Detaljerad miljöinformation

Phentermine

Environmental risk: Use of phentermine has been considered to result in insignificant environmental risk.

Degradation: Phentermine is slowly degraded in the environment.

Bioaccumulation: Phentermine has low potential for bioaccumulation.

Detailed Background Information

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) = (A × 10¹¹) ÷ (7.3 × 10¹⁴)

PEC = < 0.014 µg/L

Where:

A = < 100 kg (assumed a theoretical upper limit of total phentermine sales in Sweden in 2028, five years after Qsiva launch).

R = assumed 0 % removal rate in a sewage treatment plant

P = number of inhabitants in Sweden = 10,000,000

V = 200 L of wastewater per capita per day (ECHA default) (Ref. I)

D = 10, factor for dilution of wastewater by surface water flow (ECHA default) (Ref. I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

For the required ecotoxicity studies for FASS classification, guideline-driven aquatic toxicity studies were conducted under Good Laboratory Practices (GLP) based on exposure to phentermine.

Algae:

EC₅₀ (72-hour growth rate) = 66,000 µg/L for freshwater green alga (Raphidocelis subcapitata) (OECD 201) (Ref. II, Ref. III)

EC₅₀ (72-hour yield) = 20,000 µg/L for freshwater green alga (Raphidocelis subcapitata) (OECD 201) (Ref. II, Ref. III)

NOEC (72-hour growth rate/yield) = 6,700 µg/L for freshwater green alga (Raphidocelis subcapitata) (OECD 201) (Ref. II, Ref. III)

Crustacean:

Chronic toxicity

NOEC (21-day survival) = 11,000 µg/L for water fleas (Daphnia magna) (OECD 211) (Ref. III, Ref. IV)

NOEC (21-day reproduction) = 680 µg/L for water fleas (Daphnia magna) (OECD 211) (Ref. III, Ref. IV)

NOEC (21-day growth) = 2,700 µg/L for water fleas (Daphnia magna) (OECD 211) (Ref. III, Ref. IV)

Fish:

Chronic toxicity

NOEC (28-day post-hatch reproduction) = 720 µg/L for fathead minnows (Pimephales promelas) (OECD 210) (Ref. III, Ref. V)

Other Ecotoxicity Data:

Activated sewage sludge microorganisms:

NOEC (3-hour respiration inhibition) = 45,000 µg/L for activated sewage sludge microorganisms (OECD 209) (Ref. III, Ref. VI)

EC₁₀ (3-hour respiration inhibition) = 152,000 µg/L for activated sewage sludge microorganisms (OECD 209) (Ref. III, Ref. VI)

EC₅₀ (3-hour respiration inhibition) = 1,000,000 µg/L for activated sewage sludge microorganisms (OECD 209) (Ref. III, Ref. VI)

Calculation of PNEC

PNEC = 680 µg/L ÷ 10 = 68 µg/L

The PNEC is the lowest chronic NOEC divided by 10, where 10 is the assessment factor used for three long-term ecotoxicity data endpoints (i.e., alga, invertebrate, and fish). The NOEC of 680 µg/L for reproduction of water fleas (D. magnia) was chosen as it is the most sensitive of the three tested species.

Environmental Risk Classification (PEC/PNEC Ratio)

PEC/PNEC = < 0.014 ÷ 68 = < 0.0002

The PEC/PNEC ratio of ≤ 0.1 justifies the phrase ‘Use of phentermine has been considered to result in insignificant environmental risk.’

Degradation

Biotic Degradation

Ready degradability:

Phentermine was not identified as readily biodegradable in a 28-day OECD Guideline 301B test (Ref. III, Ref. VII).

Simulation studies:

An aerobic transformation study was conducted in two river water/sediment systems following the OECD Guideline 308 (Ref. III, Ref. VIII). Phentermine dissipated rapidly from water to sediment, with DT50 values of 20 and 39 days in the water phase. In the sediment phase, DT50 values for phentermine were 50 and 67 days. Phentermine dissipated from the total water/sediment system slowly with DT50 values of 50 and 93 days, mainly due to mineralization and irreversible binding to sediments. In this study, all reasonable efforts were made to extract sediment residues, by using 80/20 acetonitrile/0.1 M formic acid in purified reagent water for a total of up to three extractions. At the end of the study, 26-45% parent compound was present as non-extractable residue, which was considered as not bioavailable and removed from the system for the calculation of DT50 values.

Justification of chosen degradation phrase:

Phentermine is not identified as readily degradable. The phrase “Phentermine is slowly degraded in the environment” is thus chosen based on the absence of ready biodegradability and the DT50 values between 32 and 120 days for the total systems from the OECD 308 simulation study.

Bioaccumulation

Partitioning coefficient:

The octanol-water partitioning coefficient (K_ow) values were determined following OECD Guideline 107 (Ref. III, Ref. IX). All log K_ow values were less than 2, with values of −1.17, −0.842, and 1.02 at pH values of 5, 7, and 9, respectively.

Justification of chosen bioaccumulation phrase: 

Since the log K_ow at pH of 7 is < 4, phentermine has low potential for bioaccumulation.

Excretion (Metabolism)

Ingested phentermine is not extensively metabolized in the human body, and most of the phentermine dose is excreted as unchanged phentermine in urine (Ref. X). For this classification, no reduction by metabolism was assumed for phentermine entering the environment.

PBT/vPvB Assessment

Phentermine does not meet the REACH criteria for persistent (P) with the half-lives for the total systems < 120 days, the REACH criteria for bioaccumulative (B) with the measured log K_ow values at all tested pH levels < 4, or the REACH criteria for toxic (T) with all chronic NOEC > 0.01 mg/L (Ref. XI). Therefore, phentermine is not classified as PBT or vPvB.

References

I. ECHA, European Chemicals Agency. 2023. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental Exposure Assessment. Version 4.0. July.

II. Smithers. 2021a. Phentermine - 72-Hour Toxicity Test with the Freshwater Green Alga, Raphidocelis subcapitata, Following OECD Guideline 201. Smithers Study No. 13996.6145. November 9.

III. Ramboll. 2022. Environmental Risk Assessment for Qsiva. Prepared for VIVUS LLC. August 24.

IV. Smithers. 2021b. Phentermine – Chronic Toxicity to Water Fleas (Daphnia magna) Under Static-Renewal Conditions. Smithers Study No. 13996.6146. November 29.

V. Smithers. 2022a. Phentermine - Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas) Following OECD Guideline 210. Smithers Study No. 13996.6147. March 30.

VI. Smithers. 2021c. Phentermine – Activated Sludge Respiration Inhibition Test Following OECD Guideline 209. Smithers Study No. 13996.6144. November 16.

VII. Smithers Viscient. 2011. Phentermine HCl – Determination of the Biodegradability of a Test Substance Based on OECD Method 301B (CO₂ Evolution Test). Smithers Viscient Study No. 13996.6115. December 20.

VIII. Smithers. 2022b. [¹⁴C]Phentermine - Aerobic Transformation in Aquatic Sediment Systems. Smithers Study No. 13996.6143. February 11.

IX. Smithers. 2021d. Phentermine - Determining the Partition Coefficient (n-Octanol/Water) by the Shake-Flask Method. Smithers Study No. 13996.6138. July 29.

X. Hazardous Substances Data Bank (HSDB). 2023. Phentermine. Accessed on November 21, 2023: https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3158

XI. ECHA, European Chemicals Agency. 2017. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.11: PBT/vPvB Assessment. Version 3.0. January.

Detaljerad miljöinformation

Topiramate

Environmental risk: Use of topiramate has been considered to result in insignificant environmental risk.

Degradation: Topiramate is potentially persistent.

Bioaccumulation: Topiramate has low potential for bioaccumulation.

Detailed Background Information

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) = (A × 10¹¹) ÷ (7.3 × 10¹⁴)

PEC = < 0.053 µg/L

Where:

A = 389.6 kg (assumed a theoretical upper limit of total Qsiva-related topiramate sales in Sweden in 2028, five years after Qsiva launch [< 100 kg] plus existing topiramate sales in Sweden [289.6 kg], data in 2022 from Lif).

R = assumed 0 % removal rate in a sewage treatment plant

P = number of inhabitants in Sweden = 10,000,000

V = 200 L of wastewater per capita per day (ECHA default) (Ref. I)

D = 10, factor for dilution of wastewater by surface water flow (ECHA default) (Ref. I)

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

For the required ecotoxicity studies for FASS classification, guideline-driven aquatic toxicity studies were conducted under Good Laboratory Practices (GLP) based on exposure to topiramate, as listed below.

Algae:

EC₅₀ (72-hour growth rate/yield) = > 92,000 µg/L for freshwater green alga (Raphidocelis subcapitata) (OECD 201) (Ref. II, Ref. III)

NOEC (72-hour growth rate/yield) = 29,000 µg/L for freshwater green alga (Raphidocelis subcapitata) (OECD 201) (Ref. II, Ref. III)

Crustacean:

Acute toxicity

EC₅₀ (48-hour survival) = > 1,000,000 µg/L for water fleas (Daphnia magna) (FDA 4.08) (Ref. III, Ref. IV)

NOEC (48-hour survival) = 1,000,000 µg/L for water fleas (Daphnia magna) (FDA 4.08) (Ref. III, Ref. IV)

Chronic toxicity

NOEC (21-day survival/reproduction) = 1,800 µg/L for water fleas (Daphnia magna) (OECD 211) (Ref. III, Ref. V)

NOEC (21-day growth) = 730 µg/L for water fleas (Daphnia magna) (OECD 211) (Ref. III, Ref. V)

Fish:

Acute toxicity

LC₅₀ (96-hour survival) = > 2,400,000 µg/L for Bluegill sunfish (Lepomis macrochirus) (FDA 4.11) (Ref. III, Ref. IV)

NOEC (96-hour survival) = 75,000 µg/L for Bluegill sunfish (Lepomis macrochirus) (FDA 4.11) (Ref. III, Ref. IV)

Chronic toxicity

NOEC (28-day post-hatch reproduction) = 9,300 µg/L for fathead minnows (Pimephales promelas) (OECD 210) (Ref. III, Ref. VI)

Other Ecotoxicity Data:

Activated sewage sludge microorganisms:

EC₁₀ and EC₅₀ (3-hour respiration inhibition) = > 1,000,000 µg/L for activated sewage sludge microorganisms (OECD 209) (Ref. III, Ref. VII)

Calculation of PNEC

PNEC = 730 µg/L ÷ 10 = 73 µg/L

The PNEC is the lowest chronic NOEC divided by 10, where 10 is the assessment factor used for three long-term ecotoxicity data endpoints (i.e., alga, invertebrate, and fish). The NOEC of 730 µg/L for growth of water fleas (D. magnia) was chosen as it is the most sensitive of the three tested species.

Environmental Risk Classification (PEC/PNEC Ratio)

PEC/PNEC = < 0.053 ÷ 73 = < 0.0007

The PEC/PNEC ratio of ≤ 0.1 justifies the phrase ‘Use of topiramate has been considered to result in insignificant environmental risk.’

Degradation

Biotic Degradation

Ready degradability:

Topiramate was not identified as readily biodegradable in 28-day screening studies (Ref. III, Ref. IV).

Simulation studies:

An aerobic transformation study was conducted in two river water/sediment systems following the OECD Guideline 308 (Ref. III, Ref. VIII). Topiramate dissipated slowly from water to sediment, with DT50 values of 218 and 395 days in the water phase. In the sediment phase, DT50 values for topiramate were 167 and 460 days. Topiramate dissipated from the total water/sediment system very slowly with DT50 values of 395 and 491 days, mainly due to minor mineralization and irreversible binding to sediments.

Abiotic Degradation

Hydrolysis:

The hydrolysis half-life of topiramate was calculated to be approximately 80 days at pH 8 and 35°C (Ref. III, Ref. IV)

Justification of chosen degradation phrase:

Topiramate is not identified as readily degradable and does not undergo rapid hydrolysis (half-life > 40 days at environmentally relevant pH and temperatures). The phrase “Topiramate is potentially persistent” is thus chosen based on the absence of ready biodegradability and rapid hydrolysis, as well as the DT50 values of > 120 days for the total systems from the OECD 308 simulation study.

Bioaccumulation

Partitioning coefficient:

The octanol-water partitioning coefficient (K_ow) values were determined following OECD Guideline 107 (Ref. III, Ref. IX). All log K_ow values were < 1, with values of 0.559, 0.558, and 0.113 at pH values of 5, 7, and 9, respectively.

Justification of chosen bioaccumulation phrase: 

Since the log K_ow at pH of 7 is < 4, topiramate has low potential for bioaccumulation.

Excretion (Metabolism)

Ingested topiramate is not extensively metabolized in the human body, with no metabolite constituting more than 5% of the total excreted dose. Most topiramate is excreted as unconjugated topiramate in urine and feces, although the conjugated (and unconjugated) metabolites are also excreted to a lesser extent (Ref. X). Once excreted, any conjugated metabolites are likely to be de-conjugated during wastewater treatment, reverting to the parent compound form through bacterially mediated transformation (Ref. XI). For this classification, no reduction by metabolism was assumed for topiramate entering the environment.

PBT/vPvB Assessment

Although topiramate meets the REACH criteria for very persistent (vP) with half-lives for the total systems > 180 days, topiramate does not meet the REACH criteria for bioaccumulative (B) with the measured log K_ow values at all tested pH levels < 4 or the REACH criteria for toxic (T) with all chronic NOEC > 0.01 mg/L (Ref. XII). Therefore, topiramate is not classified as PBT or vPvB.

References

I. ECHA, European Chemicals Agency. 2023. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental Exposure Assessment. Version 4.0. July.

II. Smithers. 2021a. Topiramate - 72-Hour Toxicity Test with the Freshwater Green Alga, Raphidocelis subcapitata, Following OECD Guideline 201. Smithers Study No. 13996.6133. November 9.

III. Ramboll. 2022. Environmental Risk Assessment for Qsiva. Prepared for VIVUS LLC. August 24.

IV. Johnson Pharmaceutical. 1994. Environmental Assessment and Finding of No Significant Impact for Topamax (topiramate) Tablets. R.W. Johnson Pharmaceutical Research Institute, Spring House, PA.

V. Smithers. 2022a. Topiramate – Chronic Toxicity to Water Fleas (Daphnia magna) Under Static-Renewal Conditions. Smithers Study No. 13996.6134. March 8.

VI. Smithers. 2022b. Topiramate - Early Life-Stage Toxicity Test with Fathead Minnow (Pimephales promelas) Following OECD Guideline 210. Smithers Study No. 13996.6135. March 31.

VII. Smithers. 2021b. Topiramate - Activated Sludge Respiration Inhibition Test Following OECD Guideline 209. Smithers Study No. 13996.6132. September 13.

VIII. Smithers. 2022c. [¹⁴C]Topiramate - Aerobic Transformation in Aquatic Sediment Systems Following OECD Guideline 308. Smithers Study No. 13996.6131. March 10.

IX. Smithers. 2021c. Topiramate - Determining the Partition Coefficient (n-Octanol/Water) by the Shake-Flask Method. Smithers Study No. 13996.6137. September 14.

X. Caldwell GW, Wu WN, Masucci JA, McKown LA, Gauthier D, Jones WJ, Leo GC, and Maryanoff BE. 2005. Metabolism and Excretion of the Antiepileptic/Antimigraine Drug, Topiramate in Animals and Humans. European Journal of Drug Metabolism and Pharmacokinetics 30(3): 151-164.

XI. Celiz MD, Tso J, Aga DS. 2009. Pharmaceutical Metabolites in the Environment: Analytical Challenges and Ecological Risks. Environmental Toxicology and Chemistry 28(12): 2473-84.

XII. ECHA, European Chemicals Agency. 2017. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.11: PBT/vPvB Assessment. Version 3.0. January.