Detaljerad miljöinformation

Identification and characterisation

Chemical name: Erlotinib hydrochloride

CAS number: 183319-69-9 [1]

Molecular weight: 429.9 [1]

Remark: -

Brand name: Tarceva [1]

Physico-chemical properties

Aqueous solubility 810 mg/l [1]

Dissociation constant, pK_a 5.7 (base) [1]

Melting point 228–238 °C, with partial decomposition [1]

Vapour pressure 7.9*E–09 Pa QSAR

Boiling point ND

K_H 2.1*E-06 – 8.6*E-11 atm*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) = 1.5 x 10^-6 x A x (100 - R) = 0.00133 μg/L

Where:

A Sold quantity = 8.88261 kg/y (total sold amout API in Sweden year 2017, data from IQVIA)

R Removal rate = 0 % Default [2]

P Population of Sweden = 9000000

V Volume of Wastewater = 200 l/day Default [2]

D Factor for Dilution = 10 Default [2]

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green alga (Pseudokirchneriella subcapitata): [3]

ErC50 72 h (growth rate) >100 mg/l nominal concentration (OECD 201)

EbC50 72 h (biomass) >100 mg/l nominal concentration (OECD 201)

NOEC 72 h = 1.39 mg/l (OECD 201)

Water-flea (Daphnia magna): [4]

EC50 48 h (immobilisation) >100 mg/l (OECD 202)

NOEC 48 h (immobilisation) = 0.7 mg/l (OECD 202)

Water-flea (Daphnia magna): [5]

21 d NOEC (overall) = 0.6 mg/l (OECD 211)

Zebra fish (Danio rerio): [6]

LC50 96 h (mortality) >100 mg/l (OECD 203)

NOEC 96 h (mortality) = 100 mg/l (OECD 203)

Zebra fish (Danio rerio): [7]

36 d NOEC (mortality) = 0.56 mg/l (OECD 210)

Micro-organisms (activated sludge):

3 h NOEC = 1000 mg/l (OECD 209) [8]

PNEC Derivation

The PNEC is based on the following data:

PNEC (mg/l) = lowest chronic NOEC/10, where 10 is the assessment factor used. A NOEC of 560 μg/l in the fish early life stage test has been used for this calculation.

PNEC = 560 / 10 = 56 μg/l

Environmental Risk Classification (PEC/PNEC Ratio)

PEC Predicted Environmental Concentration = 0.00133 μg/L

PNEC Predicted No Effect Concentration = 56 μg/L

Ratio PEC/PNEC = 0.000024

PEC/PNEC =0.00133/56 = 0.000024 for Erlotinib hydrochloride which justifies the phrase 'Use of Erlotinib hydrochloride has been considered to result in insignificant environmental risk.'

Degradation

Biotic Degradation

Ready biodegradability: [9]

0% after 28 days of incubation BOD/ThOD (OECD 301 C)

Inherent biodegradability: [10]

0% after 28 days of incubation BOD/ThOD (OECD 302 C)

Other degradation information: [11]

DT50 (water) = <2 d (OECD 308)

DT50 (total system) = 26–86 d (OECD 308)

Abiotic Degradation

Photodegradation: stable drug stability testing [1]

Hydrolysis: stable drug stability testing [1]

Erlotinib hydrochloride is not readily biodegradable; it is also not degradable in water/sediment systems. This justifies the phrase 'Erlotinib hydrochloride is potentially persistent.'

Bioaccumulation/Adsorption

logP_OW = 2.98-3.53 (pH 4.9–6.5, 20 °C) (OECD 107) [12]

K_OC (sediment) = 5693 l/kg (OECD 308 / OECD 301 C with artificial sediment) [11]

BCF = 7.8–10.1 l/kg (OECD 305) [13]

Erlotinib hydrochloride has low potential for bioaccumulation.

Excretion/metabolism

Erlotinib is mainly Phase-I-metabolised by hepatic cytochrome -P450 enzymes CYP3A4 and, to a lesser extent, CYP1A2 as well as by pulmonary CYP1A1. Excretion of Erlotinib and its metabolites in man is mainly (≥90%) by faecal and secondarily by urinary pathway. The median half-life of elimination on repeated once-daily administration in patients is approximately 36 hours. [14]

PBT/vPvB Assessment

P: Freshwater half-life <2 d [11]

Sediment half-life 86 y [11]

Persistence criteria fulfilled? Potentially P

B: BCF (experimental) 10.1 [13]

alternatively, base or acid?

alternatively, logD_OW(p H 7)

Bioaccumulation criteria fulfilled? no significant bioaccumulation (BCF < 2000)

T: chronic NOEC < 0.01 mg/l? n not T [4][6]

CMR substance? n not CMR [1]

Endocrine-disrupting effects? n not ED

T criteria fulfilled? not T

PBT Assessment: not PBT

References

1. F. Hoffmann-La Roche Ltd. 2019. Safety Data Sheet for Tarceva, 05.03.2019; https://www.roche.com/sustainability/what_we_do/for_communities_and_environment/environment/safety_data_sheetsrow. htm

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

3. Study Report: Solvias study no. L01-009453: Toxicity of Ro 50-8231/001 to Green Algae (Growth Inhibition Test), May 2002.

4. Study Report: Solvias study no. L01-009454: Acute Toxicity of Ro 50-8231/001 to Daphnia magna (Immobilisation Test), May 2002-

5. Study Report: ibacon study no. 39571221: Influence of Tarceva (Erlotinib) to Daphnia magna in a Reproduction Test, October 2008.

6. Study Report: Solvias study no. L01-009456: Acute Toxicity of Ro 50-8231/001 to Zebrafish (Danio rerio) under Semi-Static Conditions, May 2002.

7. Study Report: ibacon study no. 39573232: Toxicity of Tarceva (Erlotinib) to Zebrafish (Danio rerio ) in an Early-Life Stage Test, December 2008.

8. Study Report: RCC study no. A15996: Tarceva: toxicity to activated sludge in a respiration inhibition test, November 2005.

9. Study Report: SPL study no. 1384/019: OSI-774-01: Assessment of ready biodegradability in the Modified MITI Test (I), May 2003.

10. F. Hoffmann-La Roche Ltd. Tarceva – Oekotoxikologische Beurteilung Nr. E-03/01, June 2003.

11. Study Report: RCC study no. A15243: [14C]-Tarceva: Route and Rate of Degradation in Aerobic Aquatic Sediment Systems, June 2006.

12. Study Report: SPL study no. 1384/018: OSI-774-01: Determination of partition coefficient, September 2002.

13. Study Report: RCC study no. A13061: Flow-through Fish Test with [14C]-Tarceva in Rainbow Trout (Oncorhynchus mykiss), May 2006.

14. F. Hoffmann-La Roche Ltd. Erlotinib: Environmental Risk Assessment Summary, April 2018. https://www.roche.com/sustainability/environment/environmental-risk assessment-downloads.htm