2-[(2S,3S)-3-[[(1,1dimethylethoxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl]-2-[[4-(2pyridinyl)phenyl]methyl]-,1,1-dimethylethyl ester

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

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

Type of information:

other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.

Adequacy of study:

key study

Study period:

26 January 2018

Reliability:

1 (reliable without restriction)

Justification for type of information:

theoretical assessment was prepared, taking all currently available relevant information into account for BMS233101, 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: Summary based on exisiting physical and chemical preoerties and existing testing

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

not specified

Test guideline

Qualifier:

no guideline required

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(pyridin-2-yl)benzyl]hydrazinecarboxylate

EC Number:

606-396-7

Cas Number:

198904-86-8

Molecular formula:

C32H42N4O5

IUPAC Name:

tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(pyridin-2-yl)benzyl]hydrazinecarboxylate

Test material form:

solid

Details on test material:

- Appearance: Off-white powder
- Storage condition of test material: At room temperature protected from light

Specific details on test material used for the study:

off white solid with 99.95% purity

Results and discussion

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

A toxicant can enter the body via the gastrointestinal tract, the lungs and the skin.In general, a substance needs to be dissolved before it can be taken up from the gastrointestinal tract after oral administration.BMS-233101-01 is a solid with alow water solubility(<0.492mg/L) and is thus expected to dissolve only to a minor extent in the gastrointestinal fluids.BMS-233101-01 has a relatively high molecular weight (562.7 Da), which will limit passage through biological membranes.Small amounts of the substance may be transported into epithelial cells by pinocytosis or persorption (passage through gaps in membranes left when the tips of villi are sloughed off). Based on the partition coefficient of 3.9(logPow), uptake via micellular solubilisation can be expected to take place.No data are available on the dissociation constant(s)of BMS-233101-01, therefore it is unclear in which state (ionized or not ionized) the substance will be present under physiological circumstances in the stomach or intestinal tract. However, one hydroxyl group is present, which is potentially ionisable.Since it is generally thought that ionized substances do not readily diffuse across biological membranes, the state of the substance might hamper uptake.

 

In conclusion, the high molecular weight (562.7Da), high logPow(3.9) and low water solubility (<0.492 mg/L) are indicative of the potential for limited systemic absorption. Therefore,for risk assessment purposes, oral absorption of BMS-233101-01 is set at 10%. Theoral toxicity data do not provide reason to deviate from the proposed oral labsorption factor.

For inhaled substances the processes of deposition of the substance on the surface of the respiratory tract and actual absorption have to be differentiated. BMS-233101-01 has avery low vapour pressure (7 *10-10Paat 25ºC),and no boiling point atatmospheric pressure (reaction and/or decomposition of the test substance starts at 214°C) which indicates that exposure to the substance as a vapour is unlikely.Determination of the particle size of BMS-233101 -01 demonstrated that about 53% has a particle size below 105μm, 51% below 60μm, 36% below 30μm and 6% of the particles are smaller than 10μm.In humans, particles with aerodynamic diameters below 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm may reach the alveolar region of the respiratory tract. Therefore,based on the particlesize distribution, BMS-233101 -01 is expected to be able to reach all parts of the lung upon inhalation. Dueto its very low water solubility, BMS-233101-01 is expected to be retained within the mucus. Based on the partition coefficient of 3.9(logPow), uptake via micellular solubilisation can be expected to take place. Based on these considerations, for risk assessment purposes the inhalation absorption of BMS-233101-01 is set at 100%.

BMS-233101-01 is a powder,and as its water solubility is very low, it will only dissolve to a very small extent into the surface moisture of the skin to allow uptake. The relatively large size (562.7 Da) is expected to hamper uptake aswell. Therefore,penetrance of the first skin layer, the stratum corneum (non-viable layer of corneocytes forming a complex lipid membrane), is expected to be limited. On the other hand, based on its lipohilicity, it can be predicted that the substance will be able to cross the viable epidermis.Since the logPow of the substance is 3.9 and the molecular weight is 562.7 Da, the substance specific data do nearly, but notfully,meet the criteria for 10% dermal absorption asgiven in the EndpointSpecific Guidance (MW>500 and logPow <-1or>4). However,as it is generally accepted that dermal absorption does not exceed oral absorption, 10% dermal absorption of BMS-233101 -01 is considered a realistic dermal absorption factor for risk assessment purposes. Therefore, a10% dermal absorption factor for BMS-233101 -01 isconsidered to be appropriate. The results of the toxicity studies do not provide reasons to deviate from this proposed dermal absorption factor.

 

Once absorbed, distribution of the test substance throughout the body is expected to below based on its low water solubility (<0.492 mg/L),relatively high molecular weight (562.7 Da) and high partition coefficient (logPow3.9).Based on a limited distribution throughout the body, but higher logPow, BMS-233101 -01 is expected to acumulate limitedly in adipose tissue.

Applicant's summary and conclusion

Conclusions:

A toxicokinetic assessment was performed based on the available data. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 10% (oral), 100% (inhalation) and 10% (dermal) for risk assessment purposes. Slight bioaccumulation potential is expected.