Registration Dossier

Administrative data

Description of key information

Skin Sensitization

It was concluded that under the conditions of the present assay, TODI has a skin sensitisation potential (sensitiser) in the guinea pig maximization study.

Respiratory Sensitization

Although there is no respective study result for TODI available, for precautionary reasons TODI was classified as a substance that "may cause allergy or asthma symptoms or breathing difficulties if inhaled" as (1) TODI was found as sensitizer in a Magnusson & Kligman maximisation study in the guinea pig and (2) similar substances as e.g. MDI (CAS no. 9016-87-9) and 4,4'-Methylendicyclohexyldiisocyanat (CAS no. 5124-30-1; EC no. 225-863-2) are also labelled with H317 and H334 due to the isocyanic moiety as a common structural alert. Based on the available data described for similar isocyanates, a potential for respiratory sensitisation is likely for TODI too.

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:
1997-11-03 to 1997-12-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 1
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:
1992
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
This Guinea Pig Maximization Test (1998) met the previous REACH requirements of Annex VII, section 8.3 as the first version of LLNA (OECD 429) was issued in 2002. The GPMT is suitable and reliable to cover this endpoint. For this reason and for animal welfare reasons, no further in vivo study (LLNA test) needs to be performed.
Test material information:
Composition 1
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Hall Limited, Burton-on-Trent, Staffordshire, UK
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 301 to 381 g
- Housing: single or in pairs
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 21
- Humidity (%): 46 to 66
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route:
intradermal
Vehicle:
arachis oil
Concentration / amount:
0.1% (w/v)
Day(s)/duration:
Day 0
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
intradermal
Vehicle:
other: 1:1 Mixture of FCA/water
Concentration / amount:
0.1 (w/v)
Day(s)/duration:
Day 0
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
50% (w/w)
Day(s)/duration:
Day 7/48 hours
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
50% (w/w)
Day(s)/duration:
Day 21/24 hours
Adequacy of challenge:
highest non-irritant concentration
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
25% (w/w)
Day(s)/duration:
Day 21/ 24 hours
Adequacy of challenge:
other: One lower concentration than the highest non-irritant concentration
No. of animals per dose:
Total: 15 guinea pigs (10 test; five control)
Details on study design:
RANGE FINDING TESTS:
A. INTRADERMAL INDUCTION
- No. of exposures: four 0.1 mL injections of each concentration
- Concentrations: 5 %, 1 %, 0.5 %, 0.1 % (w/v) in arachis oil
- Evaluation after injection: 24, 48 and 72 hours and 7 days
B.TOPICAL INDUCTION
- Concentrations: 50 %, 25 %, 10 %, 5 % (w/w) in actone
- Exposure period: 48 hours
- Evaluation after dressing removal: 1 hour, 24 and 48 hours

MAIN STUDY
A.1 INDUCTION EXPOSURE (intradermal); on day 0
- No. of exposures: three pairs of injections (0.1 mL per injection)
- Site: left and right side of the mid-line (shoulder region)
- Frequency of applications: single injection
- Test group:
a) Freund's Complete Adjuvant plus destilled water in the ratio 1:1
b) 0.1 % w/v formulation of the test material in arachis oil BP;
c) 0.1 % w/v formulation of the test material in a 1:1 preparation of Freund's Complete Adjuvant plus destilled water
- Control group:
a) Freund's Complete Adjuvant plus destilled water in the ratio 1:1
b) arachis oil BP;
c) a 50% w/v formulation of arachis oil BP in Freund's Complete Adjuvant/distilled water 1:1

A.2 INDUCTION EXPOSURE (topical application); on day 7
- Test group: 50% test substance in acetone
- Control goup: acetone
- Site: shoulder region
- Duration: 48 hours

B. CHALLENGE EXPOSURE
- No. of exposures: 2
- Day(s) of challenge: on Day 21
- Exposure period: 24 hours
- Test groups: 10
- Control group: 5
- Site: shorn right flank (50% test material formulation), left shorn flank (25% test material formulation)
- Concentrations: 50 % and 25 % in acetone
- Evaluation (hr after challenge): 24, 48 and 72 h

Challenge controls:
Yes
Positive control substance(s):
no
Positive control results:
None
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
25%
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
See "any other information on results"
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
50%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
See "any other information on results"
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
25%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
See "any other information on results"
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
50%
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
See "any other information on results"
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test group
Dose level:
25%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
See "any other information on results"
Remarks on result:
positive indication of skin sensitisation
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test group
Dose level:
50%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
See "any other information on results"
Remarks on result:
positive indication of skin sensitisation
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation

Intradermal and Topical Sighting Test

Concentrations selected for the main study:

Intradermal induction: 0.1 % w/v in archis oil BP

Topical induction: 50 % w/w in acetone

Topical challenge: 50 % and 25 % w/w in acetone

Main Study

Skin reaction observed after intradermal induction:

Well-defined erythema was noted at the intradermal induction sites of the test group animals at the 24 and 48 -hour observations.

Very slight or well-defined erythema was noted at the intradermal induction sites of control group animals at the 24 and 48 -hour observations.

Skin reactions observed after topical induction:

Well-defined erythema and slight oedema was noted at the topical induction sites of all test group animals at the one hour observation. Incidents of very slight to well-defined erythema ans very slight to slight oedema were noted in test group animals at the 24-hour observation. Incidents of bleeding from the injection sites and bleeding wounds caused by the animal scratching the test site were also noted at the induction sites of test group animals at the 1-hour observation with small superficial scattered scabs, hardened dark brown/black coloured scab, crust formation or desquamation noted at the 24-hour observation. The degree of erythema and oedama could not be evaluated at the induction sites of four test group animals a the 24-hour observation.

Skin reactions observed after topical challenge:

25 % w/w in Arachis Oil BP

Positive skin responses ( very slight to well-defined erythema - grades 1 to 2), and incidents of very slight oedema or slight oedema were noted at the challenge sites of four test group animals at the 24-hour observation and one test group animal at the 48- and 72-hour observations. The degree of erythema could not be determined at the challenge sites of four test group animals at the 24 -hour observation because of other adverse reactions (hardened dark brown/black-coloured scab, scattered scabs and residual test material). These responses were attributed to contact sensitisation and therefore regarded as positive reactions. Very slight to slight oedema was also noted at two of these challenge sites at this time.

Residual test material and incidents of physical damage caused by attempted removal of adhered test material persisted at the challenge sites of nine test group animals at the 48-hour observation and nine test group animals at the 72-hour observation.

The degree of erythema could not be evaluated at the challenge sites of eight test group animals at the 48 and 72-hour observations. Similarly the degree of oedema could not be evaluated at the challenge sites of seven test group animals at the 48-hour observation and eight test group animals at the 72-hour observation. This was due to the severity of the other adverse reactions (hardened dark brown/black colured scab, physical damage to skin caused by attempted removal of adhered test material, loss of skin elasticity and flexibility, superficial cracking of the epidermis, desquamation, small superficial scattered scabs and crust formation).

Residual test material was noted at the challenge sites of all control group animals at the 24, 48 and 72-hour observations with physical damage to skin caused by attempted removal of adhered test material noted at none of these sites of control group animals.

50 % w/w in Arachis Oil BP

Posistive skin responses (very slight or well-defined erythema - grades 1 to 2) and incidents of very slight or sligth oedema were noted at the challenge sites of five test group animals at the 24-hour observation and two test group animals at the 48-hour observation. Slight oedema persisted at one of these challenge sites at the 72-hour observation. The degree of erythema could not be determined at the challenge sites of four test group animals at the 24 -hour observation, six test group animals at the 48 -hour observation and nine test goup animals at the 72-hour observation because of the severity of other adverse reactions noted. these included physical damage to skin caused by attempted removal of adhered test material, hardened dark brown/black coloured scab, small superficial scattered scabs, loss of skin elasticity and flexibility, crust formation and desquamation. The degree of oedema could also not be determiend at the challenge sites of three test group animals at the 24 -hour observation, six test group animals at the 48-hour observation and eight test gorup animals at the 72-hour observation. Incidents of residual test material were noted at the challenge sites of two control group animals at the 24, 48 and 72-hour observations, No skin reactions were noted at these times.

Body weight gains of guineaa pigs in the test group, between Day 0 and Day 25 were comparable to those observed in the control group animals over the same period.

Interpretation of results:
Category 1A (indication of significant skin sensitising potential) based on GHS criteria
Conclusions:
TODI was assessed for skin sensitization in a maximization test in the albino guinea pig according to EU Method B.6/ OECD Guideline No. 406. It was concluded that under the conditions of the present assay, TODI has a skin sensitisation potential (sensitiser) in the maximisation study.
Executive summary:

A study was performed to assess the contact sensitisation potential of the test material in the albino guinea pig. The study was performed in compliance with the OECD Guidelines for Testing of Chemicals No. 406 "Skin Sensitisation" (adopted 17 July 1992) and Method B6 of the Commission Directive 92/69/EEC.

Ten test and five control animals were used for the main study.

Based on the results of sighting test, the concentrations of test material for the induction and challenge phases were selected as follows:

Intradermal Induction: 0,1 % w/v in arachis oil BP

Topical Induction: 50 % w/w in acetone

Topical Challenge: 50% and 25 % w/w in acetone

The test material produced a 90 % (9/10) sensitisation rate. It was concluded that under the conditions of the present assay, TODI has a skin sensitisation potential (skin sensitiser) in the maximisation study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

A study was performed to assess the contact sensitisation potential of the test material in the albino guinea pig. The study was performed in compliance with the OECD Guidelines for Testing of Chemicals No. 406 "Skin Sensitisation" (adopted 17 July 1992) and Method B6 of the Commission Directive 92/69/EEC.

Ten test and five control animals were used for the main study.

Based on the results of sighting test, the concentrations of test material for the induction and challenge phases were selected as follows:

Intradermal Induction: 0,1 % w/v in arachis oil BP

Topical Induction: 50 % w/w in acetone

Topical Challenge: 50% and 25 % w/w in acetone

The test material produced a 90 % (9/10) sensitisation rate. It was concluded that under the conditions of the present assay, TODI has a skin sensitisation potential (sensitiser) in the maximisation study.


Respiratory sensitisation

Link to relevant study records
Reference
Endpoint:
respiratory sensitisation, other
Remarks:
Expert Statement
Type of information:
other: Expert statement
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No study result but rational argumentation also considering structural analogue substances.
Reason / purpose:
reference to other study
Reference:
Composition 1
Qualifier:
according to
Guideline:
other: expert evaluation
GLP compliance:
no
Test material information:
Composition 1
Species:
other: not applicable
Strain:
other: not applicable
Details on test animals and environmental conditions:
not applicable
Route of induction exposure:
other: not applicable
Route of challenge exposure:
other: not applicable
Vehicle:
other: not applicable
Concentration:
not applicable
No. of animals per dose:
not applicable
Details on study design:
not applicable
Challenge controls:
not applicable
Results:
Although there is no respective study result for TODI available, for precautionary reasons TODI was classified as a substance that "may cause allergy or asthma symptoms or breathing difficulties if inhaled" as (1) TODI was found as sensitizer in a Magnusson & Kligman maximisation study in the guinea pig and (2) similar substances as e.g. MDI (CAS no. 9016-87-9) and 4,4'-Methylendicyclohexyldiisocyanat (CAS no. 5124-30-1; EC no. 225-863-2) are also labelled with H317 and H334.
Interpretation of results:
sensitising
Conclusions:
Although there is no respective study result for TODI available, for precautionary reasons TODI was classified as a substance that "may cause allergy or asthma symptoms or breathing difficulties if inhaled" as (1) TODI was found as sensitizer in a Magnusson & Kligman maximisation study in the guinea pig and (2) similar substances as e.g. MDI (CAS no. 9016-87-9) and 4,4'-Methylendicyclohexyldiisocyanat (CAS no. 5124-30-1; EC no. 225-863-2) are also labelled with H317 and H334 due to the isocyanic moiety as a common structural alert. Based on the available data described for similar isocyanates, a potential for respiratory sensitisation is likely for TODI too. Therefore the TODI is expected to be a respiratory sensitiser.
Executive summary:

Although there is no respective study result for TODI available, for precautionary reasons TODI was classified as a substance that "may cause allergy or asthma symptoms or breathing difficulties if inhaled" as (1) TODI was found as sensitizer in a Magnusson & Kligman maximisation study in the guinea pig and (2) similar substances as e.g. MDI (CAS no. 9016-87-9) and 4,4'-Methylendicyclohexyldiisocyanat (CAS no. 5124-30-1; EC no. 225-863-2) are also labelled with H317 and H334 due to the isocyanic moiety as a common structural alert. Based on the available data described for similar isocyanates, a potential for respiratory sensitisation is likely for TODI too. Therefore the TODI is expected to be a respiratory sensitiser.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Although there is no respective study result for TODI available, for precautionary reasons TODI was classified as a substance that "may cause allergy or asthma symptoms or breathing difficulties if inhaled" as (1) TODI was found as sensitizer in a Magnusson & Kligman maximisation study in the guinea pig and (2) similar substances as e.g. MDI (CAS no. 9016-87-9) and 4,4'-Methylendicyclohexyldiisocyanat (CAS no. 5124-30-1; EC no. 225-863-2) are also labelled with H317 and H334 due to the isocyanic moiety as a common structural alert. Based on the available data described for similar isocyanates, a potential for respiratory sensitisation is likely for TODI too. Therefore the TODI is expected to be a respiratory sensitiser.


Justification for classification or non-classification

The substance is classified as skin sensitising cat. 1A and respriatory sensitising cat.1 according to Regulation No (EC) 1272/2008 (CLP).