Detaljerad miljöinformation

Physical properties⁴

Solubility at pH 4-10:	>100 x 106 µg/L pKa: 9.2
Vapor pressure at 25 °C:	Estimated at <1x10-7 mmHg
Molecular weight:	361.35 (varenicline tartrate) 211.26 (varenicline)

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 = 2.08 x 10^-4 μg/L

Where:

A =	1.67 kg (total sold amount API in Sweden year 2020, data from IQVIA)3.
R =	9% removal rate as calculated with SimpleTreat 4.0 using an activated sludge sorption coefficient (Kd) of 26 and elimination rate constant (kbiodeg) of 0.011 per hour (Reference OECD 106 & OECD 314B)
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

Green alga (Pseudokirchneriella subcapitata) (guideline OECD 201)⁵

EC₅₀ 72 h (growth rate, chronic toxicity) = > 6 200 μg/L

NOEC 72 h (growth rate, chronic toxicity) = 1 500 μg/L

Daphnids (Daphnia magna) (guideline OECD 202)⁶

EC₅₀ 48 h (mobility & mortality, acute toxicity) = 240 μg/L

NOEC 48 h (mobility & mortality, acute toxicity) = 130 μg/L

Daphnids (Daphnia magna) (guideline OECD 211)⁷

LOEC 21 days (reproduction & growth, chronic toxicity) = 20 μg/L

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

Daphnids (Ceriodaphnia dubia) (guideline EPA 1002.0)⁸

LOEC 7 days (reproduction, chronic toxicity) = 5.0 µg/L

NOEC 7 days (reproduction, chronic toxicity) = 2.7 µg/L

Rainbow trout (Oncorphynchus mykiss) (guideline OECD 203)⁹

LC₅₀ 96 h (mortality, acute toxicity) = 48 000 μg/L

NOEC 96 h (mortality, acute toxicity) = 20 000 μg/L

Based on the lowest NOEC for the species Ceriodaphnia dubia and using the assessment factor² of 10, the PNEC is calculated to 3/10 = 0.27 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 2.08 x 10^-4 / 0.27 = 7.7 x 10^-4, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ”Use of varenicline has been considered to result in insignificant environmental risk.”

Adsorption (guideline OECD 106)¹⁰

Solid	Kd (L/Kg)	Koc (L/Kg)
Activated sludge	26	74
HOM soil (clay loam, MCL-PF)	254	7050
HOM soil (sandy clay loam, MSL-PF)	193	9220
LOM soil (loamy sand, Roger Myron)	117	8960
LOM soil (clay, Montana Clay)	117	16700

HOM = high organic matter, LOM = low organic matter

Degradation

Biotic degradation

Water-sediment transformation simulation (guideline OECD 308)¹¹

Length of study: 100 days

High organic sediment system: Turkey creek

Low organic sediment system: Choptank river

Sediment extraction solvent: Two extractions with acetonitrile (ACN) acidified with 0.1N hydrochloric acid

Supplemental extraction solvents: At day 100, an two additional extractions with unacidified ACN

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

Data on day 100 at 20°C	Turkey Creek	Choptank River
Total system
Half-life (days)	31.7	43.8
Total 14CO2 (% of AR)	0.1	0.5
% Parent (% of AR)	30.8	30.0
Aerobic Water Layer
Half-life (days)	22.1	21.7
Parent (% of AR)	11.4	6.7
Sediment Layer
Bound/NER (% of AR)	51.3	51.0
Extractables (% of AR)	20.0	25.5
Parent (% of AR)	19.4	23.3

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

WWTP degradation (guideline OECD 314B)¹²

Length of study: 28 days

Parent compound remaining at the end of the study: 25.71 %

Total mineralisation: 0.68 %

Non-extractable residue: 8.95 %

Elimination rate k-value: 0.011 per hour

Loss of parent DT₅₀: 2.6 days

Abiotic degradation

Photolysis (OECD Guideline for Testing of Chemicals, Proposal for a New

Guideline in August 2000)¹³

The environmental photolytic half-life (t_½) of varenicline at 40 degrees north latitude was determined to be rapid at 22.6 and 103 minutes during the summer and winter seasons, respectively.

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 ”varenicline is slowly degraded in the environment.”

Bioaccumulation

Partitioning coefficient (guideline OECD 107)¹⁴

pH	Log Dow
5	-1.23
7	-0.817
9	0.758

Justification of chosen bioaccumulation phrase

Since log D_ow < 4 at pH 7, varenicline 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. Champix environmental risk assessment. September 2005.

5. Study report 260A-155: Varenicline: A 72-hour toxicity test with the freshwater alga (Selenastrum capricornutum). March 2005.

6. Study report 260A-153: Varenicline: A 48-hour static acute toxicity test with the cladoceran (Daphnia magna). January 2006.

7. Study report 2438.6536: Varenicline (CP-526,555-18) – Full life-cycle toxicity test with water fleas, Daphnia magna, under static-renewal conditions. September 2010.

8. Study report 2438.6468: Varenicline (CP-526,555-18) – The life-cycle toxicity test with daphnids, Ceriodaphnia dubia, under static-renewal conditions. January 2006.

9. Study report 260A-154: Varenicline: A 96-hour static acute toxicity test with the rainbow trout (Oncorhynchus mykiss). January 2006.

10. Study report 260E-162: [¹⁴C] varenicline: Adsorption/desorption characteristics in representative soils. December 2005.

11. Study report 260E-158: [¹⁴C] varenicline: Aerobic and anaerobic transformation in aquatic sediment systems. January 2006.

12. Study report 260E-159: Varenicline: Dieaway in activated sludge. December 2005.

13. Study report 260C-112: Phototransformation potential of varenicline. September 2005.

14. Study report 260C-114: Varenicline: Determination of the n-octanol/water partition coefficient by the shake flask method. December 2005.