Detaljerad miljöinformation

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) = 1.37*10^-6 * 3.05 kg * 100 = 0.00042 μg/L = 0.42 ng/L

Where:

A = 3.05 lapatinib (3.05 kg normalized to the free base; Mw 581.1 g/mol, from 4.9350 kg lapatinib monohydrate of the ditosylate salt; Mw 943.5 g/mol) (total sold amount API in Sweden year 2021, data from IQVIA).

R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0, if no data is available.

P = number of inhabitants in Sweden = 10 * 10⁶

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Green Algae (Selenastrum caprocornutum):

IC50 96h (growth) > 17,300 μg/L (OECD 201) (Reference 5)

NOEC = 3,430 μg/L

Water flea (Daphnia magna):

Acute toxicity

No data

Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (mortality) > 108 μg/L (OECD 211) (Reference 4)

NOEC 21 days (reproduction) < 108 μg/L*

* This was considered artefact due to limited solubility in water (< 1mg/L).  There was no dose response observed for range of concentrations versus their reproductive effect. Overcoming the physicochemical characteristics of lapatinib to ensure adequate bioavailability was a major hurdle for the chronic aquatic studies.  The completion of the Daphnia reproduction study could only be achieved by pre-conditioning of test vessels, daily renewal of test media and addressing the challenges inherent in achieving consistent chemistry with such a hydrophobic compound.  In doing this the aim has to be to achieve a balance between the optimal conditions for the maintenance of the test species and the creation of those conditions which will lead to the highest levels of bioavailability of the test compound.  For lapatinib, this resulted in a significant degree of stress for the organisms (there was at least a 10% adult mortality in all exposed groups including controls) and, in turn, a lack of dose response was evident. The absence of a clear dose response implies that the effects observed at lower concentrations of lapatinib may reflect the additional stress imposed by the test conditions, a stress which is masked at higher concentrations of drug substance, therefore suggesting that the effects observed were an artefact.

Rainbow Trout (Oncorhyncus mykiss):

Acute toxicity

LC50 96 h (lethality) > 26,800 μg/L (OECD 203) (Reference 6)

NOEC ≥ 26,800 μg/L

Fathead minnow (Pimephales promelas):

Chronic toxicity

NOEC 28 days (growth) = 1 μg/L (OECD 210) (Reference 7)

Other ecotoxicity data:

Chironomid (Chironomus riparius)

NOEC 26 days (reproduction) = 11,600, μg/kg (OECD 218) (Reference 8)

Microorganisms in activated sludge

EC50 3 hours (Inhibition) = 1,735,000 μg/L (OECD 209) (Reference 3)

Terrestrial toxicity

Manure worm (Eisenia foetida)

LC50 14 days (mortality) > 616,000 μg/kg  (OECD 207) (Reference 9)

NOEC = 616,000 μg/kg

Collembola (Folsomia candida)

NOEC 28 days (reproduction) = 333,333 μg/kg (ISO 11267:1999) (Reference 10)

Soil microorganisms

EC50 28 days > 1,000,000, μg/kg (OECD 216) (Reference 11)

NOEC = 111,111 μg/kg

Wheat (Triticum aestivum)

NOEC 17 days (emergence) > 1,000,000 μg/kg (OECD208) (Reference 12)

NOEC 17 days (growth) > 333,333 μg/kg

Mung Bean (Phaseolus aureus)

NOEC 14 days (emergence) > 1,000,000 μg/kg (OECD208) (Reference 12)

NOEC 14 days (growth) > 500,000 μg/kg

Cabbage (Brassicia oleracea var)

NOEC 15 days (emergence) > 1,000,000 μg/kg (OECD208) (Reference 12)

NOEC 15 days (growth) > 333,333 μg/kg

PNEC = 1/10 = 0.1 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for fathead minnow (= 1 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 = 0.00042 μg/L / 0.1 μg/L = 0.0042, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of lapatinib has been considered to result in insignificant environmental risk.”

Degradation

Biotic degradation

Ready degradability:

32% degradation in 28 days (OECD 301B) (Reference 13)

Simulation studies:

Water-sediment study:

50% (DT₅₀) degradation for the total systems in 44-88 days (OECD 308) (Reference 14)

One major (> 10%) transformation product identified, GSK342393A 

Non-extractable residue = 17-19%

Sediment samples were transferred from the incubation vessels by washing with acetone : 10% ammonia (100 mL, 1:1 v/v) and were then extracted five times with this solvent, each time centrifuging at 3400 rpm (2300g) to separate supernatants and sediment. Radioactivity in the combined extract was determined by LSC. Remaining sediment residues were dried and ground for combustion analysis. Sub-samples (ca 120 g) of the extracts were concentrated to ca 10 mL by rotary  vaporation and were reconstituted in acetone (2 x 1 mL) prior to chromatographic analysis.

0,2% degradation in 64 days (OECD 304A) (Reference 16)

Aerobic transformation in soil (OECD 307)  (Reference 15)

Degradation rates

DT₅₀ = 70-157 days                                                                                       

DT₇₅ = 140-315 days                                                                                

DT₉₀ = 233-523 days 

Transformation products

Only one major transformant (>10%) was identified from the OECD 308 study, namely GSK342393A. In human radiolabelled studies the metabolite accounts for approximately 14.6% of the dose excreted. The pharmacological activity of GSK342393A is approximately 100-fold less than that of lapatinib when measured against EGFR or ErbB2 dependent cell lines (HN5 and BT474) and potency is lost on cell lines in the panel that are known to be less responsive to lapatinib (HFF, A549, COLO205 & MDA468). Due to lack of pharmacological potency GSK342393A is not considered to represent a risk to the aquatic environment.

Abiotic degradation

Hydrolysis:

No data

Photolysis:

No data

Justification of chosen degradation phrase:

Lapatinib is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade in water sediment systems ≤ 120 days.  As all reasonable efforts have been made to extract sediments and the non-extractable residues are thus not considered bioavailable, the phrase “Lapatinib is slowly degraded in the environment” is chosen.

Bioaccumulation

Bioconcentration factor (BCF):

                      Rainbow trout (Oncorhynchus mykiss)

BCF = 132-142 (OECD 305) (Reference 17)

Justification of chosen bioaccumulation phrase:

Since BCF < 500, the substance has low potential for bioaccumulation.

Excretion (metabolism)

Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which account for more than 14% of the dose recovered in the faeces or 10% of lapatinib concentration in plasma

The primary route of elimination for lapatinib and its metabolites is in faeces, with less than 2% of the does (as lapatinib and metabolites) excreted in urine. Recovery of lapatinib in faeces accounts for a median 27% (range 3 to 67%) of an oral dose. (Reference 2)

PBT/vPvB assessment

Lapatinib does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Lapatinib does not fulfil the criteria for PBT and/or vBvP based on a BCF < 500.

References

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

2. Global Datasheet Lapatinib. Version 19. 31 August 2016.

3. Bates ML. GW572016F: GW572016F: Determination of Inhibition of Respiration of Activated Sludge. Report No. 2990/048. Covance Laboratories Limited, December 2003.

4. Manson PS. GW572016F: Reproduction study with Daphnia magna. Report No. 1990/547. Covance Laboratories Limited, June 2005.

5. Manson PS. GW572016F: Inhibition of Growth to the Alga Selenastrum capricornutum. Report No. 1990/233. Covance Laboratories Limited, August 2004.

6. Manson PS. GW572016F: Acute toxicity to Oncorhynchus mykiss. Report No. 1990/234. Covance Laboratories Limited, August 2004.

7. Burke J. GW572016F: Lapatinib ditosylate (GW572016F): Fish Toxicity Testing to Pimephales promelas. Report No. 2990/048. Covance Laboratories Limited, February 2009.

8. Burke J and Scholey A. GW572016F: [14C]-Lapatinib ditosylate, GW572016F(GW572016X): Sediment-Water Chironomus riparius Toxicity Test using Spiked Sediment. Report No. 2990/051. Covance Laboratories Limited, March 2009.

9. Swales S. Acute toxicity of GW572016F to the earthworm Eisenia fetida. Report No. 1990/231. Covance Laboratories Limited, January 2004.

10. Sharples A. Lapatinib ditosylate (GW572016F): Determination of the Effects on the Reproductive Output of the Collembolan (Folsomia candida). Report No. 2990/050. Covance Laboratories Limited, April 2008.

11. Sharples A. GW572016F: Lapatinib ditosylate (GW572016F): Soil Nitrogen Transformation Test. Report No. 2990/218. Covance Laboratories Limited, January 2009.

12. Sharples A. Lapatinib ditosylate (GW572016F): Seedling Emergence and Growth Test Report No. 2990/048. Covance Laboratories Limited, March 2009.

13. Burwood C. GW572016F: Assessment of ready biodegradability by measurement of carbon dioxide evolution. Report No. 1990/342. Covance Laboratories Limited, December 2005.

14. Lewis C and Troth K. [14C]-Lapatinib ditosylate, GW572016F(GW572016X): Aerobic Degradation and Retention in Water-Sediment Systems. Report No. 2990/047. Covance Laboratories Limited, August 2008.

15. Lewis CJ and Gilbert G. [14C]-Lapatinib ditosylate, GW572016F(GW572016X): Aerobic Soil Metabolism and Degradation. Report No. 2990/217. Covance Laboratories Limited, September 2008.

16. Swales S. (14C)-GW572016F: Inherent Biodegradability in Soil. Report No. 1990/232. Covance Laboratories Limited, August 2004.

17. Burke J and Scholey A. GW572016F: [14C]-Lapatinib ditosylate, GW572016F(GW572016X): Fish Bioconcentration Study. Report No. 2990/219. Covance Laboratories Limited, March 2009.