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)

PEC = 0.003255394 μg/L

Where:

A = 23.762 kg (total forecasted amount API sold the coming 5 years for Sweden (2025-2030))

R = X % 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) (Ref. I)

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae

Freshwater Algal Growth Inhibition Test (Raphidocelis subcapitata) (guideline eg OECD 201) [Ref. II]:

EγC₅₀ 72 h (biomass) = 131 µg /L

NOECγ (biomass) = 111 µg /L

E_rC₅₀ 72 h (growth rate) > 139 µg /L

NOEC_r (growth rate) = 111 µg /L

Crustacean

Acute

Daphnia magna, Acute Toxicity Study (guideline eg OECD 202) (Ref. X)

EC50 48h (immobility) = 48 μg/L

Chronic

Reproduction test with water-flea (Daphnia magna) (guideline eg OECD 211) [Ref. III]:

EC50 21 days (reproduction) > 289.6 µg/L

NOEC 21 days (reproduction) = limit concentration of 289.6 µg/L

Three treatment levels (1, 10 and 100% saturated solution at a loading rate of 100 mg/L). Following a review, the EMA rapporteur recommended a NOEC = 28.96 ug/L (corresponding to the 10% saturated solution at a loading rate of 100 mg/L) considering the effects observed at the highest tested concentration (100% saturated solution at a loading rate of 10 mg/L).

Fish

Acute

Acute toxic effects in Carp (Cyprinus carpio) (guideline eg OECD 203) (Reference XI)

LC50 96 h (mortality): 0.47 mg/L

In conclusion, the 96h-LC50 for carp (Cyprinus carpio) exposed to JNJ-73841937-ZCY (Lazertinib) was beyond the range of concentrations tested, i.e. exceeded a geometric mean concentration of 0.47 mg/L, being considered the maximum concentration soluble in test medium at a loading rate of 100 mg/L.

Chronic

Fish early life stage test with fathead minnow (Pimephales promelas) in a flow-through system (guideline eg OECD 210) [Ref. IV]:

NOEC 32 days (growth) = 19 µg/L

LOEC 32 days (growth) = 61 µg/L

Other ecotoxicity data

Activated sludge respiration inhibition test (guideline eg OECD 209) [Ref. V]

NOEC = 0.019 mg/L

Environmental risk classification (PEC/PNEC ratio)

Calculation of Predicted No Effect Concentration (PNEC)

Derived Aquatic PNEC values for lazertinib

	Based on	Assessment factor	PNEC value
PNEC WATER	NOEC Fish Early-life Stage	10	1.9 µg/L
PNEC MICROORGANISM	NOEC respiration inhibition	10	3,200 µg/L
PNEC GROUNDWATER	NOEC Daphnia reproduction test	10	2.9 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC /PNEC water = 0.003255394 /1.9 = 0.0017

PEC /PNEC microorganism = 0.003255394 / 3200 = 0.00000101

PEC /PNEC groundwater = 0.003255394 /2.9 = 0.00112

i.e. PEC/PNEC < 0.1

Conclusion for environmental risk:

Use of Lazertinib has been considered to result in insignificant environmental risk.

DEGRADATION

Biotic degradation

Ready biodegradation

Lazertinib was investigated for its ready biodegradation over a period of 28 days by the CO2 Evolution (Modified Sturm) test (guideline eg OECD 301B) [Ref. VI]:

Result: 7% - Not readily biodegradable.

Simulation study Aerobic degradation in aquatic sediment systems:

Lazertinib was investigated for its aerobic degradation in a 100-day aquatic sediment test, guideline eg OECD 308 [Ref. VII]:

Upon addition of radiolabeled test material to the water layer, Lazertinib partitioned to the sediment layer and degraded to 21% of applied radioactivity in the SW total system on Day 63 and to 3% in the MP total system on Day 100. In the water layer of both systems, Lazertinib degraded to undetectable amounts after 30 days of incubation. In the sediment layer, Lazertinib increased to maximum 74% (SW) and 57% (MP) of applied radioactivity on Day 1 and Day 3, respectively, and then decreased to 22% (SW) and 3% (MP) of applied radioactivity on Day 100.

Focus: see Ref. XII

DT50 SW total system = 24 days

DT50 MP total system = 9.6 days

Thus, DT50 total system <= 32 days

Conclusion for degradation:

Lazertinib is degraded in the environment.

BIOACCUMULATION

Partition coefficient octanol/water

The partition coefficient octanol/water was determined using the shake flask method (guideline eg OECD 107) [Ref. VIII]:

Log D_ow = 3.7 (pH 7.0)

Bioconcentration

Bioaccumulation in Common carp (Cyprinus carpio) – Aqueous Exposure [guideline eg OECD 305] [Ref. IX].

BCF < 500, thus Lazertinib has low potential for bioaccumulation.

Conclusion for bioaccumulation:

Lazertinib has low potential for bioaccumulation.

Excretion (metabolism)

No data available.

PBT/vPvB assessment

	PBT-criteria	Results for Lazertinib
P	DT50 freshwater > 40 days or DT50 sediment > 120 days	DT50 SW total system = 24 days DT50 MP total system = 9.6 days
B	BCF > 2000	BCF < 500
T	Chronic NOEC < 10 µg/L or CMR or endocrine disrupting	NOECalgae = 111 µg/L NOECdaphnia = 28.96 µg/ NOECfish = 19 µg/L

None of the PBT-criteria are fulfilled. Therefore, Lazertinib is not considered a PBT-substance.

References

1. 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

2. Goris, K. 2022. Freshwater Algal Growth Inhibition Test with JNJ-73841937-ZCY (Lazertinib). Charles River Laboratories den Bosch BV., Report N°: 20311211. Sponsor Reference RMD1344.

3. Orosz, Ivett. 2024. JNJ-73841937-ZCY (Lazertinib): Amendment 1 to the Final Report: GLP Reproduction test on Daphnia (Daphnia magna). Charles River Laboratories Hungary Kft., Report N°: 21/330-124DA. Sponsor Reference RMD1347.

4. Augusiak, J. 2023. Fish Early-Life Stage Toxicity Test with JNJ-73841937-ZCY (Lazertinib) (Flow-Through). Charles River Laboratories den Bosch BV., Report N°: 20311219. Sponsor Reference RMD1348.

5. Brands, C. 2022. Activated Sludge Respiration Inhibition Test with JNJ-73841937-ZCY (Lazertinib). Charles River Laboratories den Bosch BV., Report N°: 20311210. Sponsor Reference RMD1343.

6. van Schaik, T. 2021. Determination of 'Ready' Biodegradability: Carbon Dioxide (CO2) Evolution Test (Modified Sturm Test) of JNJ-73841937-ZCY (Lazertinib). Charles River Laboratories den Bosch BV., Report N°: 20311208. Sponsor Reference.

7. Brands, C. 2023. Aerobic Transformation of JNJ-73841937-ZCY (Lazertinib) in Aquatic Sediment Systems. Charles River Laboratories den Bosch BV., Report N°: 20311209. Sponsor Reference RMD1341.

8. Volic, N., 2021. Determination of Physico-Chemical Properties of JNJ-73841937-ZCY (R605024): Validation of an analytical method for water samples; Validation of an analytical method for 1-octanol samples; Partition Coefficient at 3 pH’s. Charles River Laboratories den Bosch BV., Report N°: 20251337.

9. Agne, M. 2023. ¹⁴C-Lazertinib: Bioaccumulation in Common carp (Cyprinus carpio) – Aqueous Exposure [OECD 305]. Ibacon GmbH. Report N°: 166781233. Sponsor Reference RMD1398.

10. Goris, K. 2023. Daphnia magna, Acute Toxicity Study with JNJ-73841937-ZCY (Lazertinib). Charles River Laboratories den Bosch BV., Report N°: 20311213. Sponsor Reference RMD1345.

11. Augusiak, J. 2022. Fish, Acute Toxicity Study with JNJ-73841937-ZCY (Lazertinib). Charles River Laboratories den Bosch BV., Report N°: 20311214. Sponsor Reference RMD1346

12. FOCUS (2014) Generic guidance for Estimating Persistence and Degradation Kinetics from Environmental Fate Studies on Pesticides in EU Registration. Report of the FOCUS Work Group on Degradation Kinetics.18 December 2014. version 1.1, 440 pp.