(2S)-3-Methyl-2-[N-({2'-(1H-1,2,3,4-tetrazol-5-yl)-[1,1-biphenyl]-4-yl}methyl)pentanamido]alkanoic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

Dec 2019

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

This theoretical assessment was prepared, taking all currently available relevant information
into account, based on the REACH Guidance: Guidance on Information Requirements and
Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

absorption

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This theoretical assessment was prepared, taking all currently available relevant information
into account, based on the REACH Guidance: Guidance on Information Requirements and
Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine

EC Number:

604-045-2

Cas Number:

137862-53-4

Molecular formula:

C24 H29 N5 O3

IUPAC Name:

N-Pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine

Test material form:

solid: particulate/powder

Radiolabelling:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After exposure, a substance can enter the body via the gastrointestinal tract, the lungs, and the
skin. Since different parameters are relevant for absorption via the different routes of exposure,
the uptake via these three routes will be addressed individually.
Based on publicly available information, valsartan is rapidly absorbed orally. Following oral
administration, peak plasma concentrations are reached in 2-3 hours. Mean absolute
bioavailability of valsartan was reported to be 23%; another source reports the values of 10-
35% for absolute bioavailability of valsartan. The absorption occurs by a passive diffusion
process. The steady-state volume of distribution of valsartan after intravenous administration
is ca. 17 L, indicating that valsartan does not distribute extensively into the tissues. Valsartan
is extensively bound to the plasma proteins (94-97%), mainly serum albumin.

Details on excretion:

Because of the presence of carboxylic groups valsartan is soluble in neutral pH range and is
mainly present in the ionized form at physiological pH. Valsartan is minimally metabolised,
as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite of valsartan
has been identified in plasma at low concentrations (< 10% valsartan AUC). Following oral
administration, ca. 83% of the substance are excreted in faeces and ca. 13% is excreted in urine,
mostly as unchanged drug. The half-life of valsartan is 6 hours; bioaccumulation potential of
the substance is thus very low.

Metabolite characterisation studies

Metabolites identified:

yes

Remarks:

hydroxyl metabolite of valsartan

Details on metabolites:

Because of the presence of carboxylic groups valsartan is soluble in neutral pH range and is
mainly present in the ionized form at physiological pH. Valsartan is minimally metabolised,
as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite of valsartan
has been identified in plasma at low concentrations (< 10% valsartan AUC). Following oral
administration, ca. 83% of the substance are excreted in faeces and ca. 13% is excreted in urine,
mostly as unchanged drug. The half-life of valsartan is 6 hours[3]; bioaccumulation potential of
the substance is thus very low.

Any other information on results incl. tables

Based on the available data, oral absorption of valsartan for risk assessment purposes is set to

35% as a worst-case value.

No information on respiratory absorption of valsartan was recovered from public literature. The

vapor pressure of the substance is very low (<0.0000001 hPa) which indicates that its

availability for inhalation as a vapor is negligible. The test substance is a powdery solid, with

a median particle size of 3 μm. In humans, particles with aerodynamic diameters below 100

μm have the potential to be inhaled. Particles with aerodynamic diameter below 50 μm can

reach the thoracic region, and those below 15 μm the alveolar region of the respiratory tract.

The particles of the substance can therefore deposit in the alveolar region where they may be

engulfed by alveolar macrophages. The macrophage could then either translocate particles to

the ciliated airways or carry particles into the pulmonary interstitium and lymphoid tissues.

For risk assessment purposes, the inhalation absorption of valsartan is set at the default value

of 100%, taking into account its small particle size and its moderate water solubility.

A study on the in vitro dermal penetration of valsartan through rat skin was reported in public

literature. The passive diffusion of valsartan produced a flux of 39.3 μg/cm2/hour, and the

substance was thus able to penetrate the skin. According to the ECHA guidance, a default

value of 100% skin absorption is generally used unless molecular weight is above 500 and log

Pow is outside the range between -1 and 4. However, it is generally accepted that dermal

absorption does not exceed oral absorption. Therefore, for risk assessment purposes, it is

considered acceptable to set the dermal absorption of valsartan at 35%.

Applicant's summary and conclusion

Conclusions:

A toxicokinetic assessment was performed based on the available data of the substance.
Based on information found in public literature, and considering the physical/chemical
properties of the substance, the following absorption factors were derived for risk assessment
purposes: 35% for oral, 100% for inhalation and 35% for dermal absorption. Based on the
data reported in public literature, the substance does not bioaccumulate.