Reaction mass of (1R)‐1‐[(1S)‐3,3‐dimethylcyclohexyl]ethyl relacetate and (1R,2R)‐2,6,6‐trimethylcycloheptyl rel‐acetate

Endpoint summary

Description of key information

Overview of the aquatic toxicity data derived for Rosamusk

Species	Guideline	Result in mg/L	Remarks
Desmodesmus subspicatus	OECD TG 201 Read across	48 h-EC50 (growth rate): 3.8 48 h-EC10 (growth rate): 1.1 Static Rosamusk toxicity to algae is converted from the CP Formate EC50 (7.1 mg/L) and EC10 (1.5 mg/L) values based on the difference in measured log Kow values of 4.9 and 4, respectively, and a MW of 196 and 184 g/mol, respectively.	Data derived and recalculated from read across to CP Formate;   Key study, Rel. 2 because of read across;
Daphnia magna	OECD TG 202 Read across	48 h-EC50: 4.1 Semi-static. Rosamusk aquatic invertebrate toxicity is converted from the CP Formate EC50 (7.7 mg/L) based on the difference in measured log Kow values of 4.9 and 4, respectively, and a MW of 196 and 184 g/mol, respectively.	Data derived and recalculated from read across to CP Formate;   Key study, Rel. 2 because of read across;
Cyprinus carpio	OECD TG 203 Read across	96-LC50: 4.2 Semi-static Rosamusk short-term toxicity to fish is converted from the CP Formate LC50 (8 mg/L) based on the difference in measured log Kow values of 4.9 and 4, respectively, and a MW of 196 and 184 g/mol, respectively.	Data not critical because > Daphnia and algae Data derived and recalculated from read across to CP Formate;   Key study, Rel. 2 because of read across;

Additional information

Rosamusk (Cas no. 25225-10-9, main constituent) its algae and Daphnia toxicity using read across from CP Formate and support from other fragrance type of esters

Introduction and hypothesis for the analogue approach

Rosamusk is a reaction mass. The main constituent has a cyclohexyl hydrocarbon backbone to which methyl groups and an ethyl acetyl ester are attached. In the minor constituent the external carbons are slightly different arranged and result in a heptyl ring and an acetyl ester instead of an ethyl acetyl ester.In accordance with Article 13 of REACH,lacking information can be generated by means of applying alternative methods such asin vitrotests, QSARs, grouping and read across. For assessing the Daphnia and algae toxicity of Rosamusk the analogue approach is selected supported with a category approach because for these closely related analogues, reliable aquatic toxicity information is available.

Hypothesis: Rosamusk’s aquatic toxicity can be derived from CP Formate, its most close structural analogue, including conversion of the difference in log Kow. The derived values for Rosamusk also fits the category approach of fragrance type esters which have somewhat lower and somewhat higher log Kow values than Rosamusk.

Available experimental information for CP Formate and related esters: CP Formate’s aquatic toxicity information is presented in the data matrix. The studies were conducted according to current OECD guidelines and are Kl. 1. The details of experimental information of the other esters used for the regression line can be found on the ECHA website, the actual values are summarised in Appendix 1 and 2 for Daphnia and algae, respectively, on which bases the regression lines are based. These studies are all according to OECD guidelines and Kl 1 or 2.

Target chemical and source chemical(s)

Chemical structures of the target and the source chemicals are shown in the QSAR Toolbox matrix presented in Fig. 1. The information of Rosamusk from the closest analogues are presented in the Data matrix. The log Kow values are presented in Appendix 1.

Purity / Impurities

Rosamusk is a reaction mass containing a major and a minor constituent. The major constituent has the Cas number presented above, the minor constituent has the Smiles notation: CC(=O)O[C@@H]1CC(C)(C)CCC[C@@H]1C and no Cas number is assigned.

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 selection: For Rosamusk its close structural analogue CP Formate is selected as key. The closest esters considering log Kow are Verdox and Veilex4. Rosamusk and these 3 analogues are presented in the Data matrix. The information from the supporting fragrance type of esters are included in Appendix 1 and 2 for Daphnia and Algae, respectively.

Structural similarities and differences: Rosamusk’s two constituents have a hydrocarbon backbone and a functional ester group, which is not reactive in absence of electronegative groups close to the ester. CP Formate has the same backbones considering major and minor constituent. The difference between Rosamusk and CP formate is the acetate versus the formate ester, resulting in a higher log Kow for Rosamusk. All other esters in the category have hydrocarbon backbones and unreactive ester bonds. Esters can be of the formate, acetate, propionate or butanoate type.

Bioavailability:Rosamusk, CP Formate and all esters have log Kow between 3.8 and 6, which indicate sufficient bioavailability for causing toxicity.

Mode of Action:Rosamusk, CP Formate and all esters used are categorised similarly in the QSAR Toolbox for aquatic toxicity as presented in Figure 1.

Outcome of the aquatic toxicity assessment

Daphnia toxicity using read across to Rosamusk from CP formate: The effect value needs conversion because of the log Kow 4.9 and 4, respectively:

The calculation equation is: (Log (x ug/l source / mol weight source)) *(log Kow target / Log Kow source) * (10^)*mol weight target = ug/l target. For the conversion from ug/l to mg/l the value needs to be divided with 1000.

This results in Rosamusk EC50 Daphna of 4.1 mg/l (see calculation in Fig. 2).

To support the read-across from CP Formate, data of other esters are used and these are presented in Appendix 1. For Daphnia toxicity a regression line was calculated: y=-0.87+2.94949 (n=12; r2=0.8277) using experimental results of fragrance type of esters as presented in Appendix 1, Table 1 and Fig. 2). Using this equation for Rosamusk, its log Kow of 4.9, MW of 196, the Log mmol for Rosamusk is -1.77 and therefore results in EC50 Daphnia of 3.34 mg/l, which is close to the converted value from CP Formate (4.1 mg/l). The read across value from CP Formate is also in between Verdox and Veilex4 Daphnia results (17 and 4.8 mg/l), which have similar log Kow values compared to Rosamusk (see Data matrix). The QSAR type and the additional analogues show that read across from CP Formate is sufficiently reliable.

Algae toxicity using read across to Rosamusk from CP Formate: The effect values need conversion because of the log Kow 4.9 and 4, respectively:

The calculation equation is: (Log (x ug/l source / mol weight source)) *(log Kow target / Log Kow source) *( 10^)*mol weight target = ug/l target. For the conversion from ug/l to mg/l the value needs to be divided with 1000. This results in Rosamusk Algae EC50 and EC10 of 3.9 and 1.1 mg/l, respectively(see calculation in Fig. 2).

To support the read across for Rosamusk from CP Formate, data of other esters are used.

For the Algae EC50 and EC10 levelsdata are available for some of the same esters as for Daphnia, but the log Kow is limited related to the algae toxicity. Therefore, only the actual EC50 and EC10 data of the algae are shown in Appendix 2, table 2.

The algae EC50 values of the different esters range between 2.5 and 10.5 mg/l, which is in line with the value of Rosamusk derived from CP formate converted for log Kow of 3.8 mg/l.

Algae EC10 data are available for the same set of esters as used for the algae EC50 values. The EC10 values are between 0.96 and 4.7 mg/l (leaving out the NOEC for Verdox because when the EC10 is estimated from the Verdox report the EC10 is between 2.9 and 6 mg/l (but this EC10 is not presented yet in the REACH dossier on the ECHA site).

This means that the Algae EC10 for Rosamusk converted from CP Formate is in line with experimental information from other esters and therefore sufficiently reliable.

Uncertainty of the prediction: The aquatic toxicity of Rosamusk has been derived using the closest structural analogue which is CP formate and including conversion because of the log Kow differences. The values derived using CP Formate are very close to the supporting information from other fragrance type of esters (usually < factor of 3) Therefore the uncertainty is similar to experimental information.

In addition to the above information, for a very similar substance there is a REACH registration (EC no 949-569-5). This substance is not used for read across because the aquatic toxicity values are based on loading rates and not on measured concentrations of the substance. The EC50 values for algae and Daphnia are 52 and 30 mg/l, respectively, somewhat higher than what was calculated for Rosamusk.

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the data matrix below).

Conclusions for aquatic toxicity

For Rosamusk no aquatic toxicity information is available. For Rosamusk CP Formate is selected for read across because it has the closest structural relationship with this substance. A log Kow conversion is needed because the log Kow values are 4.9 and 4, respectively. CP Formate has EC50 values for Daphnia and algae of 7.7 and 7.1 mg/l, respectively. Its EC10 for algae is 1.5 mg/l. After the log Kow and MW conversion, the EC50 for Daphnia and algae for Rosamusk result in 4.1 and 3.8 mg/l, respectively. The EC10 becomes 1.1 mg/l. These values are in line with the supporting information using similar fragrance type of esters.

Final conclusion on hazard:Rosamusk’s EC50 for Daphnia and algae are 4.1, and 3.8 mg/l, respectively, and the EC10 for algae is 1.1 mg/l.

 

Data matrix Information on Rosamusk (target), Verdox and Veilex4 supporting the read across on aquatic toxicity

Common names	Rosamusk (Reaction mass)	CP Formate (Reaction mass)	Verdox	Veilex4
Target / Source	Target (main and minor)	Key source	Supporting Source	Supporting Source
Chemical structures of main constituent	+
Constituent concentration	65-79% major and 10-15% minor	65-85% major and 8-18% minor	Mono-constituent	Mono constituent
Cas no of the main isomer	25225-10-9	25225-08-5	20298-69-5 (mono)	63449-95-6 (mono)
EC number of the main isomer	952-480-4 (Reaction mass)	939-618-9 (Reaction mass)	243-718-1	264-165-2
REACH registered	Registered	Registered	Registered	Registered
Molecular weight	196	184	198	198
Physico-chemical data
Vapour pressure (Pa, measured)	9.1	13.4	9.72	5.35
Water solubility (mg/l, measured)	12.1	26.1	10	13.3
Log Kow (measured)	4.9	4	4.75	5.1
Aquatic toxicity
EC50-Daphnia mg/l	4.1 (read across CP Formate*)	7.7	17	4.8
EC50-Algae mg/l	3.8 (Read across CP Formate*)	7.1	4.2	3.8
EC10-Algae mg/l	1.1 (Read across CP Formate*)	1.5	0.57	0.96
Fish LC50 not relevant the value is > for algae and Daphnia	(4.2)	8	5.6	Not available

*Values are converted using the difference in log Kow and MW

 

 

Fig. 1    Overview of Fragrance type of esters as in the OECD QSAR Toolbox: Cyclacet, CP Formate, Citrolate, Isobornyl acetate, Cyclaprop, Myrcenyl Acetate, Cyclobutanate, Citronellyl acetate, Verdox, Cyclabute, Cedryl acetate, Rosamusk and Veilex4.

 

Substance	Species	Effect in ug/l source	MW Source	umol	Log uMol/l Source	Log Kow source	Log Kow target	Convert to Log umol/l target	Convert to 10^ in umol	MW Target	EC50 value in ug/l Target/	EC50 value target in mg/l
Rosamusk RA from CPFormate	Algae EC50	7100	184	38.587	1.586441	4	4.9	1.29505	19.72666	196	3866.4247	3.8664247
	Daphnia	7700	184	41.8478	1.621673	4	4.9	1.32381	21.07728	196	4131.1473	4.,1311473
	Algae EC10	1500	184	8.15217	0.911273	4	4.9	0.7439	5.544938	196	1086.8078	1.0868078

 

 

Fig 2      Calculation table to convert aquatic toxicity to Rosamusk from CP Formate

 

Appendix 1

 

Table 1 Fragrance type of esters for which IFF is lead registrant and for which experimental Daphnia toxicity information is available.

(generic) Cas no	Tradenames	MW	IFF Log Kow measured	Daphnia OECD TG 202 measured EC50 in mg/l	Log mmol EC50 esters
54830-99-8	Cyclacet	192	3.9	25	-0.88536
25225-08-5	CP Formate	184	4	17	-1.03437
67634-26-8	Citrolate	182	4.2	16.6	-1.03996
125-12-2	Isobornyl acetate	196	3.86	19.8	-0.99559
68912-13-0	Cyclaprop	206	4.4	14	-1.16774
1118-39-4	Myrcenyl acetate	196	4.4	6.3	-1.49292
113889-23-9	Cyclobutanate	212	4.48	4.7	-1.65424
150-84-5	Citronellyl acetate	198	4.6	3.48	-1.75509
88-41-5	Verdox	198	4.7	17	-1.06622
67634-20-2	Cyclabute	212	5.1	1.78	-2.07592
63349-95-6	Veilex4	198	5.1	4.8	-1.61542
77-54-3	Cedryl acetate	264	6	0.33	-2.90309

Fig 3: EC50 Experimental Daphnia results presented in a regression lines for fragrance type of esters for which IFF is lead registrant (all, except Isobornyl Acetate). The equation is used to predict the EC50 Daphnia of Rosamusk

 

Appendix 2

 

Table 2 Fragrance type of esters for which IFF is lead registrant and for which experimental Algae toxicity information is available.

EC50 Algae	Tradename	MW	Log Kow measure	EC50 Algae measure	EC50 Log mmol	EC10 mg/l	EC10 in log mmol
54830-99-8	Cyclacet	192	3.9	6.4	-1.4771	2	-1.98227
25225-08-5	CP Formate	184	4	7.1	-1.4136	1.5	-2.08873
67634-26-8	Citrolate	182	4.2	10.5	-1.2389	4.7	-1.58797
68912-13-0	Cyclaprop	206	4.4	2.5	-1.9159	1.9	-2.03511
113889-23-9	Cyclobutanate	212	4.48	1.95	-2.0363	0.63	-2.527
88-41-5	Verdox	198	4.7	4.2	-1.6734	0.57	-2.54079	*this is a NOEC (EC10 > 1 mg/l)
63349-95-6	Veilex4	198	5.1	3.8	-1.7169	0.96	-2.31439