Reaction mass of (3aR*,5aS*,9aS*,9bR*)-3a,6,6,9a-Tetramethyldodecahydronaphtho[2,1-b]furan and (3aR*,5aS*,9aS*,9bS*)-3a,6,6,9a-Tetramethyldodecahydronaphtho[2,1-b]furan

Endpoint summary

Description of key information

Acute toxicity: oral: LD50 (rat, females) > 2000 mg/kg bw (OECD 420, GLP, K, rel. 1).

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

Acute toxicity: 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:

Between 20 September 2012 and 01 November 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Study performed according to OECD test guideline No. 420 and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Version / remarks:

Adopted 17 December 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese MAFF, 2000

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

UK GLP Compliance Monitoring Programme (inspection date: 10 July 2012/ signed on 30 November 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 (RccHanTM:WISTAR)
- Source: Harlan Laboratories UK Ltd, Oxon UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 149-169 g
- Fasting period before study: overnight. Food will be returned approximately 3 to 4 hours after dosing.
- Housing: group-housed in polypropylene cages with stainless steel mesh lids and furnished with softwood flake bedding.
- Diet (e.g. ad libitum): Rodent 2014C Teklad Global Certified Diet ad libitum. Not contaminated.
- Water (e.g. ad libitum): Tap water ad libitum. Not contaminated.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION (if unusual): the test item was formulated within two hours of being applied in the test system. It is assumed that the formulation was stable for this duration.

Doses:

Sighting test: 5, 50, 300, 2000 mg/kg.
Main test: 2000 mg/kg bw.

No. of animals per sex per dose:

Sighting test: 1 female per dose
Main test: 4 additional females

Control animals:

no

Details on study design:

SIGHTING TEST
- a single animal per dose level
- dose levels: 5, 50, 300, 2000 mg/kg bw
- dosing will be sequential, allowing at least 24 hours before investigation of the next dose level.

MAIN TEST
- 5 animals per dose level (made up of one animal from the sighting test dosed at the selected dose level together with an additional 4 animals)
- Duration of observation period following administration: 14 days
- Frequency of mortality / morbity inspection: twice daily, early and late, during normal working days, once daily at weekends and public holidays.
- Frequency of clinical observations: 30 min, 1, 2 and 4 hours after dosing, then at least once daily.
- Weighing: recorded on Day 0 (prior to dosing), Day 7 and 14, or at death.
- Necropsy of survivors performed: yes, gross necropsy on all animals

Statistics:

None

Preliminary study:

There was no mortality and no signs of systemic toxicity up to 300 mg/kg bw. All the animals showed expected body weight gains. No abnormalities were noted at necropsy. Based on the results at dose levels of 5, 50 and 300 mg/kg bw, a dose level of 2000 mg/kg bw was investigated.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: Hunched posture (4/5), ataxia (5/5) and lethargy (5/5) were observed. Animals appeared normal one (1/5), three (4/5) or four (5/5) days after dosing.

Gross pathology:

No abnormalities at necropsy.

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Conclusions:

Oral LD50 Females > 2000 mg kg bw.

Executive summary:

In an acute oral toxicity study performed according to the OECD test guideline No. 420 and in compliance with GLP, groups of fasted, eight to twelve weeks of age Wistar (RccHan^TM:WIST) female rats were given a single oral dose of ST 11 C 88 in Arachis oil BP. Following a sighting test in which single animals were treated at dose levels of 5, 50, 300 and 2000 mg/kg bw, a further group of four females was given a single oral dose of 2000 mg/kg bw. All animals were observed for 14 days and subjected to gross necropsy.

Oral LD₅₀ Females > 2000 mg/kg bw

There were no deaths during the study.

Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg bw were hunched posture, ataxia and lethargy. Animals appeared normal one, three of four days after dosing. There were no signs of systemic toxicity noted at dose levels of 300, 50 or 5 mg/kg bw.

All animals showed expected gains in bodyweight.

No abnormalities were noted at necropsy.

Under the test conditions, ST 11 C 88 is not classified as toxic if swallowed 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:

study scientifically not necessary / other information available

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 very low vapour pressure (0.236 Pa at 25°C), so the potential to generate vapor is low. Nonetheless, considering the use of the substance, exposure to mist can occur. However, based on the absence of acute toxicity by oral route, no mortality is anticipated during the exposure to mist. Hence, dermal exposure is the more likely route of exposure during the manufacture and the use of the substance leading to the low penetration of the substance based on its partition coefficient (Log Kow = 5.09°C, from source substance).

Reason / purpose for cross-reference:

data waiving: supporting information

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 1979-07-10 to 1979-07-24

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Although conducted under worst-case conditions (abraded skin, occlusive dressing), no mortality was observed during this study. A repeat study is unlikely to show worse effects; therefore this study was considered sufficiently robust to cover this endpoint.

Principles of method if other than guideline:

The abraded skin of albino rabbits (3/sex) was occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.

GLP compliance:

no

Remarks:

pre-GLP

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.0 - 3.0 kg bw
No other data

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE: abraded skin
- Area of exposure: back
- % coverage: no data
- Type of wrap if used: the treated areas were covered with large gauze patches and an impervious material was wrapped snugly around the trunk of each animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data, any excess material was removed
- Time after start of exposure: 24h

Duration of exposure:

24h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 animals/sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes

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:

None

Clinical signs:

other: There were no unusual behavioural signs noted.

Gross pathology:

No effect

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Conclusions:

Dermal LD50Combined > 2000 mg/kg bw

Executive summary:

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

 

No mortality occurred during the study. There were no adverse effects.

 

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 the GHS.

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

Reference 2

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
[Further information is included as attachment to Iuclid section 13]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across approach is based on the hypothesis that the 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 the source substances are Cycloalkane ethers. The source substance is the (-)-9bR isomer, while the target substance is a reaction mass of the 9bR isomer (racemic form) together with the 9bS isomer.

3. ANALOGUE APPROACH JUSTIFICATION
The source and the target substances are expected to have the same toxicokinetic profile (ADME) based on structural similarity (Section 3.2) and similar physico-chemical properties (Section 4.1). In addition, the available systemic and local toxicity studies (acute oral toxicity, skin/eye irritation, skin sensitisation – section 4.4) are comparable between the two substances.
The source substance is therefore expected to have similar toxicological profile than the target substance.
The source substance study was performed before the adoption of OECD TGs. However, the study design is similar to the one of the OECD TG 402 based on the exposure conditions and the key parameters assessed so the results are considered adequate and reliable for the purpose of prediction. The test material was not clearly identified but it is assumed to represent the source substance in terms of constituents and impurities. The result of the study [LD50 > 5000 mg/kg bw] is adequate for classification and labelling.
Therefore, based on the considerations above, it can be concluded that the result of the acute dermal toxicity study conducted in the rabbits with the source substance is likely to accurately predict the properties of the target substance and is considered suitable to fulfil the information requirement of Annex VII, 8.5.3.

4. DATA MATRIX
See Iuclid section 13

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:

None

Clinical signs:

other: There were no unusual behavioural signs noted.

Gross pathology:

No effect

Other findings:

None

None

Interpretation of results:

GHS criteria not met

Conclusions:

Dermal LD50Combined > 2000 mg/kg bw

Executive summary:

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

 

No mortality occurred during the study. There were no adverse effects.

 

Dermal LD₅₀Combined > 2000 mg/kg bw

 

Based on the study results, the source and the target substances are 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 conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

No study was available on the target substance. In the key study on the source substance, conducted under worst-case conditions (abraded skin, occlusive dressing), no mortality was observed. An additional dermal study is unlikely to show worse effects, therefore this study was considered sufficiently robust to cover this endpoint.

Additional information

Acute toxicity: oral:

A key study was identified (Harlan, 2012, rel.1). This acute oral toxicity study was according to the OECD test guideline No. 420 and in compliance with GLP. Following a sighting test in which single animals were treated at dose levels of 5, 50, 300 and 2000 mg/kg bw, a further group of four females was given a single oral dose of 2000 mg/kg bw. There were no deaths during the study. Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg bw were hunched posture, ataxia and lethargy. Animals appeared normal one, three of four days after dosing. There were no signs of systemic toxicity noted at dose levels of 300, 50 or 5 mg/kg bw. All animals showed expected gains in bodyweight. No abnormalities were noted at necropsy.

Oral LD50 Females > 2000 mg/kg bw.

Acute toxicity: dermal

A key study was identified (Biosearch, 1979, rel.2). In this limit acute dermal toxicity study, which was performed similarly to the OECD guideline No. 402, the abraded skin of albino rabbits (3/sex) was occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations. No mortality occurred during the study. There were no adverse effects.

Dermal LD50 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 very low vapour pressure (0.236 Pa at 25°C), so the potential to generate vapor is low. Nonetheless, considering the use of the substance, exposure to mist can occur. However, based on the absence of acute toxicity by oral route, no mortality is anticipated during the exposure to mist. Hence, dermal exposure is the more likely route of exposure during the manufacture and the use of the substance leading to the low penetration of the substance based on its partition coefficient (Log Kow = 5.09°C, from source substance).

Justification for classification or non-classification

Harmonized classification:

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

Self-classification:

Acute toxicity (Oral):

Based on the available information, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 mg/kg bw.

Classification under the GHS is not warranted since neither mortality nor significant signs of toxicity were observed up to 2000 mg/kg bw.

Acute toxicity (Dermal):

Based on the available information on the source substance, the target substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 mg/kg bw.

Classification under the GHS is not warranted since neither mortality nor significant signs of toxicity were observed up to 2000 mg/kg bw.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex I of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no significant health effects were observed immediately or delayed after exposure 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 Annex I of the Regulation (EC) No. 1272/2008 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 Annex I of the Regulation (EC) No 1272/2008 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 is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex I of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

No data was available.

Aspiration hazard:

The substance is a solid, therefore the hazard class does not apply.