Generation of toxicokinetic in vitro data on chemicals identified in the Chemicals Management Plan

ADVANCED CONTRACT AWARD NOTICE Health Canada has a requirement for the generation of toxicokinetic in vitro data on chemicals identified in the Chemicals Management Plan. The Contractor will conduct experiments related to metabolic stability, blood protein binding and gut cells permeability. The purpose of this Advance Contract Award Notice (ACAN) is to signal the government’s intention to award a contract for these services to Paraza Pharma Inc. of Montréal, Québec. Before awarding a contract, however, the government would like to provide other suppliers with the opportunity to demonstrate that they are capable of satisfying the requirements set out in this Notice, by submitting a statement of capabilities during the 15 calendar day posting period. If other potential suppliers submit a statement of capabilities during the 15 calendar day posting period that meet the requirements set out in the ACAN, the government will proceed to a full tendering process on either the government's electronic tendering service or through traditional means, in order to award the contract. If no other supplier submits, on or before the closing date, a statement of capabilities meeting the requirements set out in the ACAN, a contract will be awarded to the pre-selected supplier. Background As one component of a project under the Chemicals Management Plan (CMP), Health Canada researchers and regulatory scientists are investigating the utility of integrating in vitro toxicity high-throughput screening (HTS) data for human health risk assessment. The interpretation of HTS data can be provided using toxicokinetic tools to determine the relevance of these data into estimated levels of human exposure that will provide a better basis for informed decisions on the potential toxicity of a chemical. The generation of toxicokinetic parameters is crucial to the interpretation of the HTS data. The aim of this project is to conduct in vitro experiments to generate the pharmacokinetic parameters (microsomal metabolic stability and blood protein binding) to support the needed computational in vitro-to-in vivo extrapolation (IVIVE) methods which will then be used to estimate human equivalent doses. The data obtained from these toxicokinetic evaluations will be used to facilitate the addition of a risk context to the high-throughput in vitro screening data. Previous cycles of data generation (2015-2017), supported the development of predictive tools and informed the utility of non-traditional toxicity data for the CMP 3 substituted phenols and glycol ethers group assessments.  Table 1: CMP3 Chemicals to be Investigated CAS RN* SUBSTANCE NAME 64-19-7 Acetic acid 71-23-8 1-Propanol 96-23-1 2-Propanol, 1,3-dichloro- 104-76-7 1-Hexanol, 2-ethyl- 107-18-6 2-Propen-1-ol 108-11-2 2-Pentanol, 4-methyl- 108-93-0 Cyclohexanol 111-27-3 1-Hexanol 111-87-5 1-Octanol 112-30-1 1-Decanol 112-53-8 1-Dodecanol 112-72-1 1-Tetradecanol 143-08-8 1-Nonanol 36653-82-4 1-Hexadecanol 124-13-0 Octanal 124-19-6 Nonanal 111-40-0 1,2-Ethanediamine, N-(2-aminoethyl)- 124-40-3 Methanamine, N-methyl- 100-37-8 Ethanol, 2-(diethylamino)- 102-71-6 Ethanol, 2,2’,2’’-nitrilotris- 111-42-2 Ethanol, 2,2’-iminobis- 122-20-3 2-Propanol, 1,1’,1’’-nitrilotris- 141-43-5 Ethanol, 2-amino- 156-60-5 Ethene, 1,2-dichloro-, (E)- 90-30-2 1-Naphthalenamine, N-phenyl- 121-69-7 Benzenamine, N,N-dimethyl- 2893-78-9 1,3,5-Triazine-2,4,6(1H,3H,5H)-trione, 1,3-dichloro-, sodium salt 123-77-3 Diazenedicarboxamide 102-76-1 1,2,3-Propanetriol, triacetate 577-11-7 Butanedioic acid, sulfo-, 1,4-bis(2-ethylhexyl) ester, sodium salt 6846-50-0 Propanoic acid, 2-methyl-, 2,2-dimethyl-1-(1-methylethyl)-1,3-propanediyl ester 101-84-8 Benzene, 1,1’-oxybis- 112-38-9 10-Undecenoic acid 463-40-1 9,12,15-Octadecatrienoic acid, (Z,Z,Z)- 78-51-3 Ethanol, 2-butoxy-, phosphate (3:1) 298-07-7 Phosphoric acid, bis(2-ethylhexyl) ester 51229-78-8 3,5,7-Triaza-1-azoniatricyclo[3.3.1.13,7]decane, 1-(3-chloro-2-propenyl)-, chloride, (Z)- 4098-71-9 Cyclohexane, 5-isocyanato-1-(isocyanatomethyl)-1,3,3-trimethyl- 80-15-9 Hydroperoxide, 1-methyl-1-phenylethyl 80-43-3 Peroxide, bis(1-methyl-1-phenylethyl) 110-85-0 Piperazine 57-09-0 1-Hexadecanaminium, N,N,N-trimethyl-, bromide 69-72-7 Benzoic acid, 2-hydroxy- 118-56-9 Benzoic acid, 2-hydroxy-, 3,3,5-trimethylcyclohexyl ester 2627-95-4 Disiloxane, 1,3-diethenyl-1,1,3,3-tetramethyl- 80-54-6 Benzenepropanal, 4-(1,1-dimethylethyl)-a-methyl- 80-56-8 Bicyclo[3.1.1]hept-2-ene, 2,6,6-trimethyl- 61-82-5 1H-1,2,4-Triazol-3-amine 68-26-8 Retinol * Chemical Abstracts Service Registry Number The Contractor will deliver a report on the results of toxicokinetic parameters of the chemicals listed above. The proposed contract is for a period of 18 months, from date of contract award to 31 March 2019. The estimated value of the contract is $232,000.00 (applicable taxes included).  Ownership of any Foreground Intellectual Property arising out of the proposed contract will vest in the Contractor. Minimum Essential Requirements Any interested supplier must demonstrate, by way of a statement of capabilities, that it meets the following requirements: MER 1 In-house facility with state-of-the art in vitro and analytical equipment on the premises. MER 2 A minimum of 12 months experience conducting in vitro toxicokinetic assays. MER 3 A minimum of 2 projects conducting drug metabolism pharmacokinetic (DMPK) experiments with substances; specifically,

Metabolic stability measured at different concentrations (1 and 10 µM); Blood protein binding measured using HTD-96 assays as per Banker et al., 2003; Gut permeability measured using Caco-2 cells line as per Wetmore et al., 2015.

MER 4 Experience conducting batch DMPK experiments for a minimum of 20 substances per analysis. MER 5 Experience to develop new analytical methods to detect environmental chemicals from DMPK experiments using a minimum of 10 chemicals identified in Table 1. Cited references:

Banker, MJ, Clark TH, and Williams JA. Development and Validation of a 96-Well Equilibrium Dialysis Apparatus for Measuring Plasma Protein Binding. 2003; J Pharm Sci 92:967-974. Wetmore BA, Wambaugh JF, Allen B, et al. Incorporating High-Throughput Exposure Predictions With Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing. Toxicol Sci 2015; 148(1):121-136.

Policy Information Under the Government Contracts Regulations, Section 6, a contracting authority may enter into a contract without soliciting bids where (d) only one person is capable of performing the contract. This requirement is subject to the North American Free Trade Agreement (NAFTA), the World Trade Organization – Agreement on Government Procurement (WTO-GPA) and the Canadian Free Trade Agreement (CFTA). The requirement is being directed to the proposed supplier as permitted under the following sections of the above trade agreements: Article 513 b) of the Canadian Free Trade Agreement (CFTA)

Article 1016, 2(b) of the North American Free Trade Agreement (NAFTA Article XV, 1b of the World Trade Organization – Agreement on Government Procurement (WTO-AGP)

Justification for the Pre-Selected Supplier The proposed supplier was previously awarded a contract following a competitive Request for Proposal. The proposed supplier generated the in vitro toxicokinetic data to support group assessments for CMP3 substituted phenols and glycol ethers and have demonstrated their expertise in collecting data in support of risk assessment by providing quality results. In continuation of the data generation process, it is essential to award this contract to Paraza Pharma in order to a) build on the results of the previous contract using the same methods; and, b) retain the data integrity to ensure consistency and compatibility with past work. Suppliers who consider themselves fully qualified and available to meet the specified requirements may submit a statement of capabilities in writing to the Contracting Authority identified in this Notice on or before the closing date of this Notice. The statement of capabilities must clearly demonstrate how the supplier meets the advertised requirements. The closing date and time for accepting statements of capabilities is November 10, 2017 at 2:00 p.m., EST. Inquiries and statements of capabilities are to be directed to: Robert Merrick Contracting Officer Materiel & Assets Management Division Health Canada Tel: 613-404-6575 Robert.Merrick@canada.ca