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 = 0.000158 μg/L

Where:

A = 1.153 kg (total sold amount API in Sweden year 2021, data from IQVIA/LIF)

R = 0 % removal rate (due to 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 I)

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies*

Algae (Desmodesmus subspicatus) (guideline OECD 201) (Reference II):

NOEC 72 h (growth rate) = 0.13 μg/L

Crustacean (Daphnia magna):

Chronic toxicity

NOEC 21 days (survival of parent) = 10.5 μg/L (guideline OECD 211) (Reference III)

Fish (Pimephales promelas):

Chronic toxicity

NOEC 28 days (survival) = 0.007 μg/L (guideline OECD 210) (Reference IV)

Microorganisms:

NOEC > 40,000 μg/L, i.e., there was no effect up to the highest test concentration (guideline OECD 209) (Reference V)

The PNEC was calculated by division of the NOEC of the most sensitive taxonomic group with an assessment factor (AF). The most sensitive taxonomic group were fish and the lowest NOEC was reported with 0.007 µg/L. The regulatory default standard AF of 10 was used, which is applicable when there are chronic aquatic toxicity studies representing the three trophic levels (algae, invertebrates, and fish).

PNEC = 0.007 µg/L / 10 = 0.0007 µg/L

Environmental risk classification (PEC/PNEC ratio)

The risk quotient PEC/PNEC was calculated with 0.000158 µg/L / 0.0007 µg/L = 0.226.

Justification of chosen environmental risk phrase:

With a chronic NOEC <0.01 mg/L, regorafenib fulfils the T-criteria in the PBT-assessment. Since the P and B criteria are also fulfilled, regorafenib qualifies for the phrase "Hazardous environmental properties".

Degradation

Biotic degradation

Ready degradability:

Regorafenib was studied for aerobic biodegradability in water in a manometric respiration test according to guideline OECD 301F. Test item was introduced into the test system at a concentrations of 200 mg/L as theoretical oxygen demand. There was 0% degradation after 28 days. The reference substance (sodium diacetate) was degraded to more than 60 % within 14 days and the toxicity control did not indicate an inhibiting effect on microorganisms. Therefore, regorafenib is considered not readily biodegradable.

The study results with 0 % biodegradation in 28 days (guideline OECD 301F). (Reference VI)

Simulation studies:

The transformation of [¹⁴C] regorafenib in sediments and natural water was assessed in two different aerobic sediment/water systems at a temperature of 19-23 °C for 100 days continuously in the dark. Radioactivity of [¹⁴C] regorafenib in sediment was quantified by combustion analysis and radioassay. The water fraction was measured by liquid scintillation counting (LSC). Hydrochloric acid was added to the soda lime fraction and evolving ¹⁴CO₂ was absorbed in a scintillation cocktail and analysed by LSC. The distribution of [¹⁴C] regorafenib to the sediment compartment and the disappearance from the water fraction was determined by plotting the radioactivity over time. The total mass balance accumulated to 104% and 113% for both sampling locations, respectively. No ultimate biodegradation was observed in the test system. regorafenib disappeared from the water phase within 24 hours by more than 50%. In sediments, the [¹⁴C] regorafenib fraction remained on a level between 67 and 107% with no time dependency. Therefore, it can be concluded that regorafenib was not degraded within 100 days in the aquatic sediment system. The overall degradation half-life from the system was >120 days. Therefore, the degradation half-life above 120 days justifies the phrase: regorafenib is potentially persistent.

This study reported a half-life of substance regorafenib in water DT₅₀ < 1 days and no DT₅₀ in sediment/total system due to absence of ultimate degradation (guideline OECD 308). (Reference VII)

Justification of chosen bioaccumulation phrase:

The half-life of regorafenib in freshwater sediment is >120 days, and the substance thus fulfils the P-criteria in the PBT assessment. Since all PBT-criteria are fulfilled, Regorafenib qualifies for the summary phrase "Hazardous environmental properties".

Bioaccumulation

Bioconcentration factor (BCF):

In a fish bioconcentration study with regorafenib, fish (bluegill sunfish, Lepomis macrochirus) were exposed to ¹⁴C-labeled regorafenib at two concentrations (nominally 0.16 and 1.6 µg/L) and additionally to the control for a period of 28 days. Subsequently, the fish were depurated over a period of 14 days. Two replicate tanks for the test concentrations and one tank for the control were used. Concentration in water and fish tissue were analysed by radio-assay. The BCFss (bioconcentration factor at steady state) was 2,874 and 4,444 for group 2 and 3, respectively. BCFs were normalized for 5 % lipid content.

The study reported a BCF range of 2,211-3,418 (guideline OECD 305). (Reference VIII)

Partitioning coefficient:

The log D_ow was reported with 3.7 at pH 7 (guideline OECD 107). (Reference IX)

Justification of chosen bioaccumulation phrase: 

With a BCF-value for regorafenib of >2000, the substance fulfils the B-criteria in the PBT-assessment. Since all criteria for the PBT-assessment are fulfilled, regorafenib qualifies for the phrase "Hazardous environmental properties".

PBT/vPvB assessment

Regorafenib fulfils the P-criteria in the PBT-assessment, since half-life in freshwater sediment is >120d (OECD 308 study in two freshwater/sediment systems).

Regorafenib fulfils the B-criteria in the PBT-assessment (BCF >2000), since the reported BCFss are 2900 and 4444 for the low and high concentration, respectively (OECD 305 study in bluegill sunfish, Lepomis macrochirus).

Regorafenib fulfils the T-criteria in the PBT-assessment (chronic toxicity <0.01 mg/L), since the chronic toxicity, NOEC 28 days (post hatch, larval survival) for) was 0.007 μg/L (OECD 210 study in fathead minnow, Pimephales promelas).

According to the established EU criteria, the compound should be regarded as a PBT/vPvB substance and the summary phrase "Hazardous environmental properties".

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. Growth inhibition test with regorafenib (BAY 73-4506) on green algae (Desmodesmus subspicatus). Nonclinical Drug Safety, Bayer Pharma AG, study no. T102316-3, report no. PH-39194 (2016)

3. Reproduction study of regorafenib (BAY 73-4506) in Daphnia magna. Nonclinical Drug Safety, Bayer Pharma AG, study no. T102349-7, report no. PH-37250 (2013)

4. Early-Life-Stage-Test Fish with regorafenib (BAY 73-4506). Nonclinical Drug Safety, Bayer Pharma AG, study no. T100932-5, report no. PH-38249 (2014)

5. Respiration inhibition test of regorafenib (BAY 73-4506) on activated sludge micro-organisms. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT8081559, report no. A51602 (2011)

6. Study on the biodegradability of Regorafenib (BAY 73-4506) in the manometric respiration test. Nonclinical Drug Safety, Bayer Schering Pharma AG, study no. TOXT3082139, report no. A51400 (2011)

7. Aquatic-sediment study (aerobic) with regorafenib [BAY 73-4506(14-C)]. Nonclinical Drug Safety, Bayer HealthCare AG, study no. TOXT1082461, report no. A53445 (2012)

8. Bioconcentration flow-through fish test with regorafenib [BAY73-4506(14-C)]. Nonclinical Drug Safety, Bayer HealthCare AG, study no. TOXT9082937, report no. A57715 (2012)

9. Regorafenib / BAY 73-4506 / Report on Physicochemical Properties / Partition Coefficient Octanol-Water (HPLC Method). Nonclinical Drug Safety, Bayer HealthCare AG, study no. 10100058, report no. A49999 (2010)