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Description of key information

AHTN has been assessed for skin and eye irritation and corrosion and is found not irritant or corrosive to skin.

AHTN has been tested in two dermal irritation studies in animals (Haynes). In one study, no dermal effects were observed. In the other study as a 50% solution in diethyl phthalate (DEP), slight dermal irritation was observed with the solution as well as DEP although the score for DEP was less. Based on recommended studies for hazard classification in rabbits, with the undiluted substance, AHTN does not need to be classified as a skin irritant.

AHTN has been tested for ocular irritation in rabbits in two studies. The irritation parameters for the cornea, iris, conjunctivae redness and chemosys were scored. The effects, if they occurred, were fully reversible In both studies, slight ocular irritation was observed. However, the magnitude of the effects is not high enough to require classification according to the EU guidelines.

(Source: EU Risk Assessment Report AHTN, ECB (May 2008)

Respiratory irritation: Based on practical experience over decades by the Quality Assurance staff of PFW, no respiratory irritation has been observed when staff was exposed to AHTN (see IUCLID entry 7.4.2 Respiratory sensitisation). Exposure is limited to dust, since the vapour pressure of AHTN is very low.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
172 hours
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to GLP requirements and EU method.
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
EEC Directive 79/831
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
semiocclusive
Preparation of test site:
other: Clipped
Vehicle:
water
Controls:
no
Amount / concentration applied:
undiluted AHTN moistened with water
Duration of treatment / exposure:
4 hour(s)
Observation period:
168 hour(s)
Number of animals:
3
Details on study design:
A four hour semi-occlusive patch test conducted on four female New Zealand white albino rabbits. A 0.5 ml aliquot of undiluted test material was applied to a 2.5 cm square of surgical lint B.P. which was then placed on an area of clipped, intact dorsal skin. The lint patches were held in place by encircling the trunk of the animal with a length of "Elastoplast" elastic adhesive bandage 10 cm wide. After four hours, the adhesive tapes were removed and the treated sites were cleansed by gentle swabbing with cotton wool soaked in warm water. One hour after removal of the patches and excess test material, the treated sites were assessed for reactions. Similar examinations were made at 24, 48, 72 and 168 hours after patch removal. Irritation was assessed and allocated a numerical value based on the following criteria: Erythema and Eschar Formation: 0 = No erythema; 1 = Very slight erythema (barely perceptible); 2 = Well-defined erythema; 3 = Moderate to severe erythema; 4 = Severe erythema (beet redness) to slight eschar formation (injuries in depth); Oedema Formation: 0 = No oedema; 1 = Very slight oedema (barely perceptible); 2 = Slight oedema (edges of area well defined by definite raising); 3 = Moderate oedema (raised approximately 1mm); 4 = Severe oedema (raised more than 1mm and extending beyond area of exposure).
Irritation parameter:
erythema score
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Remarks:
No erythema was observed at any time point
Irritation parameter:
edema score
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Remarks:
No edema in any rabbit at any time point
No reaction to treatment was observed in any animal throughout the study.
Interpretation of results:
GHS criteria not met
Remarks:
Migrated information An averaged value of 2 either in erythema or oedema means that the substance is an irritant to skin. Criteria used for interpretation of results: EU
Conclusions:
Classification: not irritating
Executive summary:

3 New Zealand White female rabbits were dermally exposed to 0.5 g AHTN (Tonalid®; purity>98%; moistened with 0.5 ml water) under a 6.25 cm2 semi-occlusive patch for 4 hr on the dorsal skin (clipped free of fur). Four hours later, the treated skin was cleaned by gentle swabbing with cotton wool soaked in warm water. Skin observations were at 1, 24, 48, 72, and 168 hr after patch removal. Controls were not used. No erythema or oedema was seen in any rabbit at any time point.

Source: EU Risk Asssessment Report AHTN, Luxembourg, Office for Official Publications of the European Communities, ECB (May 2008)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to GLP requirements and EU method.
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
Cited as Directive 84/449/EEC, B.5
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Healthy male young adult albino rabbits. Body weight range 2500g - 3500g obtained from ENKI konijnenfarm, Someren, The Netherlands. The animals were identified by ear marking. Animals were caged individually and did not receive hay or other extraneous material that might enter their eyes during treatment.
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
undiluted
Amount applied: 0.1 gram
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
168 hours post application
Number of animals or in vitro replicates:
3
Details on study design:
A sample of tonalid was examined for eye irritating properties in an experiment with albino rabbits. An aliquot of 0.1 g test material was instilled in 1 eye of 3 male New Zealand White albino rabbits with no further treatment (also not rinsed). The untreated eye served as a control. The eyes were examined at 1, 24, 48 and 72 hours and at 7, 14 and 21 days if reactions persisted.
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 168 hours.
Remarks on result:
other: individual means: 1-1-0
Irritation parameter:
iris score
Remarks:
opacity
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
0.22
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: individual means: 0.67-0-0
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
1.44
Max. score:
3
Reversibility:
fully reversible within: 29 days
Remarks on result:
other: individual means: 1.67-1.67-1
Irritation parameter:
chemosis score
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
1.22
Max. score:
4
Reversibility:
fully reversible within: 168 hours
Remarks on result:
other: individual means: 1.67-1-1

Individual scores for 3 animals from an eye irritation test with AHTN

Time point Cornea Iris Conjunctivae Conjunctivae
after opacity   Redness chemosis
1 hour 0-0-0 0-0-1 2-1-2 2-1-2
24 hours 1-1-0 1-0-0 2-2-1 2-1-1
48 hours 1-1-0 1-0-0 2-2-1 2-1-1
72 hours 1-1-0 0-0-0 1-1-1 1-1-1
7 days 0-0-0 0-0-0 0-1-1 0-0-0
Interpretation of results:
GHS criteria not met
Conclusions:
The cornea, iris, conjunctivae and chemosis scores were sufficiently assessed and the effects were fully reversible, except for some remaining redness in the conjunctivae after 7 days in 2 of the 3 animals. No effects were seen after 29 days.
Executive summary:

AHTN (Tonalid®; purity >98%) was applied undiluted as a finely ground powder (0.1 g) to the eyes of 3 New Zealand White albino rabbits. The test substance remained in the eyes for at least 24 hours. Eye irritation was evaluated at 1, 24, 48, 72 and 168 hour post application. Two rabbits had slight corneal opacity at 24-72 hr. Slight iritis was observed in one animal at the 1 hour observation and in another animal at the 24 and 48 hour observations. A slight (1/3 animals) to moderate (2/3 animals) redness and slight (2/3) to moderate (1/3 animals) swelling of the conjunctivae was seen after 24-48 hour. After 7 days a slight redness of the conjunctivae without any other effects was still seen in two animals. All effects had cleared by 29 days.

Source: EU risk asssessment AHTN, Luxembourg, Office for Official Publications of the European Communities, ECB May 2008, p. 179

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to GLP requirements and EU method.
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Healthy male young adult albino rabbits. Body weight range 2500g - 3500g obtained from ENKI konijnenfarm, Someren, The Netherlands. the animals were identified by ear marking. Animals were caged individually and did not receive hay or other extraneous material that might enter their eyes during treatment.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
undiluted
Amount applied: 0.1 other: gram
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
168 hours
Number of animals or in vitro replicates:
3
Details on study design:
A sample of tonalid was examined for eye irritating properties in an experiment with albino rabbits. An aliquot of 0.1 g finely ground test material was instilled in 1 eye of 3 male New Zealand White albino rabbits with no further treatment (also not rinsed). The test substance caused slight corneal opacity in one rabbits & moderate redness & slight or moderate swelling of the conjunctivae in all (3) rabbits. After seven days all eye effects had cleared completely. On the basis of the present results it was concluded that, according to the EEC-standards, tonalid is not an eye irritant.Comment: not rinsed
Irritation parameter:
cornea opacity score
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
0.22
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: individual means: 0-0.67-0
Irritation parameter:
iris score
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
other: individual means: 0-0-0
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
1.22
Max. score:
3
Reversibility:
fully reversible within: 168 hours
Remarks on result:
other: individual means: 1-1.33-1.33
Irritation parameter:
chemosis score
Remarks:
conjunctivae
Basis:
animal: All animals
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 168 hours
Remarks on result:
other: individual means: 1-1-1

Individual scores for 3 animals from an eye irritation test with AHTN

Time point Cornea Iris Conjunctivae Conjunctivae
after opacity   Redness chemosis
1 hour 0-0-0 0-0-0 2-2-2 2-2-1
24 hours 0-1-0 0-0-0 1-2-2 1-1-1
48 hours 0-1-0 0-0-0 1-1-1 1-1-1
72 hours 0-0-0 0-0-0 1-1-1 1-1-1
7 days 0-0-0 0-0-0 0-0-0 0-0-0
Interpretation of results:
GHS criteria not met
Conclusions:
Classification: not irritating
Executive summary:

AHTN (Tonalid®; purity >98%) was applied undiluted as a finely ground powder (0.1 g) to the eyes of 3 male New Zealand White albino rabbits. The test substance remained in the eyes for at least 24 hours. Eye irritation was evaluated at 1, 24, 48, 72 and 168 hour post application. One rabbit developed a slight corneal opacity (score 1 at 24 and 48 hours, only). Moderate redness and slight to moderate chemosis of the conjunctivae was seen in all three animals after one-hour post application. After 24 hours, this was reduced to slight (1/3 animals) to moderate redness (2/3 animals) and slight chemosis in all three. Complete recovery occurred by 7 days.

Source: EU risk asssessment Report AHTN, Luxembourg, Office for Official Publications of the European Communities, (ECB May 2008), p.178

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Based on structure considerations and practical experience, it was concluded that AHTN does not possess corrosive properties to the skin or eyes. This was concluded in the EU Risk Assessment Report of AHTN.

The substance is neither a strong acid (pH≤2) nor a strong base (pH≥11.5), but this is expected due to the low water solubility and the absence of groups responsible for proton release (acid) or uptake (base). It has therefore no (measurable) acid or alkaline reserve. AHTN is neither flammable in air at room temperature nor classified for skin irritation (or acute skin toxicity), up to the limit dose level of 2,000 mg/kg bw.

The leading studies in the assessment of skin irritation are two in-vivo studies on 6 rabbits that were conducted under GLP accredited laboratories. In the skin irritation study in which rabbits were exposed to AHTN moistened with water, no erythema or oedema was observed (Haynes 1984). However, exposure to AHTN also occurs when the substance is dissolved in an organic medium and subsequently, primary irritation was also assessed after exposure of 50% AHTN in diethyl phthalate. In this case, the average erythema and oedema scores were 0.6 and 0.3 respectively. Under the normal conditions, the AHTN concentration does not exceed 12% in fragrance oils.

Two in-vivo eye irritation studies (Prinsen) on 3 rabbits performed by GLP accredited laboratories showed that AHTN does not need to be classified.

Justification for classification or non-classification

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