Registration Dossier

Administrative data

Description of key information

- The substance is not a skin sensitiser.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The test was conducted by a laboratory that was not GLP accredited.
Principles of method if other than guideline:
Groups of 6 guinea pigs per induction concentration received open test material applications daily for 3 weeks. The vehicle was ethanol/acetone. Challenge applications at 1% were made days 21 and 35. Reactions were assessed 24 and 48 hours after application.
GLP compliance:
no
Type of study:
open epicutaneous test
Justification for non-LLNA method:
Currently no LLNA study is available for assessment. The open epicutaneous test has been carried out as an animal test to predict human sensitization for over a decade and is recommended by international test guidelines such as OECD.
Species:
guinea pig
Strain:
not specified
Sex:
female
Route:
intradermal
Vehicle:
other: ethanol/acetone (equal parts)
Concentration / amount:
Induction: 0.1 ml of 30%, 10% or 3% AHTN dissolved in a ethanol:acetone (1:1) mixture was applied daily for three weeks on the clipped flank skin with an area of 8cm2.
Challenge: 0.025ml of 3%, 1% or 0.3% AHTN dissolved in a ethanol:acetone (1:1) mixture was applied on day 21 and day 35.
Route:
epicutaneous, open
Vehicle:
other: ethanol/acetone (equal parts)
Concentration / amount:
Induction: 0.1 ml of 30%, 10% or 3% AHTN dissolved in a ethanol:acetone (1:1) mixture was applied daily for three weeks on the clipped flank skin with an area of 8cm2.
Challenge: 0.025ml of 3%, 1% or 0.3% AHTN dissolved in a ethanol:acetone (1:1) mixture was applied on day 21 and day 35.
No. of animals per dose:
6 animals
Details on study design:
30%, 10% and 3% AHTN dissolved in equal parts of ethanol and acetone, were used for skin irritation and induction of allergic sensitization test. The minimal irritant and maximal non-irritant concentrations were determined. All animals (including the controls) were challenged at day 21 and rechallenged at day 35. The test material is considered allergenic if the score is at least 1 out of 6 animals showing a positive response with the non-irritating concentrations used for the challenge. Scores were read 24 and 48 hours after the applications.
Challenge controls:
2 control groups of each 6 animals; an untreated and a vehicle treated control group. Control groups were not induced, but they were challenged on day 21 and rechallenged on day 35.
Positive control substance(s):
no
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
All
No. with + reactions:
0
Total no. in group:
6
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:
All
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Reading:
other: 1st and 2nd reading after 24 and 48h correspondingly
Group:
positive control
Remarks on result:
not measured/tested
Remarks:
Not tested

Repeated applications during the induction produced moderate to strong skin irritation. Therefore, the first application site had to be changed after a 2 weeks' treatment.

The 1% solution of AHTN caused no primary irritant skin reactions in the control animals. Challenge tests with the highest non-irritant solution of AHTN (1%) on days 21 and 35 were negative for all the induction concentration groups.

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
AHTN applied at 30% in an ethanol:acetone (1:1) mixture daily over three weeks at a concentration up to 30%, does not cause allergic contact dermatitis.
Executive summary:

AHTN concentrations of 3, 10 or 30% in ethanol:acetone (50:50) mixtures were applied in 0.1ml doses to 8 cm2 clipped flank skin of 6 guinea pigs per dose. These concentrations were irritating under the conditions used, hence the application site was changed after two weeks during the induction phase. The maximal non-irritating dose was 1%. At the challenge and re-challenge stage two weeks later, the non-irritating dose was applied to a 2 cm2 naïve site. Reactions were read 24 and 48 hours after each challenge dose, and compared to reactions in non-induced control animals. No sensitisation reactions were observed.

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

Although the Murine Local Lymph Node Assay is the preferred method for in-vivo testing, the conclusion on the sensitisation potential has been based on the open epicutaneous test on Guinea pigs. This test and the existing Human in-vivo study (Berger 1998) have been regarded sufficient in the EU Risk Assessment of AHTN to conclude that the substance is not a skin sensitiser.

Migrated from Short description of key information:

The skin sensitisation potential has been assessed by in-vivo studies in animals and in humans.

Respiratory sensitisation

Link to relevant study records
Reference
Endpoint:
respiratory sensitisation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
18 June 2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The report is a historical overview of the conditions of workers with regard to respiratory sensitisation.
Principles of method if other than guideline:
The olfactive quality control of Tonalid is a repeated exposure to Tonalid. The history of the staff of quality assurance has been reviewed. No specific test protocol has been developed prior to the assessment. However, the olfactive quality control procedure at the Quality Assurance (QA) department of PFW Aroma Chemicals BV has been described in detail as part of the ISO 9001 certification. PFW has been ISO 9001 certified and keeps record of the olfactive quality control.
GLP compliance:
no
Species:
human
Sex:
male/female
Route of induction exposure:
inhalation
Route of challenge exposure:
inhalation
Vehicle:
unchanged (no vehicle)
Concentration:
100% AHTN
Details on study design:
Workers at the quality assurance department conduct olfactive quality controls of pure (100%) AHTN (CAS 1506-02-1). Liquid samples, which are at elevated temperatures are cooled, solidified and ground. Powder samples are only ground. Olfactive control takes place at the head space of the sample.
Results:
No sensory irritation of the airways and no respiratory reactions like asthma, rhinitis and alveolites were reported over a period of more than two decades.
Interpretation of results:
not sensitising
Remarks:
and not a respiratory irritant
Conclusions:
Based on the human practical experience, it is concluded that AHTN is not a respiratory irritant or sensitiser.
Executive summary:

Respiratory irritation and sensitisation have been assessed on the basis of occupational exposure of the quality assurance staff to pure AHTN during the olfactive quality control of Tonalid.

No adverse respiratory responses to AHTN have been reported. It is concluded that AHTN is not a respiratory irritant or sensitiser.

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

No information requirements are present under REACH for respiratory sensitisation, but the practical experience that has been gained over years showed that Tonalid (AHTN) is not a respiratory sensitiser or a respiratory irritant. The preventive medical examination performed by a competent Dutch centre (Arbo Unie) did not reveal any work related respiratory problems as well.

Migrated from Short description of key information:

In-house examination at PFW Aroma Chemicals BV showed that AHTN is not a respiratory sensitiser or a respiratory irritant.

Justification for classification or non-classification

Based on the available information classification for skin sensitisation is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008.