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Description of key information

Acute oral and dermal toxicity studies were available for Terpineol multi, (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent)  4300 mg/kg bw and >2000 mg/kg bw (LD50), respectively. An LC50 value of 30100 mg/m3 was calculated for acute inhalation toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliability has been presented as 2 because of read across and because similar to OECD Guideline protocol has been followed but not GLP.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Four groups of each 10 male ablino (Wistar) rats were orally exposed to 2, 4, 8 and 16 g/kg bw Terpineol. They were observed for signs of toxicity and pharmacological effects at 1, 6 and 24 hours and daily thereafter for a period of 14 days. An LD50 was calculated.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 200-225 gram
- Fasting period before study: Minimum of 16 hours before dosing



Route of administration:
oral: unspecified
Vehicle:
not specified
Doses:
2000, 4000, 8000 and 16000 mg/kg
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
Four groups of each 10 male ablino (Wistar) rats were orally exposed to 2, 4, 8 and 16 g/kg bw Terpineol. They were observed for signs of toxicity and pharmacological effects at 1, 6 and 24 hours and daily thereafter for a period of 14 days. An LD50 was calculated.
Sex:
male
Dose descriptor:
LD50
Effect level:
4 300 mg/kg bw
Based on:
test mat.
95% CL:
2 900 - 5 700
Mortality:
Deaths in most cases occurred overnight or later. See "any other information results"
Clinical signs:
The animals appeared depressed or lethargic throughout the study. In several cases towards the end of the study, inner ear syndrome appeared but this was thought to be a drug effect since it is not uncommon in rats. Animals dying the day of dosing went into severe depression and looked anoxic. No stimulation was seen. Animals never did fully recover, even at the end of 14 days.
Body weight:
Anorexia was seen at all levels and, although the animals were not weighed at termination of study, most appeared to have lost weight.

Deaths per day after exposure to terpineol

Dose mg/kg

Deaths/day

total

2000

2/2, 1/4, 1/6

4/10

4000

1/2, 3/3, 1/5

5/10

8000

8/2

8/10

16000

10/3

10/10

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
An LD50 of 4300 mg/kg bw was obtained in the acute oral toxicity study with rats.
Executive summary:

In an acute oral toxicity study 4 groups of 10 male albino Wistar rats were orally exposed to 2000, 4000, 8000 and 16000 mg/kg bw of Terpineol multi. They were observed for signs of toxicity and pharmacological effects at 1, 6 and 24 hours and daily thereafter for a period of 14 days. Deaths in most cases occurred overnight or later and the animals appeared depressed or lethargic throughout the study. Anorexia was seen at all levels and, although the animals were not weighed at terminationof study, most appeared to have lost weight. In several cases towards the end of the study, inner ear syndrome appeared which is not uncommon in rats. Animals dying the day of dosing went into severe depression and looked anoxic. No stimulation was seen. A LD50 of 4300 mg/kg bw (95% CI = 2.9 -5.7) was determined.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study with Terpineol multi with a reliability of 2 is an acceptable, well documented study report which meets basic scientific principles and results in a LD50 of 4300 mg/kg bw. A 2nd study with rats showed an LD50 > 2000 mg/kg bw and a 3rd study with mice also show LD50 > 2000 mg/kg bw. The quality of the whole database is adequate.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
An LC50 can be calculated of 3010 mg/m3. This rough calculation is sufficiently adequate for assessing this endpoint. In addition, to this rough calculation, a value of Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent) is available showing the absence of inhalation toxicity of 4760 mg/m3. The quality of the whole database is adequate.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2006-01-17 to 2006-01-31
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliability has been based on read across and based on use of OECD guideline and GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Elevage Janvier, Le Genest St Isle, France
- Age at study initiation: approximately 6 weeks old
- Weight at study initiation: males between 228 g and 272 g, and females between 217g and 222 g
- Acclimatisation period: at least 5 days
- Housing: Five animals of the same sex are kept in each makrolon cage, dimensions 47 cm X 31 cm X 19 cm
- Diet (e.g. ad libitum): rats-mice maintenance pelleted diet (ad libitum)
- Water (e.g. ad libitum): tap water from public distribution system (ad libitum)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): between 19 and 25
- Humidity (%): between 30 and 50
- Air changes (per hr): at least 10 cycles
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2006-01-17 To: 2006-01-31
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure:
- % coverage: 10% of the total body
- Type of wrap if used: porous gauze dressing and non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): test group: 2.13 mL/kg body weight
- Concentration: undiluted

VEHICLE
- Amount(s) applied (volume or weight with unit): control group: 2 mL/kg body weight of distilled water
Duration of exposure:
24 h
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Systemic examinations were carried out to identify behavioral or toxic effects on physiological functions at 1, 3, 5, 24 and 48 h after administration of the product. Animals were weighed on D0 before application of the product, D2, D7, and D14.
- Necropsy of survivors performed: yes, performed on D14 for the macroscopic examination of the following organs: oesopahgus, stomach, duodenum, jejunum, ileum, caecum, rectum, spleen, liver, thymus, trachea, lungs, heart, kidneys, urinary bladder, testicles, ovaries, uterus, adrenals, pancreas and treatment area (skin).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality
Clinical signs:
No systemic clinical signs were noted.
Body weight:
Bodyweights were normal through out the study in both treated and control groups.
Gross pathology:
No significant toxic effects.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Tthe LD50 of the test item DERTOL 90 is higher than 2000 mg/kg body weight. Therefore it should not be classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (1272/2008).
Executive summary:

Acute dermal toxicity study of Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent) as a limit test was conducted according to OECD guideline 402 and in compliance with GLP. To groups of 5 Sprague-Dawley rats/sex were used: one control group exposed to distilled water and one test group. The test substance was applied to the skin by topical application for 24 h, under semi-occlusive conditions, at 2000 mg/kg bw, with a volume of 2.13 mL/kg bw. After exposure, exposure area was washed with distilled water.

Animals were observed every day for systemic clinical signs and mortalities for 14 days. The animals were weighed on D0, D2, D7 and D14. Necropsies were done on D14 for macroscopic observations. No toxic effects were observed.

Based upon these experimental conditions, the LD50 of the Dertol 90 is higher than 2000 mg/kg bw by dermal route in the rat,

and Terpineol multi does not need to be classified according to the Annex VI to the Directive 67/548/EEC and the CLP Regulation (1272/2008).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
There are two reliable acute dermal toxicity studies both indicating an LD50 > 2000 mg/kg/bw and therefore the quality of the whole database is adequate.

Additional information

Acute oral toxicity

For alpha-Terpineol as such an acute oral toxicity study with mice is available with a reliability of 2 (Yamahara et al., 1985). The preferred animal for acute toxicity is the rat and therefore i.e.for assessing the acute oral toxicity of alpha-Terpineol the information from Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent) has been selected. It can also be seen that all constituents of Terpineol multi have a similar backbone, which is the cyclohexyl ring (see toxico-kinetic section). The attached methyl groups are in all cases para-positioned. There are two functional groups. The first one is the tertiary alcohol, which is not reactive because no additional reactive groups are adjacent to this alcohol. The second functional group is the double bond, at the para–position but can be inside or outside the cyclohexyl ring, depending on the constituent. These differences are thought to be of minor importance for acute oral toxicity and therefore the same LD50 value of Terpineol multi can be used for read across to alpha-Terpineol, resulting in an LD50 4300 mg/kg bw.

In the acute oral toxicity study with Terpineol multi groups of 10 male albino Wistar rats were orally exposed to 2000, 4000, 8000 and 16000 mg/kg bw Terpineol multi (Moreno, 1971). They were observed for signs of toxicity and pharmacological effects at 1, 6 and 24 hours and daily thereafter for a period of 14 days. Deaths in most cases occurred overnight or later and the animals appeared depressed or lethargic throughout the study. Anorexia was seen at all levels and, although the animals were not weighed at termination of study, most appeared to have lost weight. In several cases towards the end of the study, inner ear syndrome appeared but this is not uncommon in rats. Animals dying the day of dosing went into severe depression and looked anoxic. No stimulation was seen. A LD50 of 4300 mg/kg bw (95% CI = 2900 -5700) was determined.

In an acute oral toxicity study with alpha-Terpineol, groups of 10 male dd-K mice received the substance by gavage (Yamahara et al., 1985). The LD50, calculated from the number of deaths during a 7-day observation period, was 2830 mg/kg bw (95% CI = 2290 – 3497).

Acute inhalation toxicity

No reliable data on acute inhalation toxicity of alpha-Terpineol are available. According to Column 2 of REACH Annex VIII, “in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure". In the present case, the inhalation exposure will be lower than the dermal route because alpha-Terpineol has a low vapour pressure and the pure substance is viscous. Furthermore, as acute toxicity data on both the oral and the dermal route of exposure is available, testing for acute inhalation toxicity is not necessary. However, the acute inhalation toxicity for alpha-Terpineol can be derived using data on the acute oral toxicity using the following methodology. The oral LD50 of alpha-Terpineol is 4300 mg/kg bw. The 4300 mg/kg bw can be converted to 301000 mg/per person. An inhalation volume of one person during 4 h (standard exposure time in OECD TG for acute inhalation toxicity) is 5m3 (assuming 10m3/8h for workers). This means that the LC50 concentration in 1m3 and 4 hours exposure is 60200 mg/m3. Taking into account that the absorption during inhalation route can be twice as high as during oral absorption the LC50 for inhalation would become 30100 mg/m3. The maximum saturated vapour pressure (SVP) for this substance in mg/m3 is (6.48 Pa x 154.MW (mg/Mol)) /(8.3 (R, gas constant) x 298°K) = 411 mg/m3. The LC50 value of 30100 mg/m3 cannot be reached because the SVP of alpha-Terpineol is 411 mg/m3.Though no correction has been done for rat versus human inhalation, the calculation clearly shows that there is no acute inhalation toxicity for alpha-Terpineol because the LC50 = 30100 mg/m3, while the maximum SVP is 411 mg/m3.

Acute dermal toxicity

For alpha-Terpineol as such no acute dermal toxicity data is available. There is an acute dermal toxicity study for Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent) which can be used for read across. In the toxico-kinetic section, it can be seen that all constituents of Terpineol multi have a similar backbone, which is the cyclohexyl ring. The attached methyl groups are in all cases para-positioned. There are two functional groups. The first one is the tertiary alcohol, which is not reactive because no additional reactive groups are adjacent to this alcohol. The second functional group is the double bond, at the para–position but can be inside or outside the cyclohexyl ring, depending on the constituent. These differences are thought to be of minor importance for acute dermal toxicity and therefore the same LD50 value of Terpineol multi can be used for read across for alpha-Terpineol, resulting in an LD50> 2000 mg/kg bw.

Terpineol multi has been tested in a GLP compliant acute dermal toxicity study performed according to OECD 402. Groups of 5 Sprague-Dawley rats/sex were used: one control group exposed to distilled water and one test group (Richeux 2006). The test substance was applied to the skin by topical application for 24 h, under semi-occlusive conditions, at 2000 mg/kg bw, with a volume of 2.13 mL/kg bw. After exposure, the exposure area was washed with distilled water. Animals were observed every day for systemic clinical signs and mortalities for 14 days. The animals were weighed on D0, D2, D7 and D14. Necropsies were done on D14 for macroscopic observations. No toxic effects were observed. Based upon these experimental conditions, the LD50 of Terpineol multi is higher than 2000 mg/kg bw by dermal route in the rat.

In a supporting acute dermal toxicity study, female albino rabbits were dermally exposed to 1000 (1 animal), 2000 (1 animal) and 3000 (3 animals)mg/kg bw Terpineol multi (Moreno 1971). The test compound was applied to the clipped skin on an area of approximately 12 cm wide and covering the entire circumference of the rabbits. After application of the material, the area was covered with a rubber sheeting and the ends taped to the rabbit to prevent leakage and to keep the material in contact with the skin. After 24 hours, the rubber sheets were removed. The animals were observed for a period of seven days. No animals died at any dose level tested. Therefore, the LD50 of the test compound is higher than 3000 mg/kg bw by dermal route in the rabbit.

Yamahara, J., Kimura, H., Kobayashi, M., Okamoto, T., Sawada, T., Fujimura, H., and Chisaka, T., Cholagogic action and characteristics of (+/-)-alpha-terpineol-beta-D-O-glucopyranoside, a new monoterpenoid glucoside, Chemical and Pharmaceutical Bulletin, 33(4), 1669-1675.


Justification for selection of acute toxicity – oral endpoint
The study with an actual LD50 value was selected as the key study. This is an acute oral toxicity study with Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent). This study is sufficiently reliable.

Justification for selection of acute toxicity – inhalation endpoint
The acute inhalation toxicity is derived via route to route extrapolation which is considered sufficiently reliable.

Justification for selection of acute toxicity – dermal endpoint
The one study available is performed in accordance with OECD 402 and GLP with Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent). This study is sufficiently adequate also for alpha-Terpineol.

Justification for classification or non-classification

Acute oral toxicity

Alpha-Terpineol does not have to be classified and labelled for acute oral toxicity based on information from Terpineol multi which is a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor. This is a sufficient close analogue to be used for read across and the LD50 of alpha-Terpineol is therefore also 4300 mg/kg bw.

Acute inhalation toxicity

Alpha-Terpineol does not have to be classified and labelled for acute inhalation toxicity based on the calculated LC50 value of 30100 mg/m3.

Acute dermal toxicity

Alpha-Terpineol does not have to be classified and labelled for acute dermal toxicity based on information from Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent) which can be used for read across to alpha-Terpineol resulting in an LD50 value of > 2000 mg/kg bw.

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