Reaction mass of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-5-yl isobutyrate and 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-6-yl isobutyrate

Endpoint summary

Additional information

In the table below the acute and long-term toxicity for Cyclabute derived from Cyclobutanate and the acute / chronic ratio for each species from Cyclaprop. Thereafter the read across justification is presented.

Species	Endpoint	Method	Result mg/l measured conc.	Comments
Fish	Acute toxicity	RA from Cyclobutanate	LC50: 3.6	Cyclobutanate OECDTG 203
	Long-term toxicity	Using A/C ratio of Cyclaprop	EC10: 0.43	A/C ratio used is 8.375
	Acute toxicity	Used to derive A/C ratio	EC10: 6.7	Cyclaprop OECD TG 202
	Long-term toxicity	Used to derive A/C ratio	EC10: 0.8	Cyclaprop OECD TG 211
Daphnia	Acute toxicity	WoE	EC50: 1.2	two OECD TG 202 and acute value derived from long-term test (OECD TG 211)
	Long-term toxicity	OECD TG 211	EC10: 0.46
Algae	Acute toxicity	RA from Cyclobutanate	EC50: 1.95	Cyclobutanate OECD TG 201
	Long-term toxicity	RA from Cyclobutanate	NOEC: 0.163	Cyclobutanate OECD TG 201
Micro-organism	Long-term toxicity	RA Cyclobutanate	EC10: >=1000	Cyclobutanate OECD TG 209

Cyclabute and the aquatic toxicity using read across information from Cyclobutanate and the derived Acute/Chronic ratio from Cyclaprop

Introduction and hypothesis for the analogue approach

Cyclabute is an isobutyl ester attached to a tricyclodecenyl fused ring structure. For this substance no algae and acute fish toxicity data are available. In accordance with Article 13 of REACH, lacking information can be generated by means of applying alternative methods such as in vitro tests, QSARs, grouping and read-across. For assessing the other than Daphnia acute aquatic toxicity of Cyclabute the analogue approach is selected because for two closely related analogue reliable acute data are available, which can be used for read across. The acute aquatic toxicity information of other closely related analogues is also presented to support the prediction.

Hypothesis: Cyclabute has the same algae and micro-organism toxicity as Cyclobutanate and similar long-term fish toxicity based on the Acute/Chronic ratio of Cyclaprop.

Available experimental information: For Cyclabute acute and long-term Daphnia toxicity are available which were tested according to OECD TG 202 and 211, respectively, all studies are Klimisch 1. The source chemicals both have a full base set for aquatic toxicity (algae, Daphnia, fish and micro-organisms) all receiving Klimisch 1, except for the algae test of Cyclobutanate, which receives 2 due to some interpretation difficulties of the experimental testing results. Long-term fish information is derived from Cyclaprop. This test is performed according to OECD TG 210 (Klimisch 1).

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemical are shown in the data matrix. Also physico-chemical properties thought relevant for aquatic toxicity are listed in there.

Purity / Impurities

The purity, the constituents and impurities of the source chemical do indicate a similar aquatic toxic potential. The impurities are all below < 10%. Also the purity, the constituents and impurities of the target chemical all indicate a similar aquatic toxicity and 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, which is presented below.

Analogue justification: For Cyclabute, Cyclobutanate is selected being a structural isomer for which the base set aquatic toxicity is available. Cyclaprop is used too because of its structural similarity and for which long-term fish test is available from which the A/C ration for these Cycla-esters can be derived.

Structural similarities and differences: The target and the source chemicals have a tricyclodecenyl fused ring structure with an unsaturated bond in the outside ring. On the other side of the ring an ester bond is attached with a short alkyl chain (C3-C4). The alkyl chain of Cyclabute (target) is an isobutyl while the source Cyclobutanate has a butyl chain. This difference between the target and source chemical is not expected to behave differently in relation to acute aquatic toxicity. Cyclaprop has a one methyl group shorter alkyl chain and is expected and has slightly lower log Kow and therefore higher ECx values.

Phys-chem properties and Bioavailability: Cyclobutanate and Cyclabute have similar bioavailability based on the similarity in chemical structure and physico-chemical properties. The molecular weight of both substances is 220. They are both liquids. The difference in measured log Kow 5.1 and 4.48, respectively, is likely due to experimental method used. Cyclobutanate has been tested with the shake flask method while Cyclabute with the HPLC method.

Mode of Action and Acute/Chronic ratio: Cyclabute, Cyclobutanate and Cyclaprop are expected to have the same mode of action because these have the same backbone and the same functional ester group only differing in isometry or one methyl group less in the alkyl chain. ECOSAR and OECD Toolbox present the same aquatic tox profile. Therefore the Acute/Chronic ratio of Cyclaprop can be applied to Cyclabute to predict the long-term fish toxicity.

Uncertainty of the prediction: The predicted acute aquatic toxicity for Cyclabute has similar uncertainty compared to experimental data, which is supported with acute Daphnia toxicity of Cyclabute and Cyclobutanate: 1.2 and 4.7 mg/l, respectively. There is an overall trend in toxicity following the log Kow. The long-term Daphnia toxicity between Cyclabute and Cyclaprop: 1 and 0.46 mg/l indicated the difference in log Kow.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the data matrix below). The substances used for the analogue approach are ordered according to the increase in alkyl chain.

Conclusions per endpoint for hazard assessment

For Cyclabute no algae and no fish acute and long-term toxicity data are available. For Cyclobutanate experimental information is available on algae, acute fish and micro-organisms; also for Cyclaprop acute and long-term aquatic toxicity are available, which can all be used for read across. The result of this read across is applicable for C&L and/or risk assessment and presented with adequate and reliable documentation. Cyclobutanate shows acute aquatic toxicity data in the 1-10 mg/l range. For Cyclabute the same values can be used, which result in an LC50 of fish of 3.6 and EC50 algae of 1.95 mg/l. The long-term fish can be derived using the Acute/Chronic ratio of Cyclaprop, which is 8.375 for fish. For Cyclabute this results in EC10/NOECs of 0.43/0.34, respectively. The long-term algae test result in 0.163 mg/l using read across from Cyclobutanate and is the lowest long-term EC10/NOEC derived which will therefore be leading for environmental risk assessment.

Final conclusion: The LC and EC50 values for Cyclabute are 3.6 and 1.95 mg/l for fish and algae, respectively. The EC10/NOECs are 0.43 and 0.163 for fish and algae, respectively, based on read across.

Data matrix of Cyclabute for aquatic toxicity using read across from Cyclobutanate and Cyclaprop                                                           

Common names	Cyclabute Target	Cyclobutanate Key source	Cyclaprop Supporting Source
Chemical structures
Cas no 5-yl Cas no of the generic	67634-20-2 93941-73-2	1361017-07-3(5-yl) 113889-23-9	67634-24-6 68912-13-0
Empirical formula	C14H20O2	C14H20O2	C13H18O2
	Target	Key source	Supporting source
MW	220	220	206
Physico-chemical data
Molecular weight	220	220	206
Physical state	liquid	liquid	liquid
Melting point °C	< -20	< -20	< -20
Boiling point °C	273	275	263
Vapour pressure Pa (measured)	0.61	11.2*	0.67
Water solubility mg/l (measured)	16	11.5	57
Log Kow (measured)	5.1 (HPLC)	4.48 (Shake-flask)	4.4 (HPLC)
Log Kow (calculated – ECOSAR)	3.76	3.83	3.34
Acute Aquatic toxicity
Fish LC50 mg/l Experimental ECOSAR esters (using predicted log Kow)	3.6 (Read across) 2.3	3.6 (OECD TG 203)  2.7	6.7 (OECD TG 203) 4.8
Daphnia EC50 mg/l Experimental ECOSAR esters (using ECOSAR predicted log Kow)	1.2 (OECD TG 202) 4.9	4.7 (OECD TG 202 4.4	14 (OECD TG 202)  8
Alga EC50 mg/l Experimental ECOSAR esters (using ECOSAR predicted log Kow)	1.95 (RA from Cyclobutanate) 1.7	1.95 (OECD TG 201) 1.5	2.5 (OECD TG 201) 3.1
Micro-organisms EC50 in mg/l	>=1000 (RA from Cyclobutanate)	>=1000 mg/l	245 RA from Cyclacet (EC no: 911-369-0)
Long-term Aquatic toxicity
Fish EC10/NOEC mg/l Derived A/C ratio ECOSAR esters using ECOSAR predicted log Kow	0.43 using A/C ratio from Cyclaprop 0.18	No data   0.2	0.8 (OECD TG 210)
Daphnia EC10/NOEC mg/l Derived A/C ratio   ECOSAR esters using ECOSAR predicted log Kow	0.46 (OECD TG 211) 0.34 using A/C ratio of Cyclaprop 1.9	No data 0.34 using A/C ratio from Cyclaprop 1.7	>=1 (OECD TG 211) 14 (A/C ratio)   3.8
Algae EC10/NOEC mg/l   ECOSAR esters using ECOSAR predicted log Kow	0.163 (RA from Cyclobutanate) 0.8	0.163 (OECD TG 201)   0.7	1.9 (OECD TG 201)   1.2
Micro-organisms EC10/NOEC in mg/l	>=1000 (RA from Cyclobutanate)	>=1000 (OECD TG 209)	53( RA from Cyclacet)
PNECs aquatic in mg/l	0.0163	0.0163	0.08

*The vapour pressure of Cyclobutanate is somewhat an outlier, which may be due to experimental error because EpiSuite calculates a vapour pressure for Cyclobutanate which is very similar to Cyclabute; RA=Read across

A/C ratio is the ratio between acute and chronic toxicity derived from Cyclaprop information.