Reaction Mass of Cyclohexanepropanol, 2,2,6-trimethyl-a-propyl-, (alpha.R,1R,6S)- and Cyclohexanepropanol, 2,2,6-trimethyl-a-propyl-, (alpha.S,1R,6S)-

Water solubility

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

water solubility

Type of information:

experimental study

Adequacy of study:

key study

Study period:

experimental phase from 2014-02-28 to 2014-08-16

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted according to an internationally recognised method, and under GLP. No major deviation was reported. The test substance is considered to be adequately characterised. Therefore full validation applies.

Qualifier:

according to guideline

Guideline:

OECD Guideline 105 (Water Solubility)

Deviations:

yes

Remarks:

excess test item

Qualifier:

according to guideline

Guideline:

EU Method A.6 (Water Solubility)

Deviations:

yes

Remarks:

excess test item

Principles of method if other than guideline:

Testing was conducted in both double distilled water and daphnia reconstituted natural medium M4 (OECD 211).

GLP compliance:

yes (incl. QA statement)

Remarks:

inspected on June 3 to 5, 2013 / signed on November 5, 2013

Type of method:

flask method

Remarks:

modified acc. to Letinski et al. (2002) and OECD 123

Water solubility:

125 µg/L

Temp.:

20 °C

pH:

7

Remarks on result:

other: isomer 1 in distilled water (alpha.R,1R,6S)-

Water solubility:

285 µg/L

Temp.:

20 °C

pH:

7

Remarks on result:

other: isomer 2 in distilled water [1a(S*),6b]- (9Cl)

Water solubility:

115 µg/L

Temp.:

20 °C

pH:

7

Remarks on result:

other: isomer 1 in M4 medium (alpha.R,1R,6S)-

Water solubility:

261 µg/L

Temp.:

20 °C

pH:

7

Remarks on result:

other: isomer 2 in M4 medium [1a(S*),6b]- (9Cl)

Details on results:

The analytical method was validated and tested with satisfactory results in regard to linearity, accuracy, precision and specificity:
System quantification limit: 1 µg/L
Linearity: 1 – 50 µg test item/L (n=8), corresponding to 0.284 – 14.2 µg isomer 1/L and 0.652 – 32.6 µg isomer 2/L, r2 ranging between 0.9923 and 0.9998
LOQ (target): nominal 4 µg test item/L, corresponding to 1.14 µg isomer 1/L and 2.61 µg isomer 2/L
Recovery rates in pure water:
1 x LOQ = 93% for isomer 1, 92% for isomer 2 (RSD=4.2% and 3.7% resp.)
5 x LOQ = 97% for isomer 1, 100% for isomer 2 (RSD=6.7% and 7.2% resp.)
125 x LOQ = 93% for isomer 1, 90% for isomer 2 (RSD=12% and 9.6% resp.)
Recovery rates in daphnia medium (M4)
1 x LOQ = 91% for isomer 1, 87% for isomer 2 (RSD=0.7% and 4.6% resp.)
5 x LOQ = 105% for isomer 1, 105% for isomer 2 (RSD=1.8% and 2.1% resp.)
125 x LOQ = 90% for isomer 1, 94% for isomer 2 (RSD=4.0% and 6.4% resp.)
Specificity: Response of blank values of control samples was significantly lower than 30 % of LOQ, actually no higher signal than the background was observed.

For the water samples before centrifugation, no Tyndall effect was observed. For the M4 samples, the positive Tyndall-effect was also observed in pure, aged daphnia M4 medium with comparable intensity and therefore considered to be not caused by the test item.

The solubility of the test item in double distilled water and daphnia M4 medium was determined for un‑centrifuged and centrifuged samples.

Equilibrium was considered reached from 173 h after application.

Medium	Pretreatment	Isomer 1	Isomer 2
		[µg/L]	[µg/L]
Double distilled water	‑	545	1270
Double distilled water	centrifugation	125	285
Daphnia M4 medium	‑	506	1141
Daphnia M4 medium	centrifugation	115	261

Isomer 1 = Cyclohexanepropanol, 2,2,6‑trimethyl‑a‑propyl‑, (alpha.R,1R,6S)
Isomer 2 = Cyclohexanepropanol, 2,2,6‑trimethyl‑a‑propyl‑, [1a(S*),6b]‑ (9Cl)

The solubilities in the two test media did not differ significantly.

According to the sponsor, the difference between centrifuged and non-centrifuged samples show that, despite the slow-stirring procedure, the substance has tendency to oversaturate, and form stable emulsions. Therefore the results after centrifugation will be retained and considered as the true water solubility in the test conditions (i.e. loading of 0.1%). Moreover, despite all efforts to avoid the technical difficulties due to emulsification properties of the substance, the variability of results suggests that centrifugation may have not totally cleaned the aqueous phase, so the result should be considered as a maximum value. 

Regarding isomers distribution, the ratio isomer 2/isomer 1 is test item is 2.29 in the test item, and 2.28 or 2.27, based on measured concentrations in centrifuged samples, in water and M4 medium respectively, therefore no differential solubility between isomers is observed.

Conclusions:

Interpretation of results (migrated information): slightly soluble (0.1-100 mg/L)
(from analogue)

Executive summary:

The water solubility of the test substance was determined according to OECD 105 / EC A.6 guideline, flask method, modified with slow stirring approach, in double distilled water and daphnia reconstituted medium M4, by measurement of the two isomers concentrations.

Samples were centrifuged due to tendency of the substance to form stable emulsions.

The analytical method (SPME‑GC‑MS, external standard) for the determination of the test item was validated and tested with satisfactory results in regard to linearity, accuracy, precision and specificity.

Equilibrium was considered achieved from 173 h after application.

The results at 20°C and pH 7 were found to be 125 and 285 μg/L in water, and 115 and 261 μg/L in M4 medium, for the (alpha.R,1R,6S)- and for the [1a(S*),6b]‑ (9Cl) isomers, respectively (to be considered as maximum values).

The solubilities in the different test media did not differ significantly.

The isomer distribution of the solubility samples is comparable to that of the external standard.

Reference 2

Endpoint:

water solubility

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Based on structural similarity (stereoisomers), constituents of both substances are not expected to have significantly different water solubility. Therefore, the result of the study will be considered for the target substance.
Further information is included in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Water solubility:

125 µg/L

Temp.:

20 °C

pH:

7

Remarks on result:

other: isomer 1 in distilled water (alpha.R,1R,6S)-

Key result

Water solubility:

285 µg/L

Temp.:

20 °C

pH:

7

Remarks on result:

other: isomer 2 in distilled water [1a(S*),6b]- (9Cl)

Executive summary:

The water solubility of the analogue test substance was determined according to OECD 105 / EC A.6 guideline, flask method, modified with slow stirring approach, in double distilled water and daphnia reconstituted medium M4.

After centrifugation (substance tends to form stable micro-emulsions), the two isomers concentrations were measured by a validated SPME‑GC‑MS analytical method.

Equilibrium was considered achieved from 173 h after application.

The results at 20°C and pH 7 were found to be 125 and 285 μg/L in water, and 115 and 261 μg/L in M4 medium, for the (alpha.R,1R,6S)- and for the [1a(S*),6b]‑ (9Cl) isomers, respectively (to be considered as maximum values).

The solubilities in the different test media did not differ significantly.

The isomer distribution of the solubility samples is comparable to that of the external standard.

A similar WS is anticipated for the target substance.

Description of key information

From analogue (test conditions: load.0.1%, 20°C, pH 7, equilibrium from 173h), the concentration of individual isomers is expected to range:

between ca 125 and 285 µg/L in distilled water

and between ca 115 and 261 µg/L in daphnia reconstituted M4 medium.

Parent substance individual isomers solubility predicted as 199 and 270 µg/L from QSAR.

Additional information

No reliable data is available on the substance itself.

However, a fully reliable experimental study, conducted according to OECD/EC guidelines and under GLP, is available on an analogue (both source and target substances are a reaction mass of stereoisomers). Based on structural similarity, minor difference is anticipated with the present dossier substance, the read-across is considered justified for a key study.

Technical difficulties were encountered during the test. Due to emulsification properties of the substance, the variability of results suggests that centrifugation may have not totally separated the water phase, so from the present experiment, the results should be considered as maximum water solubility values.

Since no quantitative risk assessment has to be conducted for the present dossier, no single key value was retained. Moreover, as a multi-constituent substance, it is considered more relevant to express the results per individual isomer. Individual isomers are expected to range between ca 125 and 285 µg/L in distilled water, and between ca 115 and 261 µg/L in M4 medium.

In addition, two validated QSAR predictions on the water solubility were also provided to support the similarity between the present dossier substance and the analogue used for the read-across: it confirms that the solubility is expected to be identical for the sum of all components for each of the two substances (501 µg/L).

Moreover, the water solubility values for the individual components (isomers) predicted for the substance tested, of 181 and 286 µg/L, are very close to the experimental values. This supports the quality of the experimental data provided, considering the separation of excess test item.