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Description of key information

A guinea pig Maximisation Test (GPMT) and a Buehler test according OECD TG 406 are reported. Although a weak skin sensitization potential of undiluted ditolyl ether cannot be fully excluded, the available data point out a very weak skin sensitizing potential and/or skin irritation potential of the pure, undiluted compound. Diluted compound (50%) showed no skin sensitization or irritation effect in both tests.

Two reliable GLP and guideline conform skin sensitisation studies are available. A guinea pig maximisation test (GPMT) and a Buehler test according OECD TG 406 was performed. Both studies are evaluated to determine a skin sensitisation potential.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

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Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990-05-15 to 1990-07-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study according OECD 406
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
For the maximisation test 3 groups were established per random: a test item group of 20 animals and 2 control groups of 10 animals each. Animals were used for two provocations (1. provocation after 7 weeks and a second provocation 24 h later). Control group 1 was used for the single 1. provocation test and control group 2 was used for the second provocation test.

The animals were initially exposed to the test substance by intradermal injection (55) and epidermal application (100%). following a rest period the animals were exposed to a challenge dose. the extend and degree of skin reaction to the challenge exposure in the test animals was compared with that demonstrated by control animals
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was conducted in the year 1990. At this time no valid OECD guideline for a LLNA was adopted.
Species:
guinea pig
Strain:
other: Bor: DHPW
Sex:
male
Details on test animals and environmental conditions:
male guinea pigs, SPF, ca. 5-8 weeks old, average weight 376 g, husbandry: standardised conditions, 5 animals per cage (makrolon type IV)
Route:
intradermal and epicutaneous
Vehicle:
other: cremophor/physiol. saline
Concentration / amount:
100% (undiluted), 50%, and 10% (in Cremphor/physiol saline)
Route:
epicutaneous, semiocclusive
Vehicle:
other: cremophor/physiol. saline
Concentration / amount:
100% (undiluted), 50%, and 10% (in Cremphor/physiol saline)
No. of animals per dose:
20 animals for the test item group, 10 animals each for the 1. + 2. control group
Details on study design:
RANGE FINDING TESTS: dose finding studies for intradermal and topical application were reported.


MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: single intradermal and topical
- Exposure period: one week after the intradermal exposure the topical exposure followed. after 3-4 weeks provocation was done
- Test groups: 20 animals
- Control group: 10 animals
- Site: back and flanks
- Frequency of applications: single
- Duration: indradermal induction 1 week , topical induction 3-4 weeks
- Concentrations: indradermal induction 5%, topical induction 100%


B. CHALLENGE EXPOSURE
- No. of exposures: 1. provocation includes the test item group and the 1. control group; 2. provocation includes the test item group and the 2. control group ¿ only one exposure
- Day(s) of challenge: 3-4 weeks after the intradermal induction
- Exposure period: 24 hours
- Test groups: 20 animals
- Control group: 10 animals
- Site: back and flanks
- Concentrations: 100, 50, 10 %
- Evaluation (hr after challenge): 48, 72 hours

Challenge controls:
2 control groups included; one group for 1. challange, second group for 2. challange
Positive control substance(s):
not specified
Reading:
1st reading
Hours after challenge:
48
Group:
test group
Dose level:
100%
No. with + reactions:
12
Total no. in group:
20
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100%. No with. + reactions: 12.0. Total no. in groups: 20.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
test group
Dose level:
100%
No. with + reactions:
2
Total no. in group:
20
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 100%. No with. + reactions: 2.0. Total no. in groups: 20.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
48
Group:
test group
Dose level:
10 or 50 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10 or 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
test group
Dose level:
10 or 50 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 10 or 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
10 or 50 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 10 or 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
10 or 50 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 10 or 50 %. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Group:
positive control
Remarks on result:
other: see 'Overall remarks, attachments'

After the 1. challenge with pure (100%) test compound 12 out of 20 animals of the test group revealed skin effects (score 1: discrete/patchy erythema); the control group revealed no skin reactions. After a 2. challenge with 10 or 50% test compound no skin effects were observed.

Treatment was tolerated without systemic symptoms by all animals. No death occured and body weight gain of the test group was identical with the control group.

A pilot experiment was conducted to define the induction and challange concentrations. After intradermal application of 5% compound erythema and a white area arround the injection site was observed. After dermal treatment of 4 animals 3/4 guinea pigs showed score 1erythema (discrete/patchy erythema) indicating some irritation property of the compound. No erythema was observed when control animal were topicall challanged with 100% compound during the test.

Interpretation of results:
GHS criteria not met
Executive summary:

In a Guinea Pig Maximization Test conducted according to OECD TG 406 and GLP animals were dosed with irritating concentrations of the test compound (5% for intradermal injection and 100% for topical application). During challenge with the undiluted compound 12 out of 20 animals showed slight erythema (grade 1) after 48 hours and 2 out of there animals showed slight erythema still after 72 hours. The remaining 10 animals showed no effect any more after 72 h. In a second, subsequent, challenge with 10 or 50% compound after a 7 day rest, no skin effects were observed in animals from the test or control group. No skin reaction was observed in any control animal throughout the main experiment. In a pilot experiment before the main experiment pure compound (100%) was topically applied to 4 naïve guinea pigs to define the topical induction and challenge dose for the main experiment. 3 out of 4 guinea pigs showed scale 1 skin erythema reaction indicating that pure compound has some irritation potential in guinea pigs. Overall, the data indicate some dermal irritation and/or low dermal sensitization potential of the compound.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study similar to OECD 406
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
The sensitisation potential of ditolyl ether was evaluated in a modified Buehler test with 3 epicutaneous inductions. 1. topical induction: 10 and 50%; 2. induction 100% and 3. induction 100% compound.
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
The study was reported in the year 1991. At this time no valid OECD guideline for a LLNA was adopted.
Species:
guinea pig
Strain:
other: Bor: DHPW
Sex:
male
Details on test animals and environmental conditions:
male guinea pigs, SPF, ca. 5-8 weeks old, average weight 376 g, husbandry: standardised conditions, 5 animals per cage (makrolon type IV)
Route:
epicutaneous, semiocclusive
Vehicle:
other: cremophor/physiol. saline
Concentration / amount:
100 % (undiluted), 50 % and 10% (in Cremphor/physiol. saline)
Route:
epicutaneous, semiocclusive
Vehicle:
other: cremophor/physiol. saline
Concentration / amount:
100 % (undiluted), 50 % and 10% (in Cremphor/physiol. saline)
No. of animals per dose:
10
Details on study design:
10 animals of the second control group of the GPMT were used (see GPMT Dieseng and Flucke 1991), whereas the dermal exposition for 24 hours with the test substance was considered as the first induction of the Buehler test. in intervals of 7 days the animals were treated again for to times for 6 hours with undiluted test substance. application volume was 0.5 ml per animal. animals of the test group and 10 untreated animals were applied the undiluted test substance and a formulation of 50%
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
100%
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100%. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 50%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
50%
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50%. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 50%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 50%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Group:
positive control
Remarks on result:
other: ee 'Overall remarks, attachments'

Two out of 10 animals treated with undiluted test substance revealed after the challenge a reddening of the skin (scale 1). One animal which was applied a formulation of 50% showed a very slight edema (scale 0.5) after 48 hours. No skin reaction was observed in the control animals.

In a pilot experiment before the main experiment pure compound (100%) was topically applied to 4 naïve guinea pigs to define the topical induction and challenge dose for the main experiment. 3 out of 4 guinea pigs showed scale 1 skin erythema reaction indicating that pure compound has some irritation potential in guinea pigs.

Interpretation of results:
GHS criteria not met
Executive summary:

In a Guinea pig test conducted according to Buehler, OECD TG 406 and GLP animals were topically induced with 10 or 50% (induction 1), 100 % undiluted compound (induction 1 and 2) and challenged with undiluted compound (group 1) and 50% compound (group 2). With the undiluted test substance (100%) erythema (scale 1) was observed in 2 out of 10 animals after 24 hours but not after 48 and 72 hours. With the 50% solution of the test substance 1 out of 10 animals showed a very slight reddening (scale 0.5) after 48 (but not after 24 or 72) hours. No skin reaction was observed in any control animal throughout the main experiment. In a pilot experiment before the main experiment pure compound (100%) was topically applied to 4 naïve guinea pigs to define the topical induction and challenge dose for the main experiment. 3 out of 4 guinea pigs showed scale 1 skin erythema reaction indicating that pure compound has some irritation potential in guinea pigs. Overall, the data indicate some dermal irritation and/or low dermal sensitization potential of the compound.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

In Guinea pig skin sensitization tests ambiguous results were reported indicating some dermal irritation and/or low dermal sensitization potential (Diesing and Flucke, 1991).

In a Guinea Pig Maximization Test conducted according to OECD TG 406 and GLP animals were dosed with irritating concentrations of the test compound (5% for intradermal injection and 100% for topical application). During challenge with the undiluted compound 12 out of 20 animals showed slight erythema (grade 1) after 48 hours and 2 out of there animals showed slight erythema still after 72 hours. The remaining 10 animals showed no effect any more after 72 h. In a second, subsequent, challenge with 10 or 50% compound after a 7 day rest, no skin effects were observed in animals from the test or control group. No skin reaction was observed in control animal throughout the main experiment.

In a subsequent topical Guinea pig test conducted in the same laboratory according to Buehler, OECD TG 406 and GLP animals were topically induced with 10 or 50% (induction 1), 100 % undiluted compound (induction 1 and 2) and challenged with undiluted compound (experimental group 1) and 50% compound (experimental group 2). With the undiluted test substance (100%) erythema (scale 1) was observed in 2 out of 10 animals after 24 hours but not after 48 and 72 hours. With the 50% solution of the test substance 1 out of 10 animals showed a very slight reddening (scale 0.5) after 48 (but not after 24 or 72) hours. No skin reaction was observed in control animal throughout the main experiment.

In a pilot experiment before the main experiments reported above pure compound (100%) was topically applied to 4 naïve guinea pigs to define the topical induction and challenge dose for the main experiment. 3 out of 4 guinea pigs showed scale 1 skin erythema reaction indicating that pure compound has some irritation potential in guinea pigs.

Overall, slight skin effects (scale 1) are seen in guinea pigs in a Maximization Test and a topical Buehler test only with the undiluted compound but not with diluted compound (10 or 50%). Since the pilot experiment indicates that the pure compound has some irritation potential in guinea pigs but not the 10 and 50% dilutions the experimental data might indicate some dermal sensitization potential for the undiluted compound (not diluted compound) and/or a dermal irritation potential in guinea pigs. Although a skin sensitization potential of undiluted ditolyl ether can not be fully excluded, the available examinations point out a very weak skin sensitizing and/or skin irritation potential.

In addition, no cases of human sensitization are published in the literature and no evidence of a sensitizing potential of ditolylether was seen in occupational health examinations of persons occupied in the production facilities of the registrant (personal communication).


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

no data


Justification for classification or non-classification

A classification is not necessary, although a weak skin sensitization potential of undiluted ditolyl ether cannot be fully excluded based on guinea pig skin sensitization tests the available experimental data point out a very weak skin sensitizing potential and/or skin irritation potential of the pure, undiluted compound. Diluted compound (50%) showed no skin effect.