Detaljerad miljöinformation

Physical properties⁴

Solubility at pH 7.6: 17 500 µg/L

pKa: 3.68

Vapor pressure: 5.9 x 10^-7 Pa at 25 °C

Molecular weight: 308.12

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:

PEC (μg/L) = (A*10⁹*(100-R))/(365*P*V*D*100) = 1.37*10^-6*A(100-R)

PEC = 8.6 x 10^-6 μg/L

Where:

A =	0.11 kg (total sold amount API in Sweden year 2020, data from IQVIA)3.
R =	43% removal rate as calculated with SimpleTreat 4.0 using the lowest activated sludge sorption coefficient (Kd) of 1110 and a conservative elimination rate constant (kbiodeg) of 0.007 per hour (Reference OECD 106 & OECD 314B): Fraction in sludge = 27.5% Fraction eliminated by biodegradation = 15.5%
P =	number of inhabitants in Sweden = 10 * 106
V (L/day) =	wastewater volume per capita and day = 200 (ECHA default)1
D =	factor for waste water dilution by surface water flow = 10 (ECHA default)1

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Activated sludge microorgansims (guideline OECD 209)⁵

EC₅₀ (respiration inhibition) = > 612 000 μg/L

NOEC (respiration inhibition) = 612 000 μg/L

Green alga (Raphidocelis subcapitata) (guideline OECD 201)⁶

EC₅₀ 72 h (growth rate, chronic toxicity) = > 670 μg/L

EC₁₀ 72 h (growth rate, chronic toxicity) = 560 μg/L

Daphnids (Daphnia magna) (guideline OECD 211)⁷

LOEC 21 days (reproduction, chronic toxicity) = > 498 μg/L

NOEC 21 days (reproduction, chronic toxicity) = 498 μg/L

Fathead Minnow (Pimephales promelas) (guideline OECD 210)⁸

LOEC 32 days (hatching success, chronic toxicity) = > 493 μg/L

NOEC 32 days (hatching success, chronic toxicity) = 493 μg/L

Based on the lowest NOEC for the species Pimephales promelas and using the assessment factor² of 10, the PNEC is calculated to 493/10 = 49.3 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 8.6 x 10^-6 / 49.3 = 1.7 x 10^-7, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ”Use of tafamidis has been considered to result in insignificant environmental risk.”

Adsorption (guideline OECD 106)⁹

Solid	Kd (L/Kg)	Koc (L/Kg)
Activated sludge (Denton WWTP)	1110	3480
Activated sludge (Easton WWTP)	1260	3430
HOM soil (silty clay loam, TB-L-PF)	231	4900
LOM soil (loamy sand, RMN-LS)	492	61500
HOM sediment (silty loam, BC-050819)	5000	116000
LOM sediment (sandy, CR-051319)	67.7	16900

HOM = high organic matter, LOM = low organic matter

Degradation

Biotic degradation

Water-sediment transformation simulation (guideline OECD 308)¹⁰

Length of study: 120 days

High organic sediment system: Brandywine creek

Low organic sediment system: Choptank river

Sediment extraction solvent: Four extractions with ethyl acetate plus 0.1% acetic acid

Supplemental extraction solvents: Water, acetone, dichloromethane or hexane

The results from the study are shown in the table below.

Data on day 120 at 20 °C	Brandywine Creek		Choptank River
Total system
Half-life (days)	53	94
Total 14CO2 (% of AR)	12.9	14.0
% Parent (% of AR)	29.2	43.3
Aerobic Water Layer
Half-life (days)	5.6	9.8
Parent (% of AR)	4.7	0.4
Sediment Layer
Half-life (days)	71	110
Bound/NER (% of AR)	47.9	34.7
Extractables (% of AR)	31.7	50.0
Parent (% of AR)	24.5	42.8

ND = not detected, NER = non-extractable residues, AR = applied radioactivity

WWTP degradation (guideline OECD 314B)¹¹

Length of study: 28 days

Parent compound remaining at the end of the study: 18.5 %

Total mineralisation: 17.8 %

Non-extractable residue: 69.0 %

Elimination rate k-value: 0.007 per hour

Loss of parent DT₅₀: 4.1 days

Justification of chosen degradation phrase

As the total system DT₅₀ value (water-sediment transformation simulation, OECD 308) was calculated to <120 days, it corresponds to the degradation phrase ”tafamidis is slowly degraded in the environment.”

Bioaccumulation

Partitioning coefficient (guideline OECD 107)¹²

pH	Log Dow
4	2.43
7	1.89
9	0.563

Justification of chosen bioaccumulation phrase

Since log D_ow < 4 at pH 7, tafamidis has low potential for bioaccumulation.

References

1. ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment chapter R16.

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment chapter R10.

3. IQVIA KG Consumption 2020 report

4. Vyndaqel Environmental risk assessment. November 2018.

5. Study report 260E-334: PF-06291826-83 (Tafamidis): An Activated Sludge Respiration Inhibition Test. February 2020.

6. Study report 260P-116: PF-06291826-83 (Tafamidis): 72-Hour Toxicity Test with Freshwater Alga (Raphidocelis subcapitata). June 2020.

7. Study report 260A-271: PF-06291826-38 (Tafamidis): A Flow-Through Life-Cycle Toxicity Test with the Cladoceran (Daphnia magna). October 2020.

8. Study report 260A-270: PF-06291826-38 (Tafamidis): An Early Life-Stage Toxicity Test with the Fathead Minnow (Pimephales promelas). October 2020.

9. Study report 260E-329: Tafamidis (PF-06291826-83): Adsorption/Desorption Characteristics in Representative Soils, Sediments and Activated Sludge Solids. August 2019.

10. Study report 260E-333: PF-06291826-83 (Tafamidis): Aerobic Transformation in Aquatic Sediment Systems. November 2020.

11. Study report 260E-333: PF-06291826-83: Biodegradation in Activated Sludge. April 2020.

12. Study report 2438.6675: “[¹⁴C]Tafamidis – Determining the Partitioning Coefficient (n‑octanol/water) by the Shake Flask Method Following OECD Guideline 107. January 2012.