Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
27 Apr - 17 Jun 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study with acceptable restrictions.
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
no reliabilty check included
Qualifier:
according to
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
yes
Remarks:
no reliabilty check included
GLP compliance:
yes
Type of study:
Buehler test
Species:
guinea pig
Strain:
other: Hsd/Win:DH
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: 340 g
- Housing: Groups of 2-3 animals in Makrolon Type IV cages with standard softwood bedding. Change of bedding: two times a week.
- Diet: Pelleted Altromin Maintenance Diet 3022 (Altromin GmbH, Lage, Germany), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 45-75
- Air changes (per hr): at least 8
- Photoperiod (hrs dark / hrs light): 12/12
- Other: Music during light hours
Route:
epicutaneous, occlusive
Vehicle:
peanut oil
Concentration / amount:
Induction: 25%
Challenge: 20%
Route:
epicutaneous, occlusive
Vehicle:
peanut oil
Concentration / amount:
Induction: 25%
Challenge: 20%
No. of animals per dose:
3 (preliminary), 5 (dose finding), 10 (controls), 20 (in test groups)
Details on study design:
PRELIMINARY STUDY
Preliminary tests were carried out to determine suitable concentrations for induction and challenge. The concentrations in a dose of 0.5 g (50%) and 0.5 mL (25%, 12.5% and 6%) were tested. The concentrations were applied on the left flanks of three animas in succession. The exposure was terminated after 6 h by removing the plaster and cleaning the skin with propylene glycol 20%.

DOSE FINDING
The non-irritating concentrations for the challenge were checked in five animals of the control group (treated with the vehicle one week before the 1st challenge). The concentrations applied on the right flank in a dose of 0.5 mL were 10%, 15%, 20% and 25%. The exposure was terminated after 6 h by removing the plaster and cleaning the skin with propylene glycol 20%. 24 and 48 hours later, dermal effects were evaluated.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 h
- Test groups: test substance in peanut oil
- Control group: peanut oil
- Site: left flank
- Frequency of applications: every 7 days
- Duration: Days 0-21
- Concentrations: 25%

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 35
- Exposure period: 6 h
- Test groups: test substance in peanut oil
- Control group: test substance in peanut oil
- Site: bilaterally to both sheared flanks (caudal) of animals of the treatment and the control group
- Concentrations: 20%
- Evaluation (hr after challenge): 24, 48 and 72 h after patch removal

EVALUATION CRITERIA
- see Table 1
Challenge controls:
The control group is actually a challenge control
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
20%
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
slight dermal effects at the left or right flank
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 20%. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: slight dermal effects at the left or right flank.
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
20%
No. with + reactions:
2
Total no. in group:
20
Clinical observations:
slight dermal effects at the left flank
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 20%. No with. + reactions: 2.0. Total no. in groups: 20.0. Clinical observations: slight dermal effects at the left flank.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
20%
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
slight dermal effects at the left or right flank
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 20%. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: slight dermal effects at the left or right flank.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
20%
No. with + reactions:
9
Total no. in group:
20
Clinical observations:
slight dermal effects in 8 animals and weak dermal effects in one animal at the left and/or right flank
Remarks on result:
other: see Remark
Remarks:
Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 20%. No with. + reactions: 9.0. Total no. in groups: 20.0. Clinical observations: slight dermal effects in 8 animals and weak dermal effects in one animal at the left and/or right flank.
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
negative control
Dose level:
20%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading:
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test group
Dose level:
20%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading:

PRELIMINARY STUDY

In the preliminary study no reaction of the test substance was observed up to 50% in the test animals. According to the author a solution of 25% was considered the minimal irritating concentration. The concentration chosen for the induction period was 25%.

DOSE FINDING

The tested solutions did not provoke any skin reactions at the 5 dose finding animals. The concentration chosen for challenge was 20%.

MAIN STUDY

Induction readings:

1 hour after the 3rd induction, three animals of the control group (15 animals: 10 control animals plus 5 animals out of the dose finding group) and four animals of the treatment group showed weak skin reactions. Only for one animal out of the treatment group slight skin reactions were observed after 24 hours (see Table 2).

Table 2. Skin reactions 1 and 24 hours (left flank) after 3rd induction.

Skin reaction/ Value

1 hour

c (15) / t (20)

24 hours

c (15) / t (20)

none / 0

12

16

15

19

slight / 0+

0

0

0

1

weak / 1

3

4

0

0

moderate / 2

0

0

0

0

strong / 3

0

0

0

0

c: control group; t: treatment group; ( ): number of animals

Challenge readings:

24 hours after challenge application, 2/20 animals of the treatment group (10%) and 2/10 animals of the control group (20%) showed slight dermal effects (see Table 3 and Table 4). After 48 hours, 8/20 animals of the treatment group (40%) and 2/10 animals of the control group (20%) showed slight skin reactions. Only for one treated animal (5%) weak skin reactions were observed after 48 hours. After 72 hours no skin reactions were observed in any animal.

Table 3. Summary of positive animals in % after challenge.

Skin reaction/ Value

control group

l / r

treatment group

l / r

 

24 h

48 h

72 h

24 h

48 h

72 h

slight / 0+

20

20

0

10

40

0

weak / 1

0

0

0

0

5

0

l: left flank; r: right flank; h: hours

Table 4. Individual gradings for animals of the treatment and the control groups.

 

Flank

Animal number

1st challenge

                            left                                                          right

     24 h             48 h             72 h            24 h           48 h             72 h

t1

0

0+

0

0

0+

0

t2

0

0+

0

0

0

0

t3

0

1

0

0

1

0

t4

0

0

0

0

0

0

t5

0

0

0

0

0+

0

t6

0

0

0

0

0

0

t7

0+

0+

0

0

0

0

t8

0

0+

0

0

0+

0

t9

0

0

0

0

0

0

t10

0

0

0

0

0

0

t11

0

0

0

0

0

0

t12

0

0

0

0

0

0

t13

0

0

0

0

0+

0

t14

0+

0+

0

0

0+

0

t15

0

0

0

0

0+

0

t16

0

0

0

0

0

0

t17

0

0

0

0

0

0

t18

0

0

0

0

0

0

t19

0

0

0

0

0

0

t20

0

0

0

0

0

0

c1

0

0

0

0

0

0

c2

0

0

0

0

0

0

c3

0

0

0

0

0

0

c4

0

0

0

0

0

0

c5

0

0

0

0

0

0

c6

0

0+

0

0+

0+

0

c7

0

0

0

0

0

0

c8

0+

0+

0

0

0

0

c9

0

0

0

0

0

0

c10

0

0

0

0

0

0

c: control group; t: treatment group; h: hours

grading: none / 0; slight / 0 +; weak / 1

Mortality/Body weight

No mortality was observed during the test period. No significant difference in the gain of the body weight between the treatment and the control group was observed.

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for grouping of substances and read-across

There is no data available on the skin sensitising potential of 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7). In order to fulfil the standard information requirements set out in Annex VII, 8.3, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from a structurally related substance is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7) is selected as reference substances for assessment of skin and eye irritation.

The read-across is based on the structural similarity between the source and target substances which are both esters of similar di-functional alcohols with the carboxylic acids. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of sensitisation

CAS#

111-21-7 (a)

91031-45-7 (b)

Chemical name

2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate

Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO)

Molecular weight (g/mol)

234.25

388.58; 416.63; 626.99; 683.1

Skin sensitisation

RA CAS 91031-45-7

Experimental result:
Not sensitising

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

Skin sensitisation

CAS 111-21-7

The available information is limited to a publication from the National Technical Information Service (Microfiche No. OTS0206591) the authors referred to a sensitisation study in guinea pigs with 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate to be not sensitising (unpublished data).

CAS 91031-45-7

A study investigating the skin sensitising properties of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) ester (3EO) is available. The study was conducted according to OECD 406 in compliance with GLP (Pittermann, 1994). Female guinea pigs (20 in test group, 10 in control group) were induced with three occlusive epicutaneous exposures at 25% of the test substance in peanut oil. The epicutaneous challenge was conducted 35 days after the first exposure using 20% of the test material. The negative control group was treated with the vehicle only. No positive control data was included in the study report for reliability check. One h after epicutaneous induction, 3 animals of the control group and 4 animals of the treatment group showed weak skin reactions. One day after challenge application, 10% of the treatment group and 20% of the control group showed slight skin reactions. The grade ‘slight skin reactions’ was additionally added by the author and was not evaluated as positive finding for skin sensitisation. After 48 h, 40% of the treatment group and 20% of the control group showed slight skin reactions. Only for one treated animal (5%) weak skin reactions were observed after 48 h and evaluated as positive result. After 72 h, no skin reactions were observed in any animal. No mortality and no significant differences in body weight gain between the treatment and the control group were observed. In summary, only one animal of the treatment group (5%) showed a positive result for skin sensitisation and thus Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) ester (3EO) was considered as not sensitising.

Conclusion for skin sensitisation

In conclusion, no evidence of skin sensitisation properties were seen after treatment with the structurally related source substance Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). Based on this result, no skin sensitisation potential for 2,2'-[ethane-1,2-diylbis(oxy)]bisethyl diacetate (CAS 111-21-7) is identified.


Migrated from Short description of key information:
Based on read-across from Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7):
Skin sensitisation: not sensitising

Justification for selection of skin sensitisation endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on read-across from the source substance Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7) following an analogue approach, the available data on skin sensitisation properties do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and the data are therefore conclusive but not sufficient for classification.