Registration Dossier

Administrative data

Description of key information

Acute oral toxicity is 4300 mg/kg bw based on read across from Terpineol multi which was tested in an OECD TG 401:

Acute dermal toxicity is > 2000 mg/kg bw based on read-across from Terpineol multi, which was tested in OECD TG 402

Acute inhalation (route to route extrapolation): is 11180 using the acute oral toxicity of Terpineol multi for read across.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across information
Justification for type of information:
The read-across justification is presented in the Endpoint summary Acute toxicity. The accompanying files are also attached there.
Reason / purpose:
read-across source
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
4 300 mg/kg bw
Based on:
test mat.
95% CL:
>= 2 900 - <= 5 700
Remarks on result:
other: read-across from Terpineol multi
Interpretation of results:
other: Not acutely harmful
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments).
Conclusions:
The oral acute toxicity is 4300 mg/kg bw in male rats, based on the results of the source substance.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
non-GLP
Justification for type of information:
This information is used for read-across to Terpene hydrocarbon alcohols
Qualifier:
equivalent or similar to
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 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.
Key result
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:
other: Not acutely harfmul
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments).
Conclusions:
The oral acute toxicity is 4300 mg/kg bw in male 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 = 2900 -5700 mg/kg bw) was determined.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The acute oral toxicity result is of sufficient quality and adequate for this dossier.

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across information
Justification for type of information:
The read-across justification is presented in the Endpoint summary Acute toxicity. The accompanying files are also attached there.
Reason / purpose:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: read-across from Terpineol multi
Interpretation of results:
other: Not acutely harmful
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments).
Conclusions:
The dermal acute toxicity is >2000 mg/kg bw in male and female rats.
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006-01-17 to 2006-01-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
This information is used for read-across to Terpene hydrocarbon alcohols
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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).
Key result
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:
other: Not acutely harmful
Remarks:
according to EU CLP (EC No. 1272/2008 and its amendments).
Conclusions:
The dermal acute toxicity is >2000 mg/kg bw in male and female rats.
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, this results in an LD50 > 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The acute oral toxicity information is sufficiently reliable and adequat.

Additional information

The Terpene hydrocarbon alcohols' acute oral toxicity is based on read-across from Terpineol multi. The executive summaries of the acute toxicity studies of Terpineol multi are presented first, thereafter the calculated inhalation LD50. Finally the read across rationale is documented.

Terpineol multi’s acute oral toxicity

Oral acute toxicity data is available from a pre-guideline study equivalent to OECD TG 401. In this 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 termination of 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.

Terpineol multi acute dermal toxicity

Dermal acute toxicity data is available from a study performed according to OECD TG 402 and in compliance with GLP criteria. In this study, a limit test, 2 groups of 5 Sprague-Dawley rats/sex were used: one control group exposed to distilled water and one test group. Terpineol Multi 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 day 0, 2, 7 and 14. Necropsies were done on day14 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.

Terpene hydrocarbon alcohols inhalation toxicity

Acute inhalation is calculated using the acute oral toxicity of Terpineol multi in accordance with the ECHA CLP guidance document (2015, 3.1.3.3.4: 1 mg/kg bw = 0.0052 mg/l (5.2 mg/m3). The converted LC50 for inhalation is 11180 mg/m3 (=4300 LD50 x 5.2 x 50/100; using 50% oral and 100% oral absorption). The calculated saturated vapour concentration is 2902 mg/m3 (MW*VP/ 8.3 (gas constant)*298K) using a MW of 136 g/mole and a VP of 51.9 Pa. This means that the acute inhalation concentration cannot be reached and therefore no acute inhalation is anticipated.

The acute oral and dermal toxicity of Terpene hydrocarbon alcohols using read across from Terpineol Multi (CAS# 8000-41-7)

Introduction and hypothesis for the analogue approach

Terpene hydrocarbon alcohols have the followingconstituent types of substances: Solely hydrocarbons-terpene type, Alcohol-type, Ketone-type and Ether-type all having a saturated or unsaturated cyclic hydrocarbon backbone.For this substance no acute oral and dermal toxicity information is available. In accordance with Article 13 of REACH, lacking information should be generated whenever possible by other means than vertebrate testing, i.e. applying alternative methods such as QSARs, grouping and read-across. For assessing the acute oral toxicity of theTerpene hydrocarbon alcohols, the analogue approach is selected because for its constituent, Terpineol multi information is available which can be used for read across.

Hypothesis: Terpene hydrocarbon alcohols have the same LD50s asTerpineol multi.

Available information: For Terpineol multi acute oral and dermal toxicity information is available according to OECD TG 401 (similar to, Rel. 2) and OECD TG 402 (Rel. 1) which resulted in LD50s of 4300 and > 2000 mg/kg bw.

Target chemical and source chemical(s)

Constituent types of the target substance and chemical structure of the source substances are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for acute toxicity.

Purity / Impurities

Constituent types of the target substanceare covered by the presented constituent types, there are no other constituent that impacts the acute toxicity.

Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. When using read across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.

Analogue selection: For Terpene hydrocarbon alcohols the substance Terpineol (in the form of Terpineol multi) is selected as an analogue because it is the major constituent of the substance and has similar metabolites as the other constituents. For this Terpineol multi acute toxicity information is available for read across.

Structural similarities and differences: Terpene hydrocarbon alcohols consist for the larger part of Alcohol-type and thus Terpineol multi type and these have the same chemical structures. Other constituents all have a similar hydrocarbon backbone with e.g. an additional double bond, alcohol or ketone as a functional group indicating similar electrophilicity.

Toxico-kinetic:All Terpene hydrocarbon alcohols are absorbed somewhat similar via all routes based on the similarities in molecular weight and physico-chemical properties, which includes the Terpineol multi constituents.Metabolism: Terpene hydrocarbon alcohols metabolism result in similar metabolites as those from Terpineol multi. The first metabolic step will result in primary, secondary or tertiary alcohols if these are not already constituents as such. Thereafter these metabolites will be further oxidised into acids and /or are conjugated. The Camphor constituent can metabolise in a more toxic metabolite because it has a lower acute oral LD50 compared to the others, which need to be accounted for because it can be present up to almost 18%.

Toxico-dynamics, acute oral toxicity: The Terpene hydrocarbon alcohols will have similar acute oral and dermal toxicity based on the similar metabolic pathways of most constituents. Camphor, however, has a lower LD50 acute oral (LD50 is 1310 mg/kg bw, EFSA, 1980), which will be considered in the conversion paragraph below. Cis-Anethole is also expected to be more reactive based on its conjugated double bond with the aromatic ring. There is one study (1959) on cis-Anethole in the RIFM data base showing an LD50 of 150 mg/kg bw. In view of its presence, < 4%, this has slight impact on the LD50 of the Terpene hydrocarbon alcohols as is presented in the conversion paragraph below. TheLD50 for acute dermal toxicityof Camphor is > 2000 mg/kg bw and therefore not affecting the overall toxicity of the substance.

Conversion to Terpene hydrocarbon alcohols from Terpineol multi, Camphor and cis-Anethole: The acute oral LD50 of Terpineol multi, Camphor and cis-Anethole are 4300, 1310 and 150 mg/kg bw, respectively. The presence of these substances is >=80, maximally 18 and maximally 4%, respectively. The LD50s of Camphor and cis-Anethole can be included in the Terpene hydrocarbon alcohols LD50 using a weighed contribution of their LD50s, this would result in an LD50 of 3682 mg/kg bw (4300*.8 (Terpineol multi) + 1310*.18 (Camphor) + 150*0.04 (cis-Anethole). This value remains in the 2000-5000 mg/kg bw band and therefore the LD50 result of Terpineol multi can still be used for Terpene hydrocarbon alcohols as a whole and does not affect the C&L or risk assessment.

Uncertainty of the prediction: There are no uncertainties other than those not already addressed above.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data Matrix.

Conclusions on acute oral and dermal toxicity for hazard and risk assessment

For Terpene hydrocarbon alcohols no acute oral and dermal toxicity information is available but for some of its constituents such information is present which can be used for read across and fill the data gap. When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation.This documentation is presented in the current text. For the source chemical Terpineol multi,reliable acute oral and dermal toxicity data is available with LD50 values of 4300 mg/kg bw and >2000 mg/kg bw, respectively.These data can be used directly for read-across to the Terpene hydrocarbon alcohols, taking into account the more toxic constituents Camphor and cis-Anethole.A weighed contribution would present a value of 3682 mg/kg bw but because this value is still within the 2000-5000 mg/kg bw band and therefore does not affect C&L and risk assessment.

Final conclusion:TheTerpene hydrocarbon alcohols have acute oral and dermal toxicity of 4300 and > 2000 mg/kg bw.

 

Data matrixpresenting the acute oral and dermal toxicity relevant for read across to theTerpene hydrocarbon alcohols from alpha-Terpineol and Terpineol multi.

Terpene hydrocarbon alcohols

Terpineol hydrocarbon alcohols

Terpineol alpha and multi

 

Target

Source

Structure

Not applicable

(α-Terpineol and γ-Terpineol)

CAS

Not applicable

98-55-5 and 8000-41-7

EC No.

945-149-0

202-680-6 /232-268-1

Reach registration

2018

Registered

Molecular weight

136-154

154

Phys-chem properties

 

 

Appearance

Liquid

Liquid

Log Kow

4.9 (3.3-5.5; IFF)

2.6

Identity, Constituent type (%)

100%

 

Solely hydrocarbons

 

 

Terpinolene type

0-15

 

Alcohol type

 

>80

Tertiary alcohols (e.g. Terpineol)

40-90

 

Secondary alcohols (e.g. Borneol)

7-40

 

Ketone type

-

 

Camphor-Type

0-17%

 

Ether type

 

 

Aromatic ether type

<4%

 

Human health

 

 

Acute oral toxicity: LD50 in mg/kg bw

4300

(Read across)

4300

(OECDTG 401)

Acute dermal toxicity: LD50 in mg/kg bw

> 2000

(Read across)

>2000

(OECD TG 402)

 

Reference

Scientific opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC) on a request from the Commission on Camphor in flavourings and other food ingredients with flavouring properties. The EFSA Journal 729, 1-15.

 

Justification for classification or non-classification

The substance does not need to be classified for acute toxicity by the oral, inhalation and dermal routeaccording to EU CLP (EC No. 1272/2008 and its amendments).