route:
epicutaneous, occlusive
Vehicle:
other: vaseline (Euro OTC Pharma, lot no. 1105029-01, expiry date: 05/2014) for the challenge
Concentration / amount:
50%
No. of animals per dose:
- 3 (dose range finding study)
- 10 (test group), 5 (positive control group), 5 (negative control group)
Details on study design:
RANGE FINDING TESTS:
For the justification of dose levels a preliminary test was performed.
- 1 animal was treated intradermally with concentrations of 2.5% and 5% of the test item (suspended with physiological saline 0.9% NaCl).
- 1 animal was treated topically with concentrations of 50% and 100% of the test item (suspended with vaseline) for 24 hours.
- 1 animal was treated topically with concentrations of 50% and 100% of the test item (suspended with vaseline) for 48 hours.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: intradermal and epicutaneous, respectively
- Exposure period: single injection (intradermal) and 48 h (epicutaneous)
- Test groups:
Intradermal (3 pairs of injections):
Injection 1: a 1:1 mixture (v/v) FCA/physiological saline 0.9% NaCl
Injection 2: a 5% concentration of the test item in physiological saline 0.9% NaCl
Injection 3: a 5% concentration of the test item formulated in a 1:1 mixture (v/v) FCA/physiological saline 0.9% NaCl
Epicutaneous: 0.5 g of 100% test item
- Control group:
Intradermal (3 pairs of injections):
Injection 1: a 1:1 mixture (v/v) FCA/physiological saline 0.9% NaCl
Injection 2: 100% physiological saline 0.9% NaCl
Injection 3: a 50% (v/v) formulation of physiological saline 0.9% NaCl in a 1:1 (v/v) mixture FCA/physiological saline 0.9% NaCl
Epicutaneous: 0.5 g of vaseline
- Site: shoulder region
- Frequency of applications: every 7 days
- Duration: Days 0 - 8
- Concentrations: 5% intradermal, 100% epicutaneous

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 20
- Exposure period: 24 h
- Test groups: 0.5 g of 50% test item in vaseline and 0.5 g vaseline only
- Control group: 0.5 g of 50% test item in vaseline and 0.5 g vaseline only
- Site: left flank (test substance) and right flank (vehicle)
- Concentrations: 50%
- Evaluation (hr after challenge): 24 and 48 h

OTHER:
- The application area was not rinsed after challenge exposure.
Challenge controls:
The control group is actually a challenge control.
Positive control substance(s):
yes
Remarks:
2-Mercaptobenzothiazole: 2% in cottonseed oil and 50% w/v formulation of 2-mercaptobenzothiazole in a 1:1 (v/v) mixture FCA/physiological saline 0.9% NaCl
Positive control results:
- 24 h after removing the patch: erythema grade 2 in 2/5, erythema grade 1 in 3/5, oedema grade 1 in 2/5, eschar in 2/5 and desquamation in 3/5 positive control animals
- 48 h after removing the patch: erythema grade 1 in 5/5, eschar in 3/5 and desquamation in 5/5 positive control animals
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
intradermal induction: 5%; epicutaneous challenge: 50%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
intradermal induction: 5%; epicutaneous challenge: 50%
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
intradermal induction: 0%; epicutaneous challenge: 50%
No. with + reactions:
0
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
intradermal induction: 0%; epicutaneous challenge: 50%
No. with + reactions:
0
Total no. in group:
5
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
25% positive control substance
No. with + reactions:
5
Total no. in group:
5
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
25% positive control substance
No. with + reactions:
5
Total no. in group:
5

Preliminary Test:

For each induction the highest concentration to cause mild-to-moderate skin irritation, but well-tolerated systemically, was used.

Based on the results of this preliminary test, a concentration of 5% was chosen for the intradermal application of the main test and a concentration of 100% was selected for the dermal induction.

A concentration of 50% was found to be the highest dose which did not cause any signs of irritation after a topical treatment over a period of 24 hours and therefore was chosen for the challenge application in the main test.

Main Test:

All animals of both groups survived throughout the test period.

Signs of irritation during the induction:

Intradermal Induction I (24-hour reading):

- Injection site 1: erythema grade 1 in 5/5 negative control-, in 5/5 positive control- and 10/10 test animals, oedema grade 1 in 5/5 negative control-, in 5/5 positive control- and 10/10 test animals

- Injection site 2: erythema grade 1 in 1/5 positive control animals, oedema grade 1 in 1/5 positive control animals

- Injection site 3: erythema grade 1 in 1/5 negative control-, in 5/5 positive control- and 5/10 test animals, oedema grade 1 in 1/5 negative control-, in 5/5 positive control- and 5/10 test animals

Intradermal Induction I (48-hour reading):

- Injection site 1: erythema grade 1 in 5/5 negative control-, in 5/5 positive control- and 10/10 test animals, oedema grade 1 in 5/5 negative control-, in 5/5 positive control- and 10/10 test animals

- Injection site 2: no signs of irritation

- Injection site 3: erythema grade 1 in 1/5 negative control-, in 5/5 positive control and 5/10 test animals, oedema grade 1 in 1/5 positive control- and 1/10 test animals

Dermal Induction II (48-hour exposure, occlusive):

- Immediately after removing the patch: no signs of irritation in any of the test or control animals.

- 24 hours after removing the patch: no signs of irritation in any of the test or control animals.

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for grouping of substances and read-across

The read-across approach uses 'bis(2-(2-butoxyethoxy)ethyl)adipate' (CAS No. 141-17-3) as structurally similar source substance to transfer (read-across) data to the target substance 'reaction mass of bis[2-[2-(2-butoxyethoxy)ethoxy]ethyl]adipate and [2-[2-(2-butoxyethoxy)ethoxy]ethyl](3,6,9,12-tetraoxahexadecyl)adipate' (EC No. 943-330-9). The common feature of the source substance and the target substance is that they are diester derivatives of adipic acid, containing only even numbered and linear ethoxylated side chains. Both carboxylic functions of adipic acid are used to form esters with ethylene glycol monobutyl ethers of varying length. While the side chains of the target substance contain tri- and/or tetraethylene glycol monobutyl ether moieties, the side chains in the source substance are made up solely of diethylene glycol monobutyl ether. Thus, the ethylene glycol monobutyl ether substituents in the target substance contain 1 or 2 additional ethylene glycol monobutyl ether units. Although the constituents of the target substance are hence larger in size and have a higher molecular weight, it can be assumed that no significant steric hindrance is introduced when compared to the smaller side chains of the source substance. All parts of the ethylene glycol monobutyl ether side chains are freely rotatable due to the fact that neither a ring system nor π-bonds exert any constraints on rotatability. Therefore, it is feasible to assume an identical environmental and metabolic fate of both substances. In order to avoid the need to test every substance for every endpoint, the read-across from an analogue substance concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted using adequate and reliable data from the source substance in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006 (REACH). Structural similarity and similarities in properties and/or activities of the source and target substance are the basis of read-across.

Discussion

No data regarding skin sensitisation obtained with the target substance are available and therefore read-across of adequate information from the source substance is used. The skin sensitising potential of bis(2-(2-butoxyethoxy)ethyl)adipate (CAS No. 141-17-3) was studied in female guinea pigs according to the maximisation method described in OECD TG 406 (BSL, 2013b). In the induction phase, intradermal injections of the test substance at 5% in physiological saline 0.9% NaCl and/or FCA were applied into the clipped skin area of 10 animals. A control group, consisting of 5 animals, was injected with vehicle only and/or FCA. Since a preliminary study showed that the undiluted test substance did not induce skin irritation, the test area of control and treated animals was pre-treated with 10% sodium lauryl sulphate in vaseline to induce local irritation on Day 6. One day later, the epicutaneous induction treatment with the undiluted test substance (100%) was conducted in the test animals on the regions of intradermal injections for a period of 48 h. Control animals were tested with Vaseline only. On Day 22, the challenge treatment was performed by topical application of 50% test substance in vaseline to the skin of all animals for 24 h. No changes in body weight gain were observed between treated and control animals. No cutaneous reactions were provoked 24 and 48 h after challenge treatment in any of the animals of the test and control groups. A positive control group treated with a formulation of 25% 2-mercaptobenzothiazole in a 1:1 (v/v) mixture of FCA/physiological saline 0.9% NaCl was included in the study to prove the sensitivity of the test strain. Therefore, the test substance had no sensitising effect on guinea pigs under the chosen experimental conditions.

Conclusion on skin sensitisation

A reliable and adequate study performed with the source substance investigating the skin sensitisation potential yielded no skin sensitisation in guinea pigs. Thus, no hazard for skin sensitisation is identified for the target substance either.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 (REACH) information on intrinsic properties of substances may be generated by means other than tests, e.g. using information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI states that “substances whose physico-chemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Thus, data gaps can be filled by a read-across approach from a structural analogue source substance to avoid unnecessary animal testing.

The analogue concept is also used to derive the C&L of the target substance taking the properties of the source substance into account. Based on the analogue concept, available data on skin sensitisation do not meet the classification criteria according to Regulation (EC) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.