Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50 > 2000 mg/kg bw (OECD 420 in rats; GLP, K, Rel.1)

Acute toxicity: dermal: LD50 > 2000 mg/kg bw (similar to OECD 402, K, rel. 2) - Read-across.

Acute inhalation: waiver

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From March 11 to April 03, 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline No. 420 without any deviation.
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
UK GLP Compliance Programme (inspected on July 10, 2012/ signed on November 30, 2012)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 153-169 g
- Fasting period before study: Animals were fasted for overnight period before administration of test material and for approximately 2-4 h after dosing.
- Housing: Animals were housed in groups of up to 4 in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet: Food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 30-70 %
- Air changes: 15 changes / h
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: March 11, 2014 To: April 03, 2014
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 2.26 mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Using available information on the toxicity of the test material, 2000 mg/kg bw was chosen as the starting dose.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
- Sighting study: 1 female/dose
- Main study: 5 females/dose (1 animal included from sighting study)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Clinical observations were made 0.5, 1, 2 and 4 h after dosing and then daily for up to 14 days. Morbidity and mortality checks were made twice daily. Body weight of each animal was recorded on Day 0 (the day of dosing) and on Days 7 and 14.
- Necropsy of survivors performed: Yes; on completion of the observation period, animals were killed by cervical dislocation and subjected to gross necropsy.
Statistics:
None
Preliminary study:
- No mortality or clinical sign was observed at 2000 mg/kg bw.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality was observed.
Mortality:
- No mortality was observed at 2000 mg/kg bw.
Clinical signs:
- No clinical signs were observed at 2000 mg/kg bw.
Body weight:
- All animals showed expected gains in body weight over the 14 day study period at 2000 mg/kg bw.
Gross pathology:
- No abnormalities were observed at necropsy.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Rat Oral LD50 (females) > 2000 mg/kg bw
Executive summary:

In an acute oral toxicity study (limit test) performed according to OECD Guideline No. 420 and in compliance with GLP, one female Wistar (RccHan™:WIST) rat was administered a single oral dose of test material at 2000 mg/kg bw by gavage (sighting study). Following a sighting study, additional 4 animals were administered a single oral dose of test item at 2000 mg/kg bw (main study). Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

No mortality or clinical signs were observed. All animals showed expected gains in body weight over the 14 day study period. No abnormalities were noted at necropsy.

Rat Oral LD50 (females) > 2000 mg/kg bw

Under the test conditions, the test material is not classified according to the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The key study is GLP compliant and of high quality (Klimisch score = 1).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with 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, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (0.194 Pa at 25°C - from analogue) and a low freezing point (<-20°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 5.79 at 25°C, WS = 125-285 µg/L at 20°C - from analogue).
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From June 15 to June 29, 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study comparable to OECD test guideline No. 402 with deviations not affecting the integrity of the result. Indeed, only 6 animals were tested instead of the 10 required by the OECD Test Guideline No. 402 for a limit test. However having 4 more animals would not impact the LD50 value since no mortality occurred within this study. Moreover half of the animals had abraded skin which improved skin permeability, and therefore absorption. GLP status not reported.
Qualifier:
equivalent or similar to guideline
Guideline:
other: Section 1500.4 - Federal Hazardous Substance Act Regulation - 16 CFR
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1981
Deviations:
yes
Remarks:
Limit test using 6 animals instead of 10, half of them having abraded skin
Principles of method if other than guideline:
Not applicable
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Inc., Boyertown, PA.
- Age at study initiation: no data
- Weight at study initiation: 2.3-3.0 kg bw.
- Fasting period before study: no.
- Housing: individually, in stainless steel cages with elevated wire mesh flooring.
- Diet (e.g. ad libitum): Wayne 15% Rabbit ration ad libitum.
- Water (e.g. ad libitum): tap water ad libitum.
- Acclimation period: appropriate time.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15.5 - 23
- Humidity (%): 40-45
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: no data
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: backs (clipped skin, 3 with abraded skin).
- % coverage: approximately 10%.
- Type of wrap if used: large gauze patches, impervious material wrapped snugly around the trunk.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no (wiping only)
- Time after start of exposure: 24 hours.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.0 g/kg bw.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations (systemic and topical): frequently during the first day, and twice per day thereafter (morning and afternoon).
- Frequency of weighting: on the day of dosage, weekly thereafter, and prior to sacrifice.
- Necropsy of survivors performed: yes (gross necropsy)
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
None.
Body weight:
A loss of body weight was noted for 1/3 female at 7 days.
Gross pathology:
No gross abnormalities were noted.
Other findings:
Mild erythema and severe oedema were observed after unwrapping at 24 hours. Eschar was noted for all animals by day 4 which was still evident at 14 days.

None

Interpretation of results:
GHS criteria not met
Conclusions:
Dermal LD50Combined > 2000 mg/kg bw.
Under the test conditions, the test material is not classified according to the Regulation EC No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In a limit acute dermal toxicity study performed similarly to the OECD test guideline No. 402, New Zealand White rabbits (3/sex) were occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs including dermal reactions and body weight for 14 days and then necropsied for macroscopic observations.

No mortality and no clinical signs were observed during the study. A loss of body weight was noted for 1/3 female at 7 days.

Mild erythema and severe oedema were observed after unwrapping at 24 hours. Eschar was noted for all animals by day 4 which was still evident at 14 days.

Dermal LD50Combined > 2000 mg/kg bw.

Under the test conditions, the test material is not classified according to the Regulation EC No. 1272/2008 (CLP) and to the GHS.

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Cf. IUCLID section 13.2

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar Physico-Chemical, and Toxicological properties because of their structural similarity.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target and source substances are both multi-constituents, as reaction mass of stereoisomers of the same substance.
The target and source substances are structurally related, in that both are a reaction mass of stereoisomers of 1-(2,2,6-Trimethylcyclohexyl)hexan-3-ol. They differ by the number of constituents. The two trans 1R,6S diastereoisomers, with both 3R and 3S hydroxyl group, of the source substance are constituents of the target substance, which contains also the trans 1S,6R pair (i.e. 2 pairs of enantiomers).

3. ANALOGUE APPROACH JUSTIFICATION
Based on structural similarity (constituents of the source and the target substance are from the same pool of substance, i.e stereoisomers of 1-(2,2,6-Trimethylcyclohexyl)hexan-3-ol) it is considered appropriate and scientifically justified to read-across the data from the source to the target substance.
Although not performed under GLP, the study design (eq. OECD 402) is sufficiently adequate and reliable for the purpose of the prediction based on read-across. The test material used represents the source substance as described in the hypothesis in terms of purity and impurities. The results of the studies are adequate for the purpose of classification and labelling. .
Therefore, based on the considerations above, it can be concluded that the result of the acute dermal toxicity test conducted with the source substance is highly likely to predict the properties of the target substance and is considered as adequate to fulfil the information requirement of Annex VIII, 8.5.3.

4. DATA MATRIX
Cf. IUCLID section 13.2
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed.
Clinical signs:
None.
Body weight:
A loss of body weight was noted for 1/3 female at 7 days.
Gross pathology:
No gross abnormalities were noted.
Other findings:
Mild erythema and severe oedema were observed after unwrapping at 24 hours. Eschar was noted for all animals by day 4 which was still evident at 14 days.

None

Interpretation of results:
GHS criteria not met
Conclusions:
Dermal LD50Combined > 2000 mg/kg bw. Under the test conditions, the source substance is not classified according to the Regulation EC No. 1272/2008 (CLP) and to the GHS. The same conclusion applies to the target substance.
Executive summary:

In a limit acute dermal toxicity study performed similarly to the OECD test guideline No. 402, New Zealand White rabbits (3/sex) were occlusively exposed to undiluted source substance for 24 hours at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs including dermal reactions and body weight for 14 days and then necropsied for macroscopic observations.

No mortality and no clinical signs were observed during the study. A loss of body weight was noted for 1/3 female at 7 days.

Mild erythema and severe oedema were observed after unwrapping at 24 hours. Eschar was noted for all animals by day 4 which was still evident at 14 days.

Dermal LD50Combined > 2000 mg/kg bw.

Under the test conditions, the source substance is not classified according to the Regulation EC No. 1272/2008 (CLP) and to the GHS. The same conclusion applies to the target substance. Read-across justification is attached to Iuclid section 13.

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The key study is of good quality (Klimisch score = 2) although GLP status is not reported.

Additional information

Acute toxicity via oral route:

A key study was identified (Harlan, 2014). In this acute oral toxicity study, performed according to OECD Guideline No. 420 and in compliance with GLP, one female Wistar (RccHan™:WIST) rat was administered a single oral dose of test material at 2000 mg/kg bw by gavage (sighting study). Following a sighting study, additional 4 animals were administered a single oral dose of test item at 2000 mg/kg bw (main study). Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

No mortality or clinical signs were observed. Surviving animals showed expected gains in bodyweight over the 14-day study period. No abnormalities were noted at necropsy.

Oral LD50 (rats, females) > 2000 mg/kg bw.

Acute toxicity via dermal route:

No study was available on the substance itself, therefore a read-across approach was used. The source substance is considered adequate for read-across purposes as the data relates to a mixture composed of the same isomers that the target substance, but at different ratios (see Iuclid section 13 for additional justification).

A key study was identified on the source substance (Biosearch Inc., 1984). In this limit acute dermal toxicity study performed similarly to the OECD test guideline No. 402, rabbits (3/sex, half clipped and half abraded)were occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. No mortality and no clinical signs were observed during the study. A loss of body weight was noted for 1/3 female at 7 days. Mild erythema and severe oedema were observed after unwrapping at 24 hours. Eschar was noted for all animals by day 4 which was still evident at 14 days.

Dermal LD50 (rabbits, combined > 2000 mg/kg bw.

Acute toxicity: inhalation

In accordance with 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, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (0.194 Pa at 25°C - from analogue) and a low freezing point (<-20°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 5.79 at 25°C, WS = 125-285 µg/L at 20°C - from analogue).

Justification for classification or non-classification

Harmonised classification:

The substance has no harmonised classification according to the Regulation (EC) No. 1272/2008 (CLP).

Self classification:

Acute toxicity (Oral):

The substance is:

- not classified according to the CLP as the LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS as the LD50 is higher than 2000 mg/kg bw and the substance does not meet the specific criteria for the Category 5 defined in the GHS.

Acute toxicity (Dermal):

The substance is:

- not classified according to the CLP as the dermal LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS as the dermal LD50 is higher than 2000 mg/kg bw and the substance does not meet the specific criteria for the Category 5 defined in the GHS.

Acute toxicity (Inhalation):

No information was available.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the CLP and to the GHS as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to the CLP and to the GHS are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

The classification criteria according to the CLP and to the GHS as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, dermal for a Category 1 classification (C ≤ 1000 mg/kg bw) and at the guidance value, dermal for a Category 2 classification (2000 mg/kg bw ≥ C > 1000 mg/kg bw). No classification required.

Specific target organ toxicity: single exposure (Inhalation):

No information was available.

Aspiration hazard:

The substance is not a hydrocarbon and no effects were observed on lungs in oral study, therefore the criteria for aspiration toxicity according to the CLP and to the GHS are not met.