Registration Dossier

Administrative data

Description of key information

Alpha-Terpineol is considered to be irritating to the skin and eye but is not expected to be a respiratory irritant.

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:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP compliant study conducted in compliance with OECD guideline 404 with minor deviation: no details on test animals and environmental conditions; no details on patch material; observations not followed until the reversibility of the effects (only 7 days)
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
. There is no certificate of analysis of the test substance; no details on test animals and environmental conditions; no details on patch material; and observations are not followed until the reversibility of the effects (only 7 days).
GLP compliance:
yes
Species:
rabbit
Strain:
other: albino
Type of coverage:
semiocclusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
7 days
Number of animals:
Test 1: 3
Test 2&3: 4
Details on study design:
SCORING SYSTEM: Draize scoring system
- tested in a multi-patch study
Irritation parameter:
erythema score
Basis:
mean
Remarks:
all animals
Time point:
other: 24, 48 and 72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Test 1
Irritation parameter:
edema score
Basis:
mean
Remarks:
all animals
Time point:
other: 24, 48 and 72 h
Score:
2.44
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Test 1
Irritation parameter:
erythema score
Basis:
mean
Remarks:
all animals
Time point:
other: 24, 48 and 72 h
Score:
2.17
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Test 2
Irritation parameter:
edema score
Basis:
mean
Remarks:
all animals
Time point:
other: 24, 48 and 72 h
Score:
2.58
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Test 2
Irritation parameter:
erythema score
Basis:
mean
Remarks:
all animals
Time point:
other: 24, 48 and 72 h
Score:
1.92
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Test 3
Irritation parameter:
edema score
Basis:
mean
Remarks:
all animals
Time point:
other: 24, 48 and 72 h
Score:
2.08
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Test 3
Irritant / corrosive response data:
Test 1: Two animals showed marked desquamation at the 7 day time interval. The other animal showed thickening and marked desquamation of the skin surface at the 7 day time interval.
Test 2: One animal showed slight desquamation at the 7 day time interval. The three other animals showed marked desquamation at the 7 day time interval.
Test 3: Two animals showed slight desquamation at the 7 day time interval. One animal showed slight desquamation at the 2, 3, and 7 day time interval. One animal showed marked desquamation at the 7 day time interval

 Test 1

 

1 hr

1 day

2 days

3 days

7 days

Mean (24, 48, 72 hrs)

Animal No. 1

Erythema

0

1

2

2

1

1.67

Oedema

1

2

2

2

1

2

Animal No. 2

 

Erythema

2

2

2

2

2

2

Oedema

2

3

2

2

1

2.33

Animal No. 3

 

Erythema

2

2

2

3

3

2.33

Oedema

2

3

3

3

3

3

 

Test 2

 

1 hr

1 day

2 days

3 days

7 days

Mean (24, 48, 72 hrs)

Animal No. 1

Erythema

2

2

2

2

2

2

Oedema

2

3

3

3

1

3

Animal No. 2

 

Erythema

2

2

3

3

2

2.67

Oedema

3

3

3

3

3

3

Animal No. 3

 

Erythema

2

2

2

2

2

2

Oedema

2

3

2

3

3

2.67

Animal No. 4

 

Erythema

1

2

2

2

1

2

Oedema

2

2

2

1

0

1.67

 

Test 3

 

1 hr

1 day

2 days

3 days

7 days

Mean (24, 48, 72 hrs)

Animal No. 1

Erythema

2

2

2

2

1

2

Oedema

2

3

3

2

0

2.67

Animal No. 2

 

Erythema

2

2

2

2

2

2

Oedema

2

2

2

2

2

2

Animal No. 3

 

Erythema

1

2

2

1

0

1.67

Oedema

0

1

1

0

0

0.67

Animal No. 4

 

Erythema

2

2

2

2

1

2

Oedema

1

3

3

3

1

3

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions the substance is considered to be irritating to the skin.
Executive summary:

In three primary dermal irritation studies performed according to OECD guideline 404 and in compliance with GLP, three or four albino rabbits were dermally exposed to 0.5 mL of undiluted alpha-Terpineol under a semi-occlusive patch for 4 hours to intact skin of the flank. Animals were then observed for 7 days. Irritation was scored by the method of Draize at 1, 24, 48 and 72 hours and 7 days after exposure. Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals of the first test were 1.67, 2 and 2.33 for erythema score and 2, 2.33 and 3 for edema score. For the second test the mean individual scores were 2, 2.67, 2 and 2 for erythema score and 3, 3, 2.67 and 1.67 for edema score. For the third test the mean individual scores were 2, 2, 1.67 and 2 for erythema score and 2.67, 2, 0.67 and 3 for edema score. Under the test conditions the substance is considered to be irritating to the skin because the average oedema score exceeded 2 (DSD C&L) or 2.5 (CLP) and the effects were not fully reversible within the observation period of 7 days.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2006-02-20 to 2006-02-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study following OECD TG 405.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Elevage de Gerome, Linxe, France
- Weight at study initiation: between 2.15 and 2.57 kg
- Housing: individual box installed in conventional air conditioned
-Diet(ad libitum): supplied by UAR, Villemoison s/Orange, France, ad libitum
-Water(ad libitum): tap water from public distribution system, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): between 20 and 22
- Humidity (%): between 30 and 37
-Air changes: at least 10 cycles per hour
-Photoperiod (hours dark / hours light): 12/12

IN-LIFE DATES: From: 2006-02-20 To: 2006-02-26
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
24 hours, no washing done
Observation period (in vivo):
Observations performed at 1, 24, 48 and 72 h up to 21 days
Number of animals or in vitro replicates:
3 females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing

SCORING SYSTEM: According to the scale of lesion scores published in Directive n° 2004/73/EC and OECD guideline n°405
Irritation parameter:
conjunctivae score
Remarks:
chemosis(A)
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 5 days
Irritation parameter:
conjunctivae score
Remarks:
redness (C)
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 6 days
Irritation parameter:
iris score
Remarks:
lesion (D)
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Remarks:
opacity (E)
Basis:
animal #1
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 5 days
Irritation parameter:
conjunctivae score
Remarks:
chemosis (A)
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 4 days
Irritation parameter:
conjunctivae score
Remarks:
redness (C)
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1.7
Max. score:
3
Reversibility:
fully reversible within: 5 days
Irritation parameter:
iris score
Remarks:
lesion (D)
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Remarks:
opacity (E)
Basis:
animal #2
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 5 days
Irritation parameter:
conjunctivae score
Remarks:
chemosis (A)
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 4 days
Irritation parameter:
conjunctivae score
Remarks:
redness (C)
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
1.3
Max. score:
3
Reversibility:
fully reversible within: 5 days
Irritation parameter:
iris score
Remarks:
lesion(D)
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Remarks:
opacity (E)
Basis:
animal #3
Remarks:
mean individual score
Time point:
other: 24, 48 and 72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
Moderate redness at the conjunctival level associated with moderate chemosis and moderate opacity at the corneal level. All effects were totally reversible within the 7th day at the latest.

Table 1: individual and mean scores of Conjunctivae, Iris and Cornea

Animal 

Time after treatment

CONJUNCTIVAE

IRIS

CORNEA

CHEMOSIS (A)

REDNESS (C)

LESION (D)

OPACITY (E)

A 7230

24 hours

1

2

0

2

48 hours

1

2

0

2

72 hours

1

2

0

2

TOTAL

MEAN

3

6

0

6

1.0

2.0

0.0

2.0

A 7231

24 hours

1

2

0

2

48 hours

1

2

0

2

72 hours

1

1

0

2

TOTAL

3

5

0

6

MEAN

1.0

1.7

0 .0

2.0

A 7232

24 hours

2

2

0

2

48 hours

2

1

0

0

72 hours

1

1

0

0

TOTAL

5

4

0

2

MEAN

1.7

1. 3

0.0

0.7

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under test conditions DERTOL 90 is irritant to eyes and should be classified R36 "irritant to eyes" according to the criteria of directive n°67/548/EEC and Category 2 according to CLP regulation (EC) n°1272/2008.
Executive summary:

In an eye irritation study conducted according to the OECD Guideline 405 and in compliance with GLP, 3 healthy adults female rabbits of the New Zealand White strain were exposed to 0.1 mL of undiluted Terpineol multi in one eye while the other eye corresponded to the control. The eyes were examined unwashed and the changes were observed at 1, 24, 48 and 72 hours after dosing and graded (scale of lesion scores according to Directive n° 2004/73/EC and OECD guideline 405).

The occular reactions observed during the study have been moderate. The individual mean scores for conjunctival chemosis were 1.0, 1.0 and 1.7, conjunctival redness scores were 2.0, 1.7 and 1.3, cornea opacity scores were 2.0, 2.0 and 0.7 and iris lesion scores were 0.0 for all animals.

At the conjuctivae level, a moderate redness, noted 24 h after the test item installation and totally reversible between the 6th and 7th day of the test, was associated with a moderate chemosis, noted 1h after the test item instillation and totally reversible between the 5th and 6th day of the test. At corneal level, moderate opacity was observed 24 h after the test substance administration and totally reversible between the 3rd and 6th day.

Under these test conditions,Terpineol multi is considered as irritating to eyes according to the criteria of directive 67/548/EEC and CLP regulation (EC) n°1272/2008.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

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

Additional information

Skin irritation/corrosion

For alpha-Terpineol three in vivo studies and one in vitro study are available.

The ECETOC study has been selected as the key study because it is the most recent and showing the highest irritation scores. In this in vivo study, skin irritating properties of alpha-Terpineol were determined in three primary dermal irritation tests performed according to OECD guideline 404 and in compliance with GLP. Three (test 1) or four (test 2 and 3) albino rabbits were dermally exposed to 0.5 mL of undiluted alpha-Terpineol, under a semi-occlusive patch for 4 hours to intact skin of the flank (ECETOC 1995). Animals were then observed for 7 days. Irritation was scored by the method of Draize at 1, 24, 48 and 72 hours and 7 days after exposure. Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals of the first test were 1.67, 2 and 2.33 for erythema score and 2, 2.33 and 3 for edema score. For the second test the mean individual scores were 2, 2.67, 2 and 2 for erythema score and 3, 3, 2.67 and 1.67 for edema score. For the third test the mean individual scores were 2, 2, 1.67 and 2 for erythema score and 2.67, 2, 0.67 and 3 for edema score. Under the test conditions the substance is considered to be irritating to the skin because of the average scores of animals and the number of animals having scores are around or fulfilling criteria for skin irritation. Though scores were lower at day 7, the end of the observation period, compared to the 24 -72 hours score, the effect add to decide that alpha-Terpineol is a skin irritant.

Skin irritating properties of alpha-Terpineol were also determined in two skin irritation studies by Hayes et al (1984, 1985 for RIFM). Three and four albino rabbits were dermally exposed to 0.5 mL of undiluted alpha-Terpineol, under a semi-occlusive patch for 4 hours to the clipped skin of the trunk. Animals were then observed for 7 days. Erythema and oedema was scored and seen at 1, 24, 48 and 72 hours and 7 days after exposure.

In the in vitro EpiDerm test, the skin irritation potential of alpha-Terpineol was assessed by undertaking a time-course assay using MTT reduction as the endpoint for determining cell viability (Fentem 2001). The goals of the performed study were to determine the inter-laboratory reproducibility of the assay and identify any refinements needed in the test protocol. The protocol involved comparing the exposure time required for the test chemical to reduce tissue viability to 50% of controls (ET50) with that required for a standard (20%) SLS (sodium lauryl sulphate) solution. The test material as well as 20% SLS and 1% Triton X-100 were tested in three valid runs in two laboratories (IIVS and ZEBET). Before the definitive assays were performed an exposure-time range-finding assay was performed to establish appropriate exposure times to be used in the definitive assay, using single cultures per exposure time. Based on the ET50 results from the exposure time range-finding assay, four appropriate, sequential exposure times were chosen for the definitive assays. Test materials and negative controls were studied in duplicate cultures at each exposure time. The ET50s and Mean Irritation Potentials ((mean ET50 for 20% SLS) / (mean ET50 for test chemical)) were calculated. ET50 values were <19.2 min and <15.2 min for IIVS and ZEBET respectively. Mean Irritation Potential values were: > 2.84 and >2.89 for IIVS and ZEBET respectively. Based on these results the test substance alpha-Terpineol is classified as irritant.

All the available data, both in vivo and vitro indicate that alpha-Terpineol is irritating to the skin. Especially the edema are presenting scores above 2.3. The irritant effects have not disappeared after 7 days (observation period) but reversibility is shown.

Eye irritation

For alpha-Terpineol as such no experimental eye irritation study is available. There is an eye irritation study for Terpineol multi ( (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent). In the toxico-kinetic section, the constituents of alpha-Terpineol and of Terpineol multi are presented. Terpineol multi is classified and labelled for eye irritation. Therefore it can be expected that alpha-Terpineol needs to be classified and labelled for eye irritation as well. Gamma-terpineol is very similar in chemical structure compared to alpha-Terpineol and therefore this constituent is expected to have similar eye irritation properties compared to alpha-Terpineol.

In the eye irritation study conducted according to the OECD Guideline 405 and in compliance with GLP, 3 healthy adult female rabbits of the New Zealand White strain were exposed to 0.1 mL of undiluted Terpineol multi in one eye while the other eye corresponded to the control (Richeux 2006). The eyes were examined unwashed and the changes were observed at 1, 24, 48 and 72 hours after dosing and graded. The ocular reactions observed during the study have been moderate. The individual mean scores for conjunctival chemosis were 1.0, 1.0 and 1.7, conjunctival redness scores were 2.0, 1.7 and 1.3, cornea opacity scores were 2.0, 2.0 and 0.7 and iris lesion scores were 0.0 for all animals. At the conjunctivae level, a moderate redness, noted 24 h after the test item installation and totally reversible between the 6th and 7th day of the test, was associated with a moderate chemosis, noted 1h after the test item instillation and totally reversible between the 5th and 6th day of the test. At corneal level, moderate opacity was observed 24 h after the test substance administration and totally reversible between the 3rd and 6th day. Under these test conditions, Terpineol multi is considered as irritating to eyes. Therefore alpha-Terpineol is also considered to be an eye irritant.

Respiratory irritation

For respiratory irritation mostly human data are used for the assessment because no suitable in vitro or in vivo tests are available that can identify respiratory irritation (REACH guidance R.7.2.3). There are no human data such as indicated in R7.2.3 of the ECHA guidance that indicate respiratory reactions of the substance e.g. from consumer experience or occupational exposure. Due to its low vapour pressure (6.48 Pa, insufficient air concentration will reach the lung during handling) and its viscosity (37.9 mP.s for the pure substance) the inhalation concentration of alpha-Terpineol will be low and because alpha-Terpineol is not corrosive or severely irritating respiratory irritation is unlikely minimising the respiratory irritation hazard (REACH guidance: 7.2.1.2).


Justification for selection of skin irritation / corrosion endpoint:
The ECETOC study selected as key is the one with the highest irritation scores. The supporting studies also conducted according to OECD TG 404 show similar results. The in vitro skin irritation study also results in skin irritation.

Justification for selection of eye irritation endpoint:
The one eye irritation study, which is performed in accordance with OECD 405 and GLP, using Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent) is sufficiently adequate for assessment of this endpoint.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Alpha-Terpineol needs to be classified as Xi:R38 according to the EU Directive 67/548 (DSD) and Category 2:H315 according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 based on available experimental data based on scores around or fulfilling the criteria..

Alpha-Terpineol will be classified for eye irritation because the read across substance Terpineol multi ( (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent) is classified and labelled as Xi:R36 according to the EU Directive 67/548 and Category 2:H319 according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Alpha-Terpineol does not need to be classified and labelled for respiratory irritation because it has a low vapour pressure (insufficient air concentrations will reach the lungs), its viscosity (37.9 Pa for the pure substance), it is not corrosive or severely irritating minimising the respiratory irritation hazard. Therefore, classification for respiratory irritation is not warranted.