Detaljerad miljöinformation

Detailed background information

Physical properties^3,4,5

Solubility at pH 4.7: 2 169 000 µg/L

Solubility at pH 8.6: 62 500 µg/L

pKa: 2.1, 6.5 & 9.8

Molecular weight: 534.57 Da

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 = 9.93×10^-5 μg/L

Where:

A =	0.75 kg (estimated total sold amount API in Sweden year 2024).
R =	3.4% removal rate due to loss by adsorption to sludge particles as calculated in the OECD 106 study
P =	number of inhabitants in Sweden = 10×106
V (L/day) =	wastewater volume per capita and day = 200 (ECHA default)1
D =	factor for wastewater dilution by surface water flow = 10 (ECHA default)1

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Activated sludge microorgansims (guideline OECD 209)⁶

NOEC (respiration inhibition) = 100 000 µg/L

EC₁₀ (respiration inhibition) = 104 000 μg/L

EC₂₀ (respiration inhibition) = 137 000 μg/L

EC₅₀ (respiration inhibition) = > 1000 000 μg/L

Green alga (Raphidocelis subcapitata) (guideline OECD 201)⁷

NOEC 72 h (growth rate, chronic toxicity) = 280 μg/L

EC₁₀ 72 h (growth rate, chronic toxicity) = 26 000 μg/L

EC₂₀ 72 h (growth rate, chronic toxicity) = 29 000 μg/L

EC₅₀ 72 h (growth rate, chronic toxicity) = 37 000 μg/L

Daphnids (Daphnia magna) (guideline OECD 211)⁸

NOEC 21 days (reproduction, chronic toxicity) = 10 000 μg/L

LOEC 21 days (reproduction, chronic toxicity) = >10 000 μg/L

Fathead Minnow (Pimephales promelas) (guideline OECD 210)⁹

NOEC 32 days (growth (weight), chronic toxicity) = 370 μg/L

LOEC 32 days (growth (weight), chronic toxicity) = 1000 μg/L

EC₁₀ 32 days (Growth (weight), chronic toxicity) = 930 μg/L

Midge (Chironomus riparius) (guideline OECD 218)¹⁰

NOEC 28 days (emergence ratio, chronic toxicity) = 1011 000 μg/kg

EC₁₀ 28 days (emergence ratio, chronic toxicity) = 623 000 μg/kg

NOEC 28 days (development rate, chronic toxicity) = 487 000 μg/kg

EC₁₀ 28 days (development rate, chronic toxicity) = >1011 000 μg/kg

Based on the lowest NOEC for the species Raphidocelis subcapitata and using the assessment factor² of 10, the PNEC is calculated to 280 / 10 = 28 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 9.93×10^-5 / 28 = 3.54×10^-6, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ”Use of rimegepant has been considered to result in insignificant environmental risk.”

Adsorption (guideline OECD 106)¹¹

Solid	Kd (L/Kg)	Koc (L/Kg)
Activated sludge (Tilburg)	307	921
Activated sludge (Aa and Maas)	214	591
HOM soil (Speyer 6S)	1893	122149
HOM soil (Speyer 2.2)	84.1	5225
LOM soil (Speyer 2.3)	65.6	10087

HOM = high organic matter, LOM = low organic matter

Fraction removed on wasted sludge = (0.165×K_d) / [(0.165×K_d) + 1000] where 0.165 represents the grams of sludge wasted per 1000 grams of wastewater treatment plants' aqueous effluent. Based on the lowest sludge K_d of 214, the fraction of rimegepant removed on wasted sludge is = (0.165×214) / [0.165×214 + 1000] = 0.034 = 3.4%.

Degradation

Biotic degradation

Ready degradability (guideline OECD 301B)¹²

The test was made over a 28-day period and resulted in a 0% biodegradation. Rimegepant is thus not readily biodegradable according to the OECD criteria for ready biodegradability.

Water-sediment transformation simulation (guideline OECD 308)¹³

Length of study: 100 days

High organic sediment system: Schoonrewoerdse Wiel

Low organic sediment system: Middle Pond

Sediment extraction solvent: 80/20 v/v acetonitrile/water

Supplemental acidic extraction solvents: 0.1 M hydrochloric acid followed by acetone

Supplemental alkaline extraction solvents: 0.1 M sodium hydroxide followed by acetone

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

Data on day 100 at 12 °C	Schoonrewoerdse Wiel		Middle Pond
Total system
Half-life (days)	88	86
Total 14CO2 (% of AR)	0.1	0.1
% Parent (% of AR)	50.5	46.7
Aerobic Water Layer
Half-life (days)	8.0	1.3
Parent (% of AR)	5.5	1.5
Sediment Layer
Bound/NER (% of AR)	50.3	51.9
Extractables (% of AR)	45.2	47.7
Parent (% of AR)	45.0	45.3

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

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 ”Rimegepant is slowly degraded in the environment”.

Bioaccumulation

Partitioning coefficient (guideline OECD 107)¹⁴

pH	Log Dow
5.5	1.43
7.4	1.56
8.8	1.91

Justification of chosen bioaccumulation phrase

Since log D_ow < 4 at pH 7.4, rimegepant 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. Parexel International, Vydura Environmental risk assessment part I. December 2021.

4. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV), Vydura Environmental risk assessment part II. March 2023.

5. Biohaven Pharmaceuticals, Inc., Vydura Module 3.2.S.1 General properties. February 2021.

6. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329866. Activated sludge respiration inhibition test with rimegepant. April 2022.

7. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329858. Freshwater algal growth-inhibition test with rimegepant. August 2022.

8. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329855. Daphnia magna, reproduction test with rimegepant (semi-static). December 2022.

9. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329861. Fish early-life stage toxicity test with rimegepant (flow-through). December 2022.

10. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329875. Sediment-water chironomid toxicity test using sediment spiked with rimegepant. June 2022.

11. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329848. Adsorption/desorption of ¹⁴C-labeled rimegepant on three soils and two sludges. October 2022.

12. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329849. Determination of ’ready’ biodegradability: Carbon dioxide (CO2) evolution test (modified Sturm test) of rimegepant. April 2022.

13. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report 20329850. Aerobic transformation of rimegepant in aquatic sediment systems. January 2023.

14. Biohaven Pharmaceuticals, Inc. (Charles River Laboratories Den Bosch BV) study report N21062. Determination of distribution coefficient (Log D5.5, Log D7.4 & Log D 8.8) of BHV-3000 by shake-flask method. January 2022.