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Diss Factsheets

Administrative data

Description of key information

TMBX is hydrolytically unstable and breaks down to form methanol and boric acid in the presence of water. Skin absorption can be predicted for TMBX based on molecular weight and chemical structure. Subsequent hydrolysis to borate and methanol can be expected in epidermal tissues. Therefore, an assessment of skin sensitisation potential was conducted taking account of the hydrolysis breakdown products of TMBX.

Both Boric acid (m.w. 61 g/mol) and methanol (m.w. 32 g/mol) can be expected to readily penetrate the stratum corneum based on their physical properties (see IUCLID Section 4.7 Partition Coefficient and IUCLID Section 4.8 Water Solubility) and be available as potential haptens for skin sensitisation induction.

A study in Guinea pigs was conducted according to OECD Guide-line 406 (Buehler test) using 95 % w/w boric acid moistened with distilled water to enhance skin contact. Very faint erythema was observed in one animal at induction stage and 2 animals at challenge stage and also in one naïve control. No other adverse effects were observed therefore the test substance was considered a non-sensitiser.

The sensitising potential of Methanol was examined using a modified Magnusson-Kligman assay in Guinea Pigs (OECD 406). In the first run, 3/10 females exhibited a slight skin response (erythema score 1) 24 h after challenge with 50% methanol, which can be interpreted as weak sensitizing potential. In a second run using 12 female animals at a concentration of 50 % methanol, 1/12 exhibited a slight skin response (erythema score 1), 24 and 48 h after challenge which can be interpreted as a weak sensitising potential. Neither studies contained enough animals to have sufficient statistical power to discount a false positive result, therefore the results of the studies were combined to ensure a large enough experimental population. 4/22 animals were noted with slight erythema (score 1), this does not meet the criteria for a positive sensitisation reaction (>=30% of animals tested) Therefore there is no significant evidence for the sensitisation potential of methanol.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
Induction phase comprised 1st and 2nd induction, each subdivided into intradermal and epidermal treatment with 1-week-intervals between each treatment.
Principles of method if other than guideline:
Study was performed as modification of the Magnusson-Kligman test before the actual guideline was adopted.
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was conducted prior to the development and adoption of the LLNA Test guideline
Species:
guinea pig
Strain:
other: Pirbright White
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Firma Hagemann, Lippische Versuchstierzucht, 4923 Extertal
- Weight at study initiation: 449 - 824 g
- Diet (e.g. ad libitum): Ssniff K, ad libitum
- Water (e.g. ad libitum): ad libitum
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
50%
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
50%
No. of animals per dose:
1st study: 10 test, 5 control
2nd study: 12 test, 5 control
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 4
- Exposure period: d 0 (1st intradermal), 7 (1st epicutaneous), 14 (2nd intradermal), 21 ( 2nd epicutaneous)
- Test groups: 1st intradermal: 6 parallel injections with Freund's adjuvant, 50% methanol and Freund's adjuvant + 50% methanol, respectively; 2nd intradermal: 4 parallel injections with 50% methanol and Freund's adjuvant + 50% methanol, respectively; both epidermal: conc. methanol
- Control group: no induction treatment
- Site: shoulder region
- Frequency of applications: weekly
- Duration: epicutaneous: 48 h occlusive
- Concentrations: 50% intradermal, 100% epicutaneous


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 34 days after 1st intradermal induction
- Exposure period: 24 h occlusive
- Test groups: 1st study: right 50% methanol, left 25% formaldehyde epicutaneous; 2nd study: concentrated methanol epicutaneous
- Control group: 1st study: right 50% methanol, left 25% formaldehyde epicutaneous; 2nd study: concentrated methanol epicutaneous
- Site: flank
- Concentrations: 50% methanol and 25% formaldehyde, respectively (study 1), 100% methanol (study 2)
- Evaluation (hr after challenge): 24, 48 and 72 hours
Challenge controls:
Control groups (no induction treatment)
Positive control substance(s):
no
Positive control results:
Positive controls not performed.
Reading:
other: 1st reading; 1st group
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
3
Total no. in group:
10
Clinical observations:
slight erythema (score 1)
Reading:
other: 2nd reading ; 1st group
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
other: 3rd reading; 1st group
Hours after challenge:
72
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Reading:
other: 1st reading; 2nd group
Hours after challenge:
24
Group:
test chemical
Dose level:
50%
No. with + reactions:
1
Total no. in group:
12
Clinical observations:
slight erythema (score 1)
Reading:
other: 2nd reading; 2nd group
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
1
Total no. in group:
12
Clinical observations:
slight erythemy (score 1)
Reading:
other: 3rd reading; 2nd group
Hours after challenge:
72
Group:
test chemical
Dose level:
50%
No. with + reactions:
0
Total no. in group:
12
Clinical observations:
none
Remarks on result:
no indication of skin sensitisation
Reading:
other: negative control
Hours after challenge:
24
Group:
negative control
Dose level:
100% water
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
no indication of skin sensitisation
Reading:
other: positive control
Hours after challenge:
24
Group:
positive control
Dose level:
nil
No. with + reactions:
0
Total no. in group:
0
Remarks on result:
not measured/tested

In the first study, 3/10 females exhibited a slight skin response (erythema score 1) 24 h after challenge, in the parallel test with formaldehyde 1/10 females exhibited a slight skin response (erythema score 1) 24 h after challenge, which can be interpreted as weak sensitizing potential.

In the second study using 12 female animals at a concentration of 50 % methanol, 1/12 exhibited a slight skin response (erythema score 1) 24 and 48 h after challenge which can be interpreted as a weak sensitising potential.

The intracutane inductions produced necroses and some open ulcerations in both studies.

In summary, the low number of 4/22 animals with slight erythema (score 1) gives no evidence of a notable sensitisation potential of methanol.

Interpretation of results:
not sensitising
Remarks:
Migrated information
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
OECD Guide-line 406 "Skin Sensitisation" method (Buehler test ) was performed before the LLNA was set as preferred test method.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Davidson’s Mill Farms, South Brunswick, NJ
- Age at study initiation: Young adult
- Weight at study initiation: Males: 314 -411 g; females: 282-376 g
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
Induction: 0.4 g 95 % w/w boric acid
Challenge: 95 % w/w boric acid
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
Induction: 0.4 g 95 % w/w boric acid
Challenge: 95 % w/w boric acid
No. of animals per dose:
Test Group: 20 animals
Naive Control: 10 animals
Positive Control: 20 animals
Positive Naive Control: 10 animals
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Concentrations: 0.4 g 95 % w/w boric acid moistened with distilled water to enhance skin contact.


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: Day 28
- Exposure period: Test substance was wiped off with water after 6 h.
Challenge controls:
No data
Positive control substance(s):
yes
Remarks:
Dinitrochlorobenzene
Positive control results:
No data
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.4 g 95% w/w/boric acid
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Very faint erythema seen in one animal at induction stage and 2 animals at challenge stage and also in one naïve control. No other adverse effect observed
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.4g 95% w/w boric acid
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100% water
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100% water
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
dinitrochlorobenzene
No. with + reactions:
10
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
dinitrochlorobenzene
No. with + reactions:
7
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation

Observations:

Treatments

Buehler test

Observations/Remarks

 

Day of treatment

 

Induction 1

day 0

Very faint erythema (0.5) observed at one test site at 24 hours after first induction dose. No other irritation observed

Induction 2

7

No irritation observed

Induction 3

14

No irritation observed

Challenge

28

No irritation observed

Scoring 1

29

Very faint erythema (0.5) observed at two test sites at 24 hours after  challenge dose. Irritation persisted at one site for 48 hours.  Very faint erythema (0.5) observed at one test site at 24 hours in one naive control.

Scoring 2

30

 

Results of skin sensitisation test:

 

Number of animals with signs of allergic reactions /
number of animals in group

 

Negative control

Test group

Positive control

scored after 24h

0 / 10

0 / 20

10/20

scored after 48h

0 / 10

0 / 20

7/20
Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
OECD Guide-line 406 "Skin Sensitisation" method (Buehler test ) was performed using 95 % w/w boric acid moistened with distilled water to enhance skin contact. Very faint erythema was observed in one animal at induction stage and 2 animals at challenge stage and also in one naïve control. No other adverse effects were observed therefore the test substance was considered a non-sensitiser.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based upon the lack of skin sensitisation potential for the hydrolysis products of TMBX, which would be available as potential haptens for skin sensitisation induction, the criteria set out in 1272/2008/EC for classification of TMBX as a skin sensitiser are not met.