Decahydrospiro[furan-2(3H),5'-[4,7]methano[5H]indene]

Endpoint summary

Description of key information

Acute oral toxicity: based on read across information: LD50 > 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

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: Results derived from a valid read across, with adequate and reliable documentation / justification.

Justification for type of information:

The full read across justification is presented in the Endpoint summary and the accompanying file is also attached there.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: Read across information

Remarks on result:

other: Based on acute oral toxicity of Amber Xtreme and Cedramber (LD50 > 2500 mg/kg bw and LD50 > 5000 mg/kg bw, respectively) using conversion.

Interpretation of results:

other: Not classified, criteria not met

Remarks:

according to EU CLP 1272/2008 and its amendments

Conclusions:

For Vigoflor for acute oral toxicity LD50 >2000 mg/kg bw has been derived.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Between 15 May 2003 and 11 June 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Information used for read across to Vigoflor.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK
- Age at study initiation: eight to twelve weeks
- Weight at study initiation: bodyweights fell within an interval of ± 20% of the mean initial bodyweight of the first treated group
- Fasting period before study: overnight fast and for approximately three to four hours after dosing
- Housing: groups of three in suspended solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): 12 hrs continuous light (06:00 to 18:00) and 12 hrs darkness

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2.15 ml/kg

DOSAGE PREPARATION (if unusual): For the purpose of the study the test material was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: In absence of data suggesting test material is toxic, 2000 mg/kg was chosen as the starting dose.

Doses:

2000 mg/kg

No. of animals per sex per dose:

6 (female)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: 1/2, 1, 2, 4 hours after dosing and subsequently once daily for 14 days. Weighing: prior to dosing and seven and fourteen days after treatment.
- Necropsy of survivors performed: yes.
- Other examinations performed: clinical signs, body weight. gross pathalogical examination.

Statistics:

None recorded.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 500 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Confidence intervals are not applicable in view of the absence of effects

Mortality:

There were no deaths.

Clinical signs:

There were no signs of systemic toxicity.

Body weight:

All animals showed expected gains in bodyweight over the study period.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

None

Table 1          Mortality

Dose Level mg/kg	Sex	Number of Animals Treated	Deaths During Day of Dosing (Hour)				Deaths During Period After Dosing (Days)								Deaths
			½	1	2	4	1	2	3	4	5	6	7	8-14
2000	Female	3	0	0	0	0	0	0	0	0	0	0	0	0	0/3
	Female	3	0	0	0	0	0	0	0	0	0	0	0	0	0/3

Table 2          Individual Clinical Observations

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	1-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

Table 3          Individual Bodyweights and Weekly Bodyweight Changes

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
2000	1-0 Female	223	248	273	25	25
	1-1 Female	222	263	283	41	20
	1-2 Female	242	275	298	33	23
	2-0 Female	213	258	278	45	20
	2-1 Female	214	258	283	44	25
	2-2 Female	236	259	291	23	32

Table 4          Individual Necropsy Findings

Dose Level mg/kg	Animal Number and Sex	Macroscopic Observations
2000	1-0 Female	No abnormalities detected
	1-1 Female	No abnormalities detected
	1-2 Female	No abnormalities detected
	2-0 Female	No abnormalities detected
	2-1 Female	No abnormalities detected
	2-2 Female	No abnormalities detected

 

Interpretation of results:

other: Not classified, criteria not met

Remarks:

according to EU CLP 1272/2008 and its amendments

Conclusions:

In an acute toxicity study performed according to the acute toxic class method (OECD423) and under GLP conditions, the acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated as being greater than 2500 mg/kg bodyweight.

Executive summary:

In an acute oral toxicity study which was performed in accordance with the Acute Toxic Class method (OECD423) and under GLP conditions, a group of three fasted female Sprague-Dawley CD strain rats was treated with the test material at a dose level of 2000 mg/kg bodyweight. This was followed by a further group of three fasted females at the same dose level. The test material was administered orally undiluted. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

No mortality was observed. All animals showed expected bodyweight gains over the study period. There were no signs of systemic toxicity and no abnormalities were noted at necropsy.

The acute oral median lethal dose (LD₅₀) of the test material in the female Sprague-Dawley CD strain rat was estimated as being greater than 2500 mg/kg bodyweight, based on Annex 2d of OECD 423.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Information used for read across to Vigoflor.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: unspecified

Vehicle:

not specified

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

10 animals per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality observed

Clinical signs:

No clinical signs observed

Interpretation of results:

other: Not classified, criteria not met

Remarks:

according to EU CLP 1272/2008 and its amendments

Conclusions:

The acute oral toxicity test showed an LD50 of > 5000 mg/kg bw

Executive summary:

In a pre-GLP acute toxicity study similar to OECD 401, 10 rats were orally exposed to 5000 mg/kg bw test substance. All animals survived the 14 -day observation period. Under the conditions of the test the acute oral LD50 was determined to be >5000 mg/kg bw in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

In this endpoint summary the experimental information of Amber Xtreme and Cedramber is presented being used for read across to Vigoflor. First the executive summaries of the acute oral toxicity tests of Amber Xtreme and Cedramber are presented, thereafter the justification of the read across.

Amber Xtreme acute oral toxicity information:

In an acute oral toxicity study which was performed in accordance with the Acute Toxic Class method (OECD423) and under GLP conditions, a group of three fasted female Sprague-Dawley CD strain rats was treated with the test material at a dose level of 2000 mg/kg bodyweight. This was followed by a further group of three fasted females at the same dose level. The test material was administered orally undiluted. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

No mortality was observed. All animals showed expected bodyweight gains over the study period. There were no signs of systemic toxicity and no abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated as being greater than 2500 mg/kg bodyweight, based on Annex 2d of OECD 423.

Cedramber acute oral toxicity information:

In a pre-GLP acute toxicity study similar to OECD 401, 10 rats were orally exposed to 5000 mg/kg bw test substance. All animals survived the 14 -day observation period. Under the conditions of the test the acute oral LD50 was determined to be >5000 mg/kg bw in rats.

Conversion for Vigoflor:

Vigoflor has a somewhat lower molecular weight than Amber Xtreme and Cedramber and therefore a conversion of the acute toxicity values of the source substances to Vigoflor was done. The Vigoflor LD50 would be >1819 mg/kg bw when converted from Amber Xtreme. This value is slightly below 2000 mg/kg bw and therefore for support Cedramber's LD50 was used to make sure that the LD50 of Vigoflor can be set to > 2000 mg/kg bw. The converted LD50 from Cedramber for Vigoflor is > 4067 mg/kg bw. Based on both data the LD50 for Vigoflor is considered to be >2000 mg/kg bw.

Read across justification:

The acute oral toxicity of Vigoflor (Cas no 68480-11- 5) using read across from Amber Xtreme (Cas no 476332-65-7) and Cedramber (Cas no 67874-81-1)

 

Introduction and hypothesis for the analogue approach

Vigoflor has a hydrocarbon backbone with a cyclic ether; it contains a bridged cyclohexane attached to two 5-ring structures: a cyclopentane and in the other 5-ring (oxacyclopentane) an ether group is incorporated. For this substance no acute oral toxicity data are available. In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i. e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the acute oral toxicity of Vigoflor the analogue approach is selected because for two closely related analogues, Amber Xtreme and Cedramber acute oral toxicity information is available which can be used for read across. The LD50 of Amber Xtreme is > 2500 mg/kg bw but it has a higher molecular weight than Vigoflor. Conversion using molecular weight would result in an LD50 for Vigoflor of > 1819 mg/kg bw. To support the LD50 of Vigoflor predicted to be above 2000 mg/kg bw Cedramber, with an LD50 of > 5000 mg/kg bw is selected to support the Vigoflor LD50 being above 2000 mg/kg bw.

Hypothesis: Vigoflor has similar acute oral toxicity compared to Amber Xtreme and Cedramber resulting in a similar LD50 based on a similar hydrocarbon backbone and ether as a functional group.

Available information: Amber Xtreme was tested in a well conducted acute oral toxicity study (in accordance with OECD TG 423 and under GLP conditions, Kl. 1) at a dose level of 2000 mg/kg bw (Resulting in an LD50 of > 2500 mg/kg bw).No mortality was observed. All animals showed expected bodyweight gains over the study period. There were no signs of systemic toxicity and no abnormalities were noted at necropsy. For Cedramber an acute oral toxicity study is available (study similar to OECD TG 401, pre-GLP, Kl. 2) in which 5000 mg/kg bw was tested. All animals survived the 14 -day observation period. Under the conditions of the test the acute oral LD50 was determined to be >5000 mg/kg bw in rats.

Target chemical and source chemical(s)

Chemical structures of Vigoflor and both Amber Xtreme and Cedramber are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for acute oral toxicity, of all substances.

Purity / Impurities

Vigoflor has two constituents that are stereo-isomers of each other, which indicate the same acute oral toxicity potential. The impurities are all below 10%.

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.

Analogue selection:A clear documentation is needed on the selection of potential source substances. In the RIFM Database no analogues were identified for Vigoflor. A further search in the OECD QSAR toolboxby using structural similarity with Tanimoto 60% on Atom Pairs, Atom Centred Fragments or a combined search on both molecular features revealed no analogues. Amber Xtreme and Cedramber are selected from IFFs portfolio: These two source substances have a similar hydrocarbon backbone and similar functional group compared to Vigoflor.

Structural similarities and differences

Vigoflor, Amber Xtreme and Cedramber are similar because all contain hydrocarbon cyclic rings and an ether group. Vigoflor and Amber Xtreme contain a cyclohexane with attached two 5-ring structures: a cyclopentane and in the other 5-ring (oxacyclopentane) the ether group is incorporated.

The main difference between Vigoflor and Amber Xtreme is that the oxacyclopentane is co-planar in Vigoflor and planar in Amber Xtreme, due to the binding of this Vigoflor 5-ring to a single tertiary C. Furthermore, in contrast to Amber Xtreme, the cyclohexane of Vigoflor is bridged. The main difference between Vigoflor and Cedramber is that the latter has a bridged cycloheptane instead of a bridged cyclohexane. The ether-bond in Cedramber is external and not incorporated in a ring structure. Both Amber Xtreme and Cedramber have additional methyl groups attached to the rings resulting in higher molecular weight compared to Vigoflor.

Toxico-kinetic:Absorption:Vigoflor and both Amber Xtreme and Cedramber indicate similar toxico-kinetic characteristics based on the similarities in chemical structure and physico-chemical properties.The molecular weights are around 200: 192.29, 264.25 and 236.39, respectively. All three substances are liquids. They have similar Log Kow’s: 4.7, 4.42 and 5.1 respectively, indicating ready oral absorption.

Themetabolisationof the substances is assessed using OECD Toolbox 4 liver metabolism simulator. Vigoflor and Cedramber may form alcohols on the carbons of the ring. The opening of the ether ring in Vigoflor may form an alcohol on one end and an acid, aldehyde or alcohol at the other end. Amber Xtreme and Cedramber may become oxidized and turn into alcohols, aldehydes or acids at the methyl groups on their rings.

 

Fig. 1: The metabolisation pathway of Vigoflor.

Toxico-dynamics:The reactivity of Vigoflor compared to Amber Xtreme and Cedramber is considered similar based on the similar weak sensitization profile (likely due to the ether group generating some hydroperoxides) and absence of eye irritation, despite Vigoflor being a skin irritant while the other two are not. The OECD Toolbox presents a similar profile between Vigoflor and Amber Xtreme (Cramer class III, data not shown). The dynamic profile is similar between these substances. 

Similarities in results for toxicological endpoints between Vigoflor and both Amber Xtreme and Cedramber:In the data matrix a summary of other toxicological data is presented. As is presented in the toxico-dynamic section, a similar reactivity is anticipated between Vigoflor and the source substances.

Conversion forthe difference in molecular weight: In view of Vigoflor having a lower molecular weight, the LD 50s of both Amber Xtreme and Cedramber for the acute oral toxicity data were converted using the following equation:

(>2500 mg/kg bw Amber Xtreme / 264.25 MW Amber Xtreme) * 192.29 MW Vigoflor = >1819 mg/kg bw Vigoflor. In view of this value > 1819 mg/kg bw and absence of any mortality at 2000 mg/kg bw in Amber Xtreme the Vigoflor LD50 can be considered to be > 2000 mg/kg bw. To strengthen this assumption the result of Cedramber is included and also converted to predict the LD 50 for Vigoflor.

A similar conversion is used to correct the LD50 > 5000 mg/kg bw of Cedramber for Vigoflor resulting in an LD50 > 4067 mg/kg bw.

Uncertainty of the prediction:In view of the reasoning above there are no remaining uncertainties, also because the values of Amber Xtreme and Cedramber are converted based on their molecular weights.

In view of the acute oral toxicity converted from Amber Xtreme and Cedramber to Vigoflor, LD 50 > 1819 mg/kg bw and LD50 > 4067 mg/kg bw, respectively, the LD50 for Vigoflor is considered to be >2000 mg/kg bw.

Data matrix

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

Conclusions per endpoint for hazard and C&L 

When using read across the result derived should be applicable for C&L, cover an exposure period duration comparable or longer than the corresponding method and be presented with adequate and reliable documentation.For Amber Xtremea well conducted acute oral toxicity test is available (Reliability 1) with a LD50 of >2500 mg/kg bw. In addition, for Cedramber an acute oral toxicity study is available (Reliability 2) with a LD50 of > 5000 mg/kg bw. In view of the similarity in hydrocarbon backbone, the ether being the common functional group, physico-chemical properties and toxicological data, a converted LD50 of Amber Xtreme and Cedramber is used for Vigoflor resulting in an LD50 > 2000 mg/kg bw.

Final conclusion on hazard and C&L:

For Vigoflor for acute oral toxicityLD50 >2000 mg/kg bw has been derived. Based on this value classification and labeling is not needed for this endpoint according to CLP Regulation (EC) No. 1272/2008 and its updates.

 

Data matrix for the read across to Vigoflor from Amber Xtreme and Cedramber

Common names	Vigoflor	Amber Xtreme	Cedramber
Chemical structures
CAS no	68480-11-5	476332-65-7	67874-81-1; 19870-74-7
EC no	270-887-9	449-360-4	267-510-5
Reach registration	Registered for 2018	EINECS	Registered for 2018
Empirical formula	C13H20O	C18H32O	C16H28O
Physico-chemical data
Molecular weight	192.29	264.25	236.39
Physical state	Liquid	Liquid	Liquid
Vapour pressure, Pa	1.97	0.38	0.5
Water solubility, mg/L	4.64	<0.202	4.3
Log Kow	4.7	4.42	5.1
Human health endpoints
Acute oral tox (mg/kg bw)	LD50 > 2000 Read Across from Amber Xtreme and Cedramber	LD50 >2500 (OECD 423)	LD50 >5000 (similar to OECD 401)
Skin irritation	Irritating (OECD 439)	Not irritating (OECD 404)	Not irritating (OECD 439)
Eye irritation	Not irritating (OECD 438)	Not irritating (OECD 405)	Not irritating (OECD 438)
Skin sensitisation	Sensitising EC3=68% (OECD 429)	Sensitising EC3=43.44% (OECD 429)	Sensitising EC3=32% (OECD 429)
Genotoxicity – Ames test	Negative (similar to OECD 471)	Negative (OECD 471)	Negative (OECD 471)

 

Justification for classification or non-classification

According to the criteria outlined in Annex I of 1272/2008/EC (CLP) and its amendments, the substance does not have to be classified as acute toxic by the oral route.