Tricyclo[3.3.1.13,7]decane-1-acetic acid, .alpha.-[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxy-, (.alpha.S)-

Partition coefficient

Administrative data

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31 December 2004 to 23 May 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted in 2005 according to EU and OECD Method and in accordance with GLP. The study material is well characterized.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method A.8 (Partition Coefficient)

Deviations:

no

GLP compliance:

yes

Type of method:

HPLC method

Partition coefficient type:

octanol-water

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid

EC Number:

700-361-0

Cas Number:

361442-00-4

Molecular formula:

C17H27NO5

IUPAC Name:

(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid

Constituent 2

Reference substance name:

1-Hydroxyadamantanyl-3-(S)-Boc-glycine

IUPAC Name:

1-Hydroxyadamantanyl-3-(S)-Boc-glycine

Details on test material:

Off-white powder; stored at room temperature; received at testing laboratory on 06-10-2004.

Study design

Analytical method:

high-performance liquid chromatography

Results and discussion

Partition coefficient

Type:

log Pow

Partition coefficient:

0.55

Details on results:

The compound BMS 528233-01 eluted as a single peak with an earlier retention time than all of the calibration substances, but after the unretained solute formamide. Therefore the results of the estimation were calculated by extrapolation rather than interpolation. It was possible to establish the calibration line with five different calibration compounds.

There were only minimal differences between the replicates of retention times for each of the calibration and test substances, and between the two injection sequences. The resultant calculated values differed only to a small extent, therefore the results may be considered as acceptable for regulatory purposes.

The partition coefficient of BMS 528233-01 was successfully evaluated using the HPLC simulation technique, with a mobile phase of acetonitrile/0.05% trifluoroacetic acid, 50:50, v/v. The test substance eluted as a single component with a retention time corresponding to a log Pow value of + 0.55, which was within a 95% confidence range of -0.03 to + 0.97.

Any other information on results incl. tables

CALIBRATION DATA
Calibration substance	First estimation				Second estimation
	time (min)		factor (log K)			time (min)		factor (log K)
Formamide	2.170		NA			2.170		NA
Acetophenone	5.790		0.222			5.770		0.220
Methyl benzoate	7.960		0.426			7.960		0.426
Ethyl benzoate	11.530		0.635			11.510		0.634
Bromobenzene	15.375		0.784			15.365		0.784
Phenanthrene	40.670		1.249			40.630		1.249
STATISTICAL DATA
Slope:			0.3592				0.3596
Intercept:			-0.3352				-0.3372
Correlation (R2):			0.9886				0.9883
ANALYTICAL DATA
Compound		Retention time (min)	log K mean	log Pow   Mean          95% min      95% max
First estimation
Test substance injection 1		3.750	-0.136	0.55          -0.03				0.96
Test substance injection 2		3.760
Back-calculated calibration compound (Pow = 1.70)
Acetophenone		5.790	0.222	1.55               1.18				1.82
Second estimation
Test substance injection 1		3.750	-0.138	0.55              -0.04				0.97
Test substance injection 2		3.750
Back-calculated calibration compound (Pow = 1.70)
Acetophenone		5.770	0.220	1.55                1.17				1.82

Analytical Procedure (CLE (E) 1340-428-01V)

The concentrations of BMS 528233-01 in double distilled water were determined by HPLC with UV detection at 205 nm (HPLC-UV), using gradient elution.

Reagents and Solutions

HPLC Mobile Phase A - 0.05% Trifluroacetic acid in Acetonitrile Acetonitrile (1000 mL) was fortified with trifluoroacetic acid (0.5 mL)

HPLC Mobile Phase B - 0.05% Trifluoroacetic acid in Water Ultrapure water (1000 mL) was fortified with trifluoroacetic acid (0.5 mL)

Generation of Calibration Line

BMS 528233-01 (10 mg) was accurately weighed, dissolved in the mobile phase starting mixture and made to a final volume of 100 mL, to achieve a concentration of nominally 100 mg/mL. Appropriate volumes of this stock solution were diluted with the mobile

phase starting mixture to produce a set of calibrants in the range 1.0 to 100 mg/mL.

Generation of Quality Control Samples

QC sample solutions in mobile phase starting mixture were prepared from an independent test substance stock solution to that used for the calibrants. The chosen final concentration(s) fell within the calibration range used with any particular batch.

Sample Analysis

Aqueous samples were diluted with mobile phase starting mixture, where necessary, to bring the concentrations within the calibration range, prior to injection into the HPLC system.

Applicant's summary and conclusion

Conclusions:

The octanol:water partition coefficient of BMS 528233-01 was evaluated using the HPLC simulation technique, with a mobile phase of acetonitrile/0.05% trifluoroacetic acid, 50/50, v/v. The test substance eluted as a single component with a retention time corresponding to a log Pow value of +0.55, which was within a 95% confidence range of -0.03 to + 0.97.

Executive summary:

The partition of a chemical between water and octan-1-ol is a model for the partition between aqueous and fat based matrices in man and the environment, and is evaluated for regulatory purposes.

The octanol:water partition coefficient of BMS 528233-01 was evaluated using the HPLC simulation technique, with a mobile phase of acetonitrile/0.05% trifluoroacetic acid, 50/50, v/v. The test substance eluted as a single component with a retention time corresponding to a log Pow value of +0.55, which was within a 95% confidence range of -0.03 to + 0.97.

As Substances having a log₁₀P_owof greater than 3 are regarded as having the potential to bioaccumualate in the environment, this study has shown that this substance would not be expected to pose a bioaccumulation risk.