Octahydro-4,7-methano-1H-inden-5-yl acetate

Endpoint summary

Description of key information

The Acute oral toxicity of Cyclacet Dihydro, using read across from Cyclacet: 2750 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: The value is based on read across

Justification for type of information:

Cyclacet Dihydrowill have the same acute oral toxicity as Cyclacet in view of high similarity in structure: backbone and functional group, resulting in the same LD50 value of 2750 mg/kg bw.
Structural similarities and differences: Cyclacet Dihydro, the target, and the source chemical Cyclacet have identical structural features consisting of a tricyclodecan-e/yl fused ring structure and an acetic ester attached at the bridged hexyl ring. The difference is that Cyclacet Dihydro (as presented in the name) does not have a double bond in the pentyl -ring which Cyclacet has. The absence of the double bond in Cyclacet Dihydro possibly makes the structure a bit more flexible and the one for Cyclacet somewhat more planar.
Toxico-kinetics: Absorption: The molecular weight, appearance, physic-chemical properties all indicate a similar bioavailability; Metabolism: In both Cyclacet Dihydro and Cyclacet the ester bond will be cleaved by bacteria in the gut and/or enzymes in the liver (Toxicological Handbook, Yamada et al 2013). Acetic acid will be one product and the Cyclacet Dihydro- and Cyclacet-alcohol the other metabolite. Both alcohols are expected to be conjugated and excreted via the urine. The anticipated flexibility within the Cyclacet Dihydro structure may slightly hinder the passage through membranes and decrease the bioavailability. In such a case the LD50 of Cyclacet may be conservative.
Toxico-dynamic: Cyclacet Dihydro and Cyclacet are anticipated to have similar toxicity based on their similarity in structure and similar metabolites.
Uncertainty: There is no uncertainty in the prediction based on the same functional group and very similar backbone.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 750 mg/kg bw

Based on:

test mat.

Executive summary:

Cyclacet Dihydro has the same acute oral toxicity as Cyclacet in view of high similarity in structure: backbone and functional group, resulting in the same LD50 value of 2750 mg/kg bw.Structural similarities and differences:Cyclacet Dihydro, the target, and the source chemical Cyclacet have identical structural features consisting of a tricyclodecan-e/yl fused ring structure and an acetic ester attached at the bridged hexyl ring. The difference is that Cyclacet Dihydro (as presented in the name) does not have a double bond in the pentyl -ring which Cyclacet has. The absence of the double bond in Cyclacet Dihydro possibly makes the structure a bit more flexible and the one for Cyclacet somewhat more planar.

Toxico-kinetics:Absorption: The molecular weight, appearance, physic-chemical properties all indicate a similar bioavailability;Metabolism: In both Cyclacet Dihydro and Cyclacet the ester bond will be cleaved by bacteria in the gut and/or enzymes in the liver (Toxicological Handbook, Yamada et al). Acetic acid will be one product and the Cyclacet Dihydro- and Cyclacet-alcohol the other metabolite. Both alcohols are expected to be conjugated and excreted via the urine. The anticipated flexibility within the Cyclacet Dihydro structure may slightly hinder the passage through membranes and decrease the bioavailability. In such a case the LD50 of Cyclacet may be conservative.

Toxico-dynamic:Cyclacet Dihydro and Cyclacet are anticipated to have similar toxicity based on their similarity in structure and similar metabolites. The double bond in Cyclacet

Uncertainty: There is no uncertainty in the prediction based on the same functional group and very similar backbone.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20/03/1980 - 30/08/1980

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Test according to methodology comparable to OECD Guideline 401 under GLP.

Justification for type of information:

Information is used for read across to Cyclacet Dihydro.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: TacN(SD)fBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms (Germantown, N.Y.)
- Weight at study initiation: 180-280 grams
- Fasting period before study: animals were fasted overnight
- Housing: the animals were housed singly in wire cahes
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow 5001 ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
Animals were kept under standard laboratory conditions meeting the standards described in the "Guide for the care and use of laboratory animals" (DHEW Publication No. (NIH) 78-23 Revised 1978).

Route of administration:

oral: gavage

Vehicle:

ethanol

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 0.5 ml/100 g body weight

Doses:

Preliminary assay: 4.0, 4.5 and 5.0 g/kg bw.
Definitive study: 3.5, 4.0, 4.5, 5.0 and 5.6 g/kg bw.

No. of animals per sex per dose:

Preliminary study: 1 male and 1 female per dose
Definitive study: 8 males and 8 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for mortality and pharmacotoxic signs at 1, 3, 5 and 24 hours following dosing and twice daily (once daily on weekends) for the remainder of the 14 day observation period. Surviving animals were weighed at the end of the observation period.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

LD50 determined by Probit analysis

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

2 750 mg/kg bw

95% CL:

2 020 - 3 740

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

3 350 mg/kg bw

95% CL:

2 600 - 4 320

Mortality:

Most deaths occurred within 24 hours after dosing.

Clinical signs:

At 3.5 g/kg ataxia or adoption of the prone position were observed in all of males. All the females adopted the prone position.; the signs were observed in the first twenty-four hours and survivors had recovered by 48 hours after having been dosed. Similar signs including lethargy chromodacryorrhea, and oral discharge were observed in both males and females dosed at 4.0, 4.5, 5.0 and 5.6 g/kg. One animal at 4.0 and one animal at 4.5 g/kg became moribund within 24 hours and one animal at 5.0 became moribund at 24 hours and remained so through Day 2.

Body weight:

All survivors gained weight in a normal manner (>10 g).

Gross pathology:

There were no signs indicative of toxicity in any of the animals necropsied at term. In animals that died the only signs were of yellow fluid in the stomach and intestines and reddish fluid in the intestines.

Other findings:

Not relevant

Summary of mortality

Dose level	Mortality
	Male	Female	Total
3.5/kg bw	6/8	7/8	13/16
4.0 g/kg bw	5/8	8/8	13/16
4.5 g/kg bw	4/8	5/8	9/16
5.0 g/kg bw	6/8	8/8	14/16
5.6 g/kg bw	7/8	6/8	13/16

Interpretation of results:

other: Criteria not met

Remarks:

according to EU CLP (1272/2008 and its amendments)

Conclusions:

In acute oral toxicity study which was performed according to methodology comparable to OECD401 and under GLP conditions, the acute 14d-LD50 of 80-006-04 towards rats was observed to be 3.35 and 2.75 g/kg bw for male and female rats respectively, under the conditions of the test.

Executive summary:

The acute oral toxicity of 80-006-04 towards rats was investigated according to methodology comparable to OECD Guideline 401 and under GLP conditions. Based on the results of a preliminary assay, the test substance was dosed at 3.5, 4.0, 4.5, 5.0 and 5.6 g/kg bw in the main test. Mortality was observed in all doses. The definitive 14d-LD50 values were determined to be 3.35 (2.60 - 4.32) and 2.75 (2.02 - 3.74) g/kg for male and female rats respectively, under the conditions of this test.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

The acute oral toxicity of Cyclacet Dihydro has been derived by using read across from Cyclacet. First the acute oral toxicity information of Cyclacet will be presented and thereafter the read across documentation.

Cyclacet Dihydro (Cas no 64001-15-6)and its acute oral toxicity derived from Cyclacet (Cas no generic 54830-99-8)

Introduction

Cyclacet Dihydro has a tricyclodecanyl fused ring structure to which an acetic-ester is attached (see Data matrix). For this substance no acute oral toxicity information is available. In accordance with Article 13 of REACH, lacking information can be generated by means of applying alternative methods such as in vitro, QSARs, grouping and read-across. For Cyclacet Dihydro the acute oral toxicity will be derived from the analogue Cyclacet.

Hypothesis: Cyclacet Dihydro will have the same acute oral toxicity as Cyclacet in view of high similarity in structure: backbone and functional group, resulting in the same LD50 value of 2750 mg/kg bw.

Available experimental information: For Cyclacet a reliable OECD TG 401 study is available (GLP and Klimisch 1) in which an LD50 of 2750 mg/kg bw was found.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemical are shown in the data matrix.

Purity / Impurities

The purity and impurities of the target chemical do not indicate other constituents or impurities (all< 10%) that indicated a different acute oral toxicity potential.

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.

In accordance with ECHA guidance (2017, RAAF) Cyclacet is selected as the key source because of the similarities in structure of both substances considering backbone and functional group.

Structural similarities and differences:Cyclacet Dihydro, the target, and the source chemical Cyclacet have identical structural features consisting of a tricyclodecan-e/yl fused ring structure and an acetic ester attached at the bridged hexyl ring. The difference is that Cyclacet Dihydro (as presented in the name) does not have a double bond in the pentyl -ring which Cyclacet has. The absence of the double bond in Cyclacet Dihydro possibly makes the structure a bit more flexible and the one for Cyclacet somewhat more planar.

Toxico-kinetics:Absorption: The molecular weight, appearance, physic-chemical properties all indicate a similar bioavailability;Metabolism: In both Cyclacet Dihydro and Cyclacet the ester bond will be cleaved by bacteria in the gut and/or enzymes in the liver (Toxicological Handbook, Yamada et al 2013). Acetic acid will be one product and the Cyclacet Dihydro- and Cyclacet-alcohol the other metabolite. Both alcohols are expected to be conjugated and excreted via the urine. The anticipated flexibility within the Cyclacet Dihydro structure may slightly hinder the passage through membranes and decrease the bioavailability. In such a case the LD50 of Cyclacet may be conservative.

Toxico-dynamic:Cyclacet Dihydro and Cyclacet are anticipated to have similar toxicity based on their similarity in structure and similar metabolites.

Uncertainty: There is no uncertainty in the prediction based on the same functional group and very similar backbone. In accordance with ECHA guidance (RAAF, 2017) the read across receives score 5.

Data matrix

In the Table at the end of the section the data matrix is presented.

Conclusions for acute oral toxicity and classification and labelling

Hazard:The acute oral LD50 of Cyclacet Dihydro is derived from Cyclacet. Cyclacet has an acute oral LD50 of 2750 and therefore Cyclacet Dihydro is also anticipated to have an LD50 of 2750 mg/kg bw.Classification and Labelling: Cyclacet Dihydro has an LD50 of 2750 and therefore the substance does not need to be classified and labelled according to CLP (EC 1272/2008 and its amendments).

 

Table 1: Data matrix presenting the characteristics of Cyclacet Dihydro and its source Cyclacet to support the read across for acute oral toxicity

Common names	Cyclacet Dihydro	Cyclacet
Chemical structures
	Target	Source
Cas no of the main isomer Cas no of the generic	64001-15-6	2500-83-6 (5-yl) 54830-99-8
Einecs	264-598-7	911-369-0
REACH registration	REACH registered for 2018	REACH registered
Empirical formula	C12H18O2	C12H16O2
Smiles	CC(=O)OC3CC1CC3C2CCCC12	CC(=O)OC3CC1CC3C2CC=CC12
Physico-chemical data
Molecular weight	194	192
Physical state	liquid	liquid
Vapour pressure Pa (measured)	2.2	2.1
Water solubility mg/l (measured)	89	186
Log Kow (measured)	4.5	3.9
Log Kow (calculated – ECOSAR)	3.1	2.85
Human health
Acute oral toxicity LD50 in mg/kg bw	Read across from Cyclacet	2750

 

References

Yamada, T., Tanaka, Y., Hasegawa, R., Sakuratani, Y., Yamada, J., Kamata, E., Ono, A., Hirose., A., Yamazoe, Y., Mekenyan, O., Hayashi, M., 2013, A category approach to predicting the repeated-dose hepatotoxicity of allyl esters, Reg. Toxicol. Pharmacol, 65, 189-195.

Justification for classification or non-classification

The substances does not need to be classified for acute oral toxicity based on the LD50 of 2750 mg/kg bw in accordance with CLP (EC 1272/2008) and its amendments.