Detaljerad miljöinformation

Note . Valganciclovir is a prodrug of Ganciclovir with rapid, nearly quantitative metabolic ester hydrolysis, hence environmentally relevant data will only be listed for Ganciclovir.

The assessment is based on the following entries of sales data from IQVIA / LIF - kg consumption 2021:

Substance	CAS no.	M	kg
Ganciclovir sodium	84245-13-6	277,215	2,6116
Valganciclovir	175865-60-8	354,365	1,9492
Valganciclovir hydrochloride	175865-59-5	390,826	105,0277

The assessment is made for:

Substance	CAS no.	M	kg
Ganciclovir (total)	82410-32-0	255,233	72,3979 (calculated sales data 2021)

Identification and characterisation

Brand name: Valcyte [1]

API: Valganciclovir hydrochloride [1]

CAS number: 175865-59-5 [1]

Molecular weight: 390.826 [1]

Physico-chemical properties

Aqueous solubility 2670 mg/L (pH 7.0) [1, 2]

Dissociation constant pK_a1 = 9.57 (acidic group), 24 °C; pK_a2 = 9.57 (basic group, extrapolated) [1, 3]

Melting point 242–255 °C (with decomposition) [1]

Vapour pressure ≤0.001 hPa (22 °C) [1]

Boiling point 613.89 °C QSAR

K_H 1.56E-18 Pa*m3/mol QSAR

QSAR = QSAR-modelled (EPISuite, SPARC, ACD Solaris)

Predicted Environmental Concentration (PEC)

PEC is calculated according to the formula:

PEC (μg/L) = (A x 1'000'000'000 x (100-R)) / (365 x P x V x D x 100) = 1.37 x 10^-6 x A x (100 - R) = 0.010 μg/l

Where:

A Sold quantity = 72.3979 kg/y calculated sales data for Ganciclovir (total)

R Removal rate = 0 % Default value [4]

P Population of Sweden = 10 000 000

V Volume of Wastewater = 200 l/day Default value [4]

D Factor for Dilution = 10 Default value [4]

Predicted No Effect Concentration (PNEC)

Ecotoxicological Studies

Green alga (Raphidocelis subcapitata): [5, 6]

ErC50 72 h (growth rate) >109 mg/l geometric mean (OECD 201)

EyC50 72 h (yield) >109 mg/l geometric mean (OECD 201)

NOEC 72 h = 109 mg/l geometric mean (OECD 201)

Water-flea (Daphnia magna): [5, 7]

NOEC 21 d (overall*) = 3.3 mg/l mean measured (OECD 211)

* overall NOEC for adult survival, juvenile production, growth and intrinsic rate of population increase

Fathead minnow (Pimephales promelas), Fish Partial Life Cycle Test: [5, 8]

NOEC 21 d (F0 generation, hatching success) = 1.1 mg/l mean measured (OECD 229/210)

NOEC 35 d (F1 generation, hatching success) = 0.012 mg/l mean measured (OECD 229/210)

Micro-organisms: [5, 9]

NOEC 3 h (respiration inhibition) = 1000 mg/l nominal (OECD 209)

PNEC Derivation

The PNEC is based on the following data:

PNEC (μg/l) = lowest NOEC/10, where 10 is the assessment factor used. A NOEC of 12 μg/l for fish has been used for this calculation. [5]

PNEC = 12 μg/l / 10 = 1.2 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.010 μg/l

PNEC Predicted No Effect Concentration = 1.2 μg/l

Ratio PEC/PNEC = 0.008

PEC/PNEC = 0.010/1.2 = 0.008 for Ganciclovir / Valganciclovir which justifies the phrase 'Use of Ganciclovir / Valganciclovir has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: ND

Inherent biodegradability: ND

Other degradation information:

A concentration of 1 mg/l [¹⁴C]-Ganciclovir was exposed in closed systems with CO₂ traps to 7 different inocula for 28 days at 25 °C (no standard method used): [5,10]

1. activated sludge: 1.77% ¹⁴CO₂ produced

2. activated sludge + anaerobic digester sludge (10 h aerobic / 14 h anaerobic cycling): 3.44% ¹⁴CO₂ produced

3. anaerobic digester sludge + HgCl2 (abiotic): 0.20% ¹⁴CO₂ produced

4. secondary effluent: 1.59% ¹⁴CO₂ produced

5. soil suspension: 56.77% ¹⁴CO₂ produced

6. river water/sediment: 34.16% ¹⁴CO₂ produced

7. anaerobic digester sludge (anaerobic): 0.88% ¹⁴CO₂ produced

A biodegradation screening test was conducted with ¹⁴C-ganciclovir using a variety of ecosystems as sources of microbial inocula. The test was conducted at 22 ± 3 °C (except for the anaerobic system at 25 ± 1 °C) for 28 days. A total of seven test systems were investigated at an initial dose of 1.0 mg/l of ¹⁴C-ganciclovir. Systems 1, 3, 4, 5, and 6 were maintained under aerobic conditions and inoculated with activated sludge, secondary effluent, soil suspension, and river water/sediment, respectively. System 2 was a repeat of system 1 but was supplemented with anaerobic digester sludge and operated on a 10-hour aerobic/14-hour anaerobic cycle. System 3 (served as a poisoned control for abiotic degradation) was similar to system 1 but was pasteurized and contained 1.0 g/l mercuric chloride System 7 was inoculated with anaerobic digester mixed liquor imspended solids (MLSS) and was maintained under anaerobic conditions. The percent bilodegradability of test compound was calculated as a function of the ¹⁴CO₂ produced as compared to the applied ¹⁴C-activity. After the 28-day incubation period, 1.77, 3.44, 0.20, 1.59, 56.77, 34.16 and 0.88% of the applied ¹⁴C-activity was biodegraded to ¹⁴CO₂ for systems 1 to 7, respectively. This indicated that the test compound ¹⁴C-ganciclovir could be easily mineralized using soil suspension or river water/sediments as an inoculum source. [10]

Transformation in Aquatic Sediment Systems [5, 11]

DT50 = 14 d (Sediment 1, total system) (OECD 308)

DT90 = 46 d (Sediment 1, total system) (OECD 308)

DT50 = 18 d (Sediment 2, total system) (OECD 308)

DT90 = 82 d (Sediment 2, total system) (OECD 308)

Evolved ¹⁴CO₂ in the KOH traps increased continuously from day 7 to reach 37.3% (Sediment system 1), and 69.5% (Sediment system 2) by day 100.

By LC–MS/MS analysis, the parent Ganciclovir in surface water plus sediment extracts decreased rapidly in both systems, from >99% on day 0 to 5% in Sediment system 1 and to <5% in Sediment system 2 on day 100.

Sediment samples were extracted on the day of collection with acetonitrile:water by shaking. Extracts were pooled prior to analysis. Bound residue fractionation was performed following initial extraction. The method used was based on that recommended by the American Institute Biological Sciences Environmental Chemistry Task Group (AIBS).

Abiotic Degradation

Hydrolysis: stable [1]

Photodegradation: ND

Ganciclovir / Valganciclovir is not readily degradable. In sediment/water fate systems according to OECD 308 a DT50 of 14–18 days (≤32 days) for the total system was observed. The parent compound (i.e. water and sediment extractions added together) compared to the total amount applied at the start of the study was <15%. Moreover, a mineralisation of up to 69.5% was observed. The results of this study indicate that Ganciclovir / Valganciclovir is unlikely to persist in natural water-sediment systems. This justifies the phrase 'Ganciclovir / Valganciclovir is degraded in the environment.'

Bioaccumulation/Adsorption

log DOW	= -1.96 (pH 5.02, 25 °C) (FDA method 3.02, stirrring method) [1, 12]
	= -1.94 (pH 6.99, 25 °C) (FDA method 3.02, stirrring method) [1, 12]
	= -2.00 (pH 8.79, 25 °C) (FDA method 3.02, stirrring method) [1, 12]
log KOW	= -1.95 (average of pH 5 and 7, unionised, 25 °C) (FDA method 3.02, stirrring method) [1, 12]
KOC	83.65 - 105.58 l/kg (OECD 106) [5, 13]
BCF	<500 l/kg QSAR

Ganciclovir / Valganciclovir has low potential for bioaccumulation (log K_OW <4).

Excretion/metabolism

After oral ingestion, Valganciclovir is rapidly hydrolyzed to Ganciclovir and L-valine by enteric and hepatic esterases; there is essentially no further metabolism, and GCV is excreted by the urinary pathway. [5]

References

1. F. Hoffmann-La Roche Ltd (2021): Environmental Risk Assessment Summary for Valganciclovir. https://www.roche.com/sustainability/environment/environmental-risk-assessment-downloads.htm.

2. Nicholson V, Licato N (1992): Solubility of ganciclovir in aqueous buffers. Analytical and Environmental Research, Syntex Discovery Research, Palo Alto, CA, USA.

3. Nicholson V, Licato N (1992): Dissociation constant of ganciclovir. Analytical and Environmental Research, Syntex Discovery Research, Palo Alto, CA, USA.

4. European Medicines Agency (EMA) (2006/2015): Guideline on the environmental risk assessment of medicinal products for human use. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), 01 June 2006, EMA/CHMP/SWP/447/00 corr 2.

5. Straub JO. 2017. Combined environmental risk assessment for the antiviral pharmaceuticals ganciclovir and valganciclovir in Europe. Environ Toxicol Chem. 36(8):2205-2216.

6. Study Report: Smithers Viscient (ESG) study no. 3200781: Ganciclovir - Inhibition of Growth to the Alga Pseudokirchneriella subcapitata, May 2015.

7. Study Report: Smithers Viscient (ESG) study no. 3200782: Ganciclovir - Daphnia magna Reproduction Test, May 2015.

8. Study Report: Smithers Viscient (ESG) study no. 3200783: Ganciclovir - Fish Partial Life Cycle Test (Pimephales promelas), July 2015.

9. Study Report: Smithers Viscient (ESG) study no. 3200788: Ganciclovir - Activated Sludge Respiration Inhibition Test, August 2015.

10. Study Report: ABC study no. 40403: Survey of Inoculum Sources for Biodegradation of 14C-Ganciclovir, October 1993.

11. Study Report: Smithers Viscient (ESG) study no. 3200729: Ganciclovir - Degradation in Water-Sediment Systems under Aerobic Conditions, September 2015.

12. Carlson T, Licato N (1991): n-Octanol-water distribution ratio of ganciclovir in aqueous buffers. Analytical and Environmental Research, Syntex Discovery Research, Palo Alto, CA, USA.

13. Study Report: Smithers Viscient (ESG) study no. 3200728: Ganciclovir - Adsorption/Desorption in Two Soils, Two Activated Sludges and Two Sediments, September 2015.