Detaljerad miljöinformation

Environmental Risk Classification

NOTE

Valaciclovir is a pro-drug which is fully metabolised to the active pharmaceutical ingredient Aciclovir. As a result this assessment is based on aciclovir.

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 = 0.41 μg/L

Where:

A = 2,981.35 kg (total sold amount API in Sweden year 2022, data from IQVIA). Total volume of Valacyclovir hydrochloride = 2019.24 = 1817.32 Kg of Valaciclovir free base. Total volume of Valaciclovir hydrochloride monohydrate = 4062.47 = 2991.31 Kg of Valaciclovir free base. Total Valaciclovir = 1817.32 + 2991.31 = 4808.63 Kg. 

The quantity of aciclovir free base (active ingredient) has been calculated by removing the salt constituent and pro-drug constituent from the drug substance. Total volume of Aciclovir free base active = 2,981.35

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 10 *10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)

(Reference 1)

D = factor for dilution of wastewater by surface water flow = 10 (ECHA default) (Reference 1)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

All data refers to Aciclovir

Green Algae (Selenastrum caprocornutum):

IC50 72h (inhibition biomass) > 99,000 μg/L (OECD 201) (Reference 3)

NOEC = 99,000 μg/L

Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 1,000,000 μg/L (OECD 202) (Reference 3 )

NOEC = 1,000,000 μg/L

Water flea (Ceriodaphnia dubia):

Chronic toxicity

EC50 7 days (reproduction) > 10,000 μg/L (EPA 1002) (Reference 9)

NOEC = 10,000 μg/L

Fathead Minnow (Juvenilee Pimephales promelas):

Acute toxicity

LC50 96 h (lethality) > 95,000 μg/L (OECD 203) (Reference 3)

NOEC = 95,000 μg/L

Other ecotoxicity data:

Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 1,000,000 μg/L (OECD 209) (Reference 7)

PNEC = 10,000/50 = 200 μg/L

PNEC (μg/L) = lowest NOEC/50, where 50 is the assessment factor applied for two long-term NOECs. NOEC for water flea (= 10,000 ug/L) has been used for this calculation since it is the most sensitive of the three tested species.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.41/200 = 2.05 x 10^-3, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of aciclovir has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

0.7% degradation in 28 days (TAD 3.11) (Reference 5)

Inherent degradability:

100% primary (loss of parent) degradation in 14 days (OECD 302B) (Reference 8)

Abiotic degradation

Hydrolysis:

Half-life, pH 7 > 1 year (TAD 3.09) (Reference 5)

Photolysis:

Half-life, pH 7 = 3.5 hours (TAD 3.10) (Reference 4)

Justification of chosen degradation phrase:

Aciclovir is not readily biodegradable nor inherently biodegradable. The phrase “Aciclovir is potentially persistent” is thus chosen.

Bioaccumulation

Partitioning coefficient:

Log P_calc = -1.55. (Chemaxon) (Reference 10)

Justification of chosen bioaccumulation phrase:

Since log Pow < 4, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Valaciclovir, an antiviral, is the L-valine ester of aciclovir. Aciclovir is a purine (guanine) nucleoside analogue. Valaciclovir is rapidly and almost completely converted in man to aciclovir and valine, probably by the enzyme referred to as valaciclovir hydrolase.

In adults the terminal plasma half-life of aciclovir after administrations of intravenous aciclovir is about 2.9 hours. Most of the drug is excreted unchanged by the kidney. Renal clearance of valaciclovir is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration contributes to the renal elimination of the drug. 9-carboxymethoxymethylguanine is the only significant metabolite of aciclovir, and accounts for approximately 10 - 15% of the administered dose recovered from the urine (Reference 2).

Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp.

References

1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

2. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Valtrex (Valaciclovir hydrochloride) Tablets. GlaxoSmithKline, April 2013.

3. Smith MF. Hydrolysis of 14C-Acyclovir as a Function of pH. Report No. 41609. ABC Laboratories, June 1994.

4. Gorman M. Determination of Aqueous Photodegradation of 14C-Acyclovir. Report No. 41308. ABC Laboratories, June 1994.

5. Franklin BB. Aerobioc Biodegradation in Water using 14C-Acyclovir. Report No. 41309. ABC Laboratories, March 1994.

6. Ziegenfuss MC. Ecotoxicity Evaluation of Acyclovir (CCl22890). Report No. ERL-2001-041. GlaxoSmithKline Environmental Research Laboratory, July 2001.

7. Koper CM. Acute Toxicity of CCL22890 (Acyclovir) to Activated Sludge Microorganisms. Report No. ERL-2001-047. GlaxoSmithKline Environmental Research Laboratory, October 2001.

8. Mather JI, Smyth DV and Kent SJ. Aciclovir: Determination of Inherent Biodegradability Using the Zahn-Wellens/EMPA Test. Report No. BL7606/B. Brixham Environmental Laboratories, July 2004.

9. Young BE and Kent SJ. Acyclovir: Determination of the 3-brood (7 day) Chronic Toxicity of Ceriodaphnia dubia. Report No. BL8144/B. Brixham Environmental Laboratories, April 2006.

10. Chemaxon /LogD. May 2012. Instant J Chem, ChemAxon Ltd.