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 = 0,0000337 µg/L

Where:

A = 0,246 kg (total sold amount API in Sweden year 2023, data from IQVIA)

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)(Ref 1)

D = factor of dilution of waste water by surface water flow = 10 (ECHA default)(Ref 1)

(Note: The factor 10⁹ converts the quantity used from kg to μg).

Predicted No Effect Concentration (PNEC)

(Note: Whilst vandetanib is metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100 % of excreted metabolites have the same ecotoxicity as parent vandetanib).

Metabolism

After oral administration 69 % of vandetanib was excreted either as parent compound or metabolites. Approximately 44 % was excreted via faeces and 25 % via urine (Ref 2).

Ecotoxicological studies

Endpoint	Species	Common Name	Method	Time	Result	Reference
EC50 - Based on Growth Rate	Pseudo-kirchneriella subcapitata	Green Algae	OECD 201	72 h	0.30 mg/L Note 1	3
NOEC - Based on Growth Rate					0.11 mg/L Note 1
EC50 - Based on Immobilisation	Daphnia magna	Giant Water Flea	OECD 202	48 h	2.6 mg/L Note 4	4
NOEC - Based on Immobilisation					0.10 mg/L Note 4
EC50 - Based on Reproduction & Length	Daphnia magna	Giant Water Flea	OECD 211	21 d	>0.61 mg/L Note 1	5
NOEC - Based on Reproduction & Length					0.30 mg/L Note 1
LOEC - Based on Reproduction & Length					0.61 mg/L Note 1
NOEC - Based on Overall Endpoints Note 5	Chironomus riparius	Midge	OECD 218	28 d	100 mg/kg sediment (dry weight) Note 3	6
LOEC - Based on Overall Endpoints Note 5					100 mg/kg sediment (dry weight) Note 3
LC50	Oncorhynchus mykiss	Rainbow Trout	OECD 203	96 h	4.1 mg/L Note 4	7
NOEC - Based on Mortality					2.5 mg/L Note 4
NOEC - Based on Overall Endpoints	Pimephales promelas	Fathead Minnow	OECD 210	32 d	0.010 mg/L Note 4	8
LOEC - Based on Overall Endpoints					>0.010 mg/L Note 4
EC50 - Based on Activated Sludge Respiration Inhibition	-	-	OECD 209	3 h	>100 mg/L Note 3	9
NOEC - Based on Activated Sludge Respiration Inhibition					10 mg/L Note 3

Long term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on results from the assessment of the most sensitive species, fathead minnow (Pimephales promelas), NOEC = 10 µg/L and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref.  10).

PNEC = 10/10 μg/L = 1.0 μg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0000337 μg/L / 1.0 μg/L = 0.0000337 i.e. PEC/PNEC < 0.1 which justifies the phrase “Use of vandetanib has been considered to result in insignificant environmental risk”.

Environmental Fate Data

Endpoint	Method	Test Substance Concentration	Time	Result	Reference
Percentage Biodegradation	OECD 301F	10 mg/L Note 3	28 d	<5 %	11
Soil Dissipation Rate	OECD 307	Sandy Loam Soil	119 d	Bound rapidly to soil, no degradation observed	12
		Clay Soil	119 d	Bound rapidly to soil, no degradation observed
Percentage Mineralisation	OECD 308	HOM sediment (aerobic system)	98 d	<1 %	13
		LOM sediment (aerobic system)		<1 %
		HOM sediment (anaerobic system)		<1 %
		LOM sediment (anaerobic system)		<1 %
Dissipation Half lives from water*		HOM and LOM sediment (aerobic system)	-	<11 days
		HOM and LOM sediment (anaerobic system)	-	<11 days
Sewage Adsorption Coefficient	OPPTS 835.1110	0.250 mg/L	-	Kd = 8400	14

HOM = High Organic Matter, LOM = Low Organic Matter

*Only a small % of the Applied Radioactivity could be extracted from the sediment. Not possible to determine total system half-life.

Biodegradation

Vandetanib is not readily biodegradable in accordance to the OECD 301F. There is evidence that the substance will strongly bind to sludge and sediment in the aquatic environment.

In the OECD 308 study, radiolabeled test substance was dosed into the overlying water and the subsequent dissipation from the water phase, and partitioning and/or degradation in the sediment, phase was observed over a 98 day test period. Aerobic and anaerobic test systems containing water and sediment differing in organic carbon content were used in the study. Evidence from the study shows that vandetanib is likely to rapidly dissipate from the aqueous phase and partition into the solid phase in both aerobic and anaerobic systems. By Day 11, in both high organic matter (HOM) and low organic matter (LOM) of the aerobic and anaerobic test systems, <2 % of the applied radioactivity (AR) remained in the overlying waters with the rest partitioning into the sediment. Despite extraction using Ethanol, Tetrahydrofuran (THF) and Soluene, only a small proportion of the AR was extractable from the sediment (<17 % aerobic test system; <24 % anaerobic test system). Non extractable residues accounted for >74 % of the AR at Day 98 so it was not possible to establish degradation half-lives in the sediment and the total system, or to determine whether primary degradation had taken place.

No degradation products or extractable metabolites with concentrations of > 10 % of the AR were detected during the study.

No significant mineralization or volatile components were detected throughout the study.

Based on the data above, vandetanib is not predicted to be readily biodegradable during wastewater treatment, and therefore the phrase "Vandetanib is potentially persistent" is assigned.

Physical Chemistry Data

Endpoint	Method	Test Conditions	Result	Reference
Solubility Water	OECD 105	30°C followed by 24 h @ 20°C	≥3200 mg/L @ pH 5 260 mg/L @ pH 7 1.2 mg/L @ pH 9	15
Partition Coefficient Octanol Water	OECD 107	-	LogDow = -0.684 @ pH 3, 20°C LogDow = 2.21 @ pH 7, 20°C LogDow >3.90 @ pH 11, 20°C	16
Percentage Hydrolysis	OECD 111	-	<10 % @ pH 4, 7 & 9, 50°C	17
Hydrolysis Half-life			T½ ≥1 yr (Estimated)
Dissociation Constant	OECD 112	-	pKa = 5.14 (NH Group)	18
Dissociation Constant	Estimated using ACD Software for N with adjoining methyl group	-	pKa = 9.32
Soil Adsorption Coefficient	OECD 121	-	Log Koc = 2.1 @ pH 1.0 Log Koc > 5.0 @ pH 11.5	19

Note 1: Results are expressed as mean measured concentrations

Note 2: The relevant endpoints measured were emergence, survival and growth

Note 3: Results are expressed as nominal concentrations

Note 4: Concentrations were confirmed by analysis, and results expressed as nominal

Bioaccumulation

Log D_ow = < 4 at pH 7.

Vandetanib has no significant bioaccumulation potential, as indicated by the Log D_ow. Therefore the "statement" Vandetanib has low potential for bioaccumulation’ is assigned.

Metabolism

After oral administration 69 % of vandetanib was excreted either as parent compound or metabolites. Approximately 44 % was excreted via faeces and 25 % via urine (Ref 2).

References

1. [ECHA] European Chemicals Agency. February 2016. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0) http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

2. Investigator’s Brochure Vandetanib (Zactima. ZD6474), Section 5 Effects in humans. January 2007.

3. ZD674: Toxicity to the green alga Selenastrum capricornutum.

   Brixham Environmental Laboratory, Report BL7990. Feb 2005.

4. ZD6474: Acute toxicity to Daphnia magna.

   Brixham Environmental Laboratory, Report BL7991. Feb 2005.

5. ZD6474. Chronic Toxicity to Daphnia magna.

   Brixham Environmental Laboratory, Report BL8340. July 2007.

6. [14C]ZD6474: Effects in sediment on emerging midge, Chironomus riparius.

   Brixham Environmental Laboratory, Report BL8389. Dec 2006.

7. ZD6474Acute toxicity to rainbow trout (Oncorhynchus mykiss).

   Brixham Environmental Laboratory, Report BL7992. Feb 2005.

8. ZD6474: Determination of effects of the Early –Life Stage of the fathead minnow (Pimephales promelas). Brixham Environmental Laboratory, Report BL8374. October 2006.

9. ZD6474: Effect on the respiration rate of activated sludge.

   Brixham Environmental Laboratory, Report BL7950. January 2005.

10. ECHA, European Chemicals Agency. May 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

11. ZD6474: Determination of 28 day ready biodegradability.

    Brixham Environmental Laboratory, Report BL8023. Feb 2005.

12. ZD6474: Transformation in soil. Brixham Environmental Laboratory, Report No. BL8676/B. December 2008.

13. ZD6474: Aerobic and anaerobic transformation in aquatic sediment systems. Brixham Environmental Laboratory, Report BL8312. January 2007.

14. ZD6474: Adsorption to Sewage Sludge. Brixham Environmental Laboratory, Report BL8348. April 2007.

15. ZD6474: Water solubility. Brixham Environmental Laboratory, Report BL8075. July 2005.

16. ZD6474: Determination of n-octanol/water partition coefficient. Report No. BL8076/B. Brixham Environmental Laboratory, Brixham, UK. July 2005.

17. ZD6474: Hydrolysis as a function of pH. Brixham Environmental Laboratory, Report BL8077. June 2005.

18. BL8055. ZD6474: Determination of dissociation constants in water.

    Safepharm Laboratories. March 2005.

19. BL7993. ZD6474: Estimation of the adsorption coefficient on soil. (HPLC method).

    Brixham Environmental Laboratory. June 2005.