Registration Dossier

Administrative data

Description of key information

Acute oral and dermal toxicity studies (limit test) with test substance terpineol multiconstituent were conducted in Sprague-Dawley rats

following OECD guidelines 401 and 402. Oral and dermal LD50 of the test substance were higher than 2000 mg/kg bw for males and females.
Acute inhalation toxicity study with test substance terpineol multiconstituent was conducted in Sprague-Dawley rats following OECD guideline 403. No mortality occurred: LC50 was considered to be higher than 4.76 mg/L.

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:
experimental study
Adequacy of study:
key study
Study period:
26 May to 9 June 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
GLP study conducted according to OECD guideline with minor deviation: no certificate of analysis
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
No certificate of analysis
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley OFA
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA-CREDO, l'Arbresle, France
- Age at study initiation: about 6 weeks
- Weight at study initiation: 196-207 g for males; 174-171 g for females
- Fasting period before study: overnight
- Housing: 5/sex/cage
- Diet (e.g. ad libitum): UAR A04-10, Epinay sur Orge, France
- Acclimation period: at least 5 days
- Housed according to directive 86/609/EEC

IN-LIFE DATES: From: 26 May 1998 To: 9 June 1998
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
No data
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations at least once a day, bodyweights recorded just prior to dosing and at days 4, 8 and 15
- Necropsy of survivors performed: yes
Statistics:
None
Preliminary study:
No data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
One female was found dead at day 2.
Clinical signs:
Piloerection and a decrease in motor activity and in muscular tonus were observed in all animals for the first 6 h after dosing. All effects were reversed at day 3.
Body weight:
Body weight increase was normal (see table 1).
Gross pathology:
In the female found dead, congestions in the lungs, liver, spleen and kidneys were observed. Stomach and intestines were bloated by gas. In the other animals, no particular finding was identified.
Other findings:
No data

Table 1: individual bodyweights in males and females

 

Individual bodyweights (g) in males

Weight gain Day 1-Day 15

Animal number

Day 1

Day 4

Day 8

Day 15

9325

198.7

219.7

269.9

319.9

121.2

9326

196.0

196.7

240.7

288.7

92.7

9327

206.4

243.3

286.2

338.0

131.6

9328

198.2

221.6

266.6

307.2

109.0

9329

203.6

239.4

286.5

330.9

127.3

Mean ± SD

200.6 ± 4.3

224.1 ± 18.6

270.0 ± 18.7

316.9 ± 19.6

116.4 ± 15.7

 

Individual bodyweights (g) in females

Weight gain Day 1-Day 15

Animal number

Day 1

Day 4

Day 8

Day 15

9330

180.9

197.7

214.5

243.3

62.4

9331

174.3

-

-

-

-

9332

174.7

195.9

219.8

246.2

71.5

9333

175.7

202.3

222.5

250.0

74.3

9334

175.7

196.5

226.8

245.7

70.0

Mean ± SD

176.3 ± 2.7

198.1 ± 2.9

220.9 ± 5.1

246.3 ± 2.8

69.6 ± 5.1

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The oral LD50 of the test substance is higher than 2000 mg/kg bw for males and females. According to CLP regulation (EC) No 1272/2008, the test substance should not be classified.
Executive summary:

Acute oral toxicity study (limit test) with test substance Terpineol multiconstituent was conducted in 10 Sprague-Dawley OFA rats (5 males and 5 females) following OECD guideline 401. The test substance was administered undiluted through oral gavage at the single dose of 2000 mg/kg bw. Animals were observed for clinical signs at least once a day for 14 days. Body weights were taken just before dosing and at days 4, 8 and 15.

Piloerection and a decrease in motor activity and in muscular tonus were observed in all animals for the first 6 h after dosing. All effects were reversed at day 3 except for one female, found dead at day 2. In this female, congestions in the lungs, liver, spleen and kidneys were observed. Stomach and intestines were bloated by gas. In the other animals, no particular finding was identified at necropsy. Bodyweight increase throughout the study was normal.

The oral LD50 of the test substance is higher than 2000 mg/kg bw for males and females. Therefore, according to CLP regulation (EC) No 1272/2008, the test substance should not be classified.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Beta-terpineol one of the main impurities of multiconstituent substance TERPINEOL MULTICONSTITUENT. Therefore, data on beta-terpineol can be used for extrapolation to TERPINEOL MULTICONSTITUENT.
Reason / purpose:
read-across source
Preliminary study:
No data
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
One animal died at day 1 in the treated group.
Clinical signs:
Loss of activity was observed just after treatment. 2 h after ingestion, the animals had difficulties in moving, with absence of response to stimuli (for 4 animals), and they all had difficulties in breathing. General state was improved from day 2.
Body weight:
Body weight increase was the same as in the control group.
Gross pathology:
White deposit in both sides of the spleen was found in one animal of the treated group.
The animal found dead at day 1 had congestion in lungs, heart, liver, spleen and kidneys. Liquid was found in all digestive system.
Other findings:
No data

Table 1: Individual body weights in control and treated groups

 

Body weight (g) in the control group

 

Animal number

Day -1

Day 0

Day 3

Day 7

Day 14

Weight gain

Day 1-Day 14

3743

265

250

299

330

370

105

3744

282

263

310

347

378

96

3745

266

253

300

334

375

109

3746

266

244

290

317

355

89

3747

259

246

287

332

376

117

 

Body weight (g) in the treated group

 

Animal number

Day -1

Day 0

Day 3

Day 7

Day 14

Weight gain

Day 1-Day 14

3773

270

256

295

325

367

97

3774

277

262

288

324

368

91

3775

258

236

205

271

346

88

3776

254

236

257

294

338

84

3777

265

248

-

-

-

-

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Oral LD50 of the test substance is higher than 2000 mg/kg bw. According to CLP regulation (EC) No 1272/2008, the test substance should not be classified.
Executive summary:

Acute oral toxicity study (limit test) with test substance beta terpineol N was conducted in 10 male rats (5 control and 5 treated animals) following OECD guideline 401. The test substance was administered undiluted through oral gavage at the single dose of 2000 mg/kg bw. Animals were observed for 14 days. Body weights were taken the day before dosing, just before dosing and at days 3, 7 and 14.

Loss of activity was observed just after treatment. 2 h after ingestion, the animals had difficulties in moving, with absence of response to stimuli (for 4 animals), and they all had difficulties in breathing. General state was improved from day 2 except for one animal found dead at day 1. This animal had congestion in lungs, heart, liver, spleen and kidneys. Liquid was found in all its digestive system. For the other animals, body weight increase was the same as in the control group. White deposit in both sides of the spleen was found in one animal of the treated group at necropsy, at the end of the observation period.

The oral LD50 of the test substance is higher than 2000 mg/kg bw. therefore, according to CLP regulation (EC) 1272/2008, the test substance should not be classified.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Studies conducted according to OECD guideline 401 with only minor deviations, considered as appropriate and reliable to complete this endpoint.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2006-04-19 to 2006-06-14
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
GLP, followed OECD guidelines, well conducted with minor deviation: bodyweights at day 1 and 3 were not recorded.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Bodyweights at day 1 and 3 were not recorded.
Principles of method if other than guideline:
Not applicable
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: Charles River (UK) Ltd, Margarate, Kent
- Age at study initiation: between 8 and 12 weeks old
- Weight at study initiation: between 250 g and 350 g
- Housing: housed in groups of 5 by sex in solid-floor polypropylene cages with stainless steel lids
- Diet (e.g. ad libitum): EU rodent Diet 5LF2, BCM IPS Limited, London, UK (ad libitum)
- Water (e.g. ad libitum): normal drinking water (ad libitum)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2006-04-19 To: 2006-06-14
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: concentric jet nebuliser (Radleys, Saffron Walden, Essex, UK)
- Exposure chamber volume: cylindrical chamber with the volume of approximately 30 L: 28 cm diameter x 50 cm high
- Method of holding animals in test chamber: each rat was individually held in a tapered, polycarbonate restraining tube fitted into a single tier of the chamber and sealed by means of rubber "O" ring
- Source and rate of air: compressed air, rate of flow is at 45 L/min providing 90 air changes per hour
- Method of conditioning air: water trap and respiratory quality filters
- System of generating particulates/aerosols: concentric jet nebuliser (Radleys, Saffron Walden, Essex, UK)
- Method of particle size determination: Marple Personal Cascade Impactor (Schaefer Instruments Ltd, Oxon., UK)
- Treatment of exhaust: with high efficiency filter

TEST ATMOSPHERE
- Brief description of analytical method used: the actual concentrations of test material were measured off-line by high performance liquid chromatography. The test atmospheres were sampled after theoritical chamber equilibration and then approximately thirty minute intervals during the exposure period (see table 1).
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: three times during the exposure period using a Marple Personal Cascade Impactor
- Mean MMAD (Mass median aerodynamic diameter): 2.78 µm

Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
5 mg/L
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: at hourly interval during exposure, one hour after termination of exposure, and subsequently once daily for fourteen days. Bodyweights were recorded prior to the treatment on the day of exposure and on days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: The respiratory tract was subjected to a detailed macroscopic examination for signs of irritancy and local toxicity
Statistics:
None
Preliminary study:
No data
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 4.76 mg/L air (analytical)
Exp. duration:
4 h
Mortality:
No mortality
Clinical signs:
Signs of hunched posture and pilo-erection were seen in animals for short periods on removal from the chamber following 4-hour inhalation. Wet fur was recorded both during and for a short period after exposure. Increased respiratory rate, noisy respiration and ataxia were noted in all animals. Frequent instances of increased respiratory rate and occasional instances of decreased respiratory rate were noted.
One day after exposure all animals exhibited hunched posture and pilo-erection. By Day 2 one animal exhibited fur loss. Further animal exhibited
fur loss on Day 12 post-exposure.
Body weight:
Variations in bodyweight gain were seen for female animals during the study.
One male animal showed a reduced bodyweight gain during Week 1 but recovered to show normal development during Week 2.
Gross pathology:
No macroscopic abnormalities were detected among animals at necropsy.
Other findings:
No data

Table 1: Exposure Chamber Atmosphere Concentration

Duration of Exposure (minutes)

Volume of Air Sampled

(L)

Chamber Flow Rate (L/min)

Atmosphere Concentration (mg/L)

2

4

45

3.00

30

4

45

5.96

59

4

45

0.00

90

4

45

5.52

117

4

45

5.78

151

4

45

5.53

180

4

45

5.75

210

4

45

5.64

233

4

45

5.63

Mean achived atmosphere concentration (mg/L) = 4.76

Standard deviation = 2.00

Table 2: Individual body weights

Mean Achieved Atmospere

Concentration

(mg /L)

Animal Number and Sex

Body weight (g) on Day

 

 

 

 

 

0                                    7                     14

Increment (g) During Week

 

 

 

 

1                                  2

 

 

 

 

4.76

1 Male

355

371

395

16

24

2 Male

357

373

406

16

33

3 Male

376

379

410

3

31

4 Male

339

348

369

9

21

5 Male

380

392

436

12

44

6 Female

248

252

248

4

4

7 Female

267

278

291

11

13

8 Female

262

255

258

-7

3

9 Female

237

240

259

3

19

10 Female

239

242

247

3

5

Interpretation of results:
other: non toxic
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
No deaths occured in a group of ten rats to a mean achieved atmosphere concentrations of 4.76 mg/L for four hours.
It was therefore concluded that acute inhalation median lethal concentration 4 h LC50 of Terpineol multiconstituent was greater than 4.76 mg/L.
Executive summary:

In an acute inhalation toxicity study performed according to the OECD guideline 403, groups of rats (Sprague-Dawley, 5/sex) were exposed by nose-only inhalation to Terpineol multiconstituent for 4 hours at a mean concentration of 4.76 mg/L. The mass median aerodynamic diameter (MMAD) of the Terpineol multiconstituent aerosol was 2.78 µm and approximately 66.3% of the particulates were considered as inhalable (< 4 µm aerodynamic diameter).

Animals were then observed for 14 days.

Clinical signs as exagerated breathing were evident for all test rats from 30 minutes during the exposure and immediately post exposure, persisting for most animals to day 4. Gasping and noisy breathing were noted for a proportion af animals post-exposure, the latter sign persisting in one male to Day 4 of the observation.

One male animal had reduced body weight gain during Week 1 but recovered to show normal development during Week 2.Variations in body weight gain were seen in females but were considered not to be significant.

No mortality occurred: LC50 is higher than 4.76 mg/L.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
4 760 mg/m³
Quality of whole database:
GLP study performed according to OECD guideline 403, considered as appropriate and reliable to complete this endpoint.

Acute toxicity: via dermal route

Link to relevant study records
Reference
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
Remarks:
GLP study following OECD guideline, well conducted and documented, including certificate of analysis.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable
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).
Statistics:
no data
Preliminary study:
No data
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.
Other findings:
No data

No data

Interpretation of results:
GHS criteria not met
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 CLP Regulation (EC) No 1272/2008.
Executive summary:

Acute dermal toxicity study of Terpineol multiconstituent 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 Terpineol multiconstituent is higher than 2000 mg/kg bw by dermal route in the rat,

and Terpineol multiconstituent should not be classified according to CLP Regulation (EC) No 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
GLP study performed according to OECD Guideline 402, considered as appropriate and reliable to complete this endpoint.

Additional information

Acute oral toxicity study (limit test) with test substance terpineol multiconstituent was conducted in rats according to OECD guideline 401. One female was found dead at day 2. In this female, congestions in the lungs, liver, spleen and kidneys were observed. Stomach and intestines were bloated by gas. In the other animals, no particular finding was identified at necropsy. Oral LD50 > 2000 mg/kg bw for males and females.

Acute dermal toxicity study of terpineol multiconstituent as a limit test was conducted in rats according to OECD guideline 402. 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. No systemic toxic effects were observed. Dermal LD50 > 2000 mg/kg for males and females.

Acute inhalation toxicity study with terpineol multiconstituent was conducted according to OECD guideline 403 in rats exposed by nose-only inhalation for 4 hours at a mean concentration of 4.76 mg/L. No mortality occurred. LC50 > 4.76 mg/L.


Justification for classification or non-classification

Under the test conditions used in the above studies, and according to CLP regulation (EC) No 1272/2008, the test substance should not be classified for oral, dermal and inhalation acute toxicity.