Detaljerad miljöinformation

Environmental Risk Assessment (ERA)

Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula (FASS 2021, Ref. I):
PEC (μg/L) = (A x 10⁹ x (100-R)) / (365 x P x V x D x 100)

Where:

A= 18.4298 kg (total sold amount API in Sweden year 2021, data provided by IQVIA).

R = 0 (maximum % removal rate due to loss by adsorption to sludge particles; No data available for unchanged apremilast)

P = number of inhabitants in Sweden = 10 x 10⁶ (SCB Statistics Sweden Ref. II)

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default; Ref. III)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default; Ref. II)

PEC (μg/L) = (18.4298 x 10⁹ x (100-0)) / (365 x 10 x 10⁶ x 200 x 10 x 100)
PEC = 0.0025 μg/L

Predicted No Effect Concentration (PNEC)
Ecotoxicological studies

Algae (Raphidocelis subcapitata) (Guideline OECD 201 study; Ref. IV)

NOEC (72 hours; inhibition of growth rate): 3.5 x 10³ µg/L

Crustacean (Daphnia magna) (Guideline OECD 211 study; Ref. V)

Chronic toxicity

NOEC (21 days; mortalities, length and reproduction): 6.3 x 10³ µg/L

Fish (Pimephales promelas) (Guideline OECD 210 study; Ref. VI)

Chronic toxicity

NOEC (28 days post-hatch; hatching success, survival, growth): 7.2 x 10³ µg/L

Environmental risk classification (PEC/PNEC ratio)

The most sensitive species was algae (NOEC 3.5 x 10³ µg/L). As three long-term toxicity tests were conducted, an assessment factor of 10 is appropriate.

PNEC = 3.5 x 10³ µg/L / 10 = 3.5 x 10² µg/L

PEC/PNEC = 0.0025 µg/L/350 = 7 x 10^-6

Degradation

• Biotic degradation: (Ready degradability) (Guideline OECD 301B study; Ref. VII)
  There was no significant biodegradation of apremilast. Therefore, apremilast was considered not to be readily biodegradable.

• Transformation in freshwater sediment (Guideline OECD 308 study; Ref. VIII)
  The fate of [¹⁴C]-apremilast was investigated up to 62 days under aerobic conditions after application in two freshwater sediment systems (Swiss Lake (SL) and Schoonrewoerdsewiel (SCH)).
  
  Most of the radioactivity remained in the aqueous phase (72% in SL at 62 days; 56.1% in SCH at 62 days). Sediments were extracted five times with acidified aqueous acetonitrile to leave non-extractable residues at 62 days of 4.9% (SL) and 17.2% (SCH).
  
  In both aquatic systems apremilast was extensively metabolised such that unchanged apremilast accounted for <1% of the applied radioactivity in both aqueous and sediment phases at 62 days. Two major metabolites (M1 and M2) were detected. The identification of these two metabolites is ongoing.
  
  In SL, M1 increased in the water to 55.5% at 62 days but was only present in sediment at 6.2%. In water, M2 reached a maximum of 36.8% at Day 7 but in sediment was ≤1.5% at all sampling times.
  
  In the SCH, M1 was in the range 44% to 49% from Day 4 to Day 62. In sediment M1 reached a maximum of 16.6% at 28 days. In water, M2 reached a maximum of 34.4% at 7 days. In sediment, M2 was ≤3.3% at all sampling times.
  
  The decline (half-life) of apremilast, M1 and M2 (fitted simultaneously) are shown in the Table below. The study data have been extrapolated from the study temperature of 20°C to 12°C using the Arrhenius equation with a conversion factor of 2.123.

Table. The decline (half-life) of apremilast

Compartment	Swiss Lake	Schoonrewoerdsewiel
	DT50 (days)	DT50 (days)
Apremilast
Water	3.2	1.3
Sediment
Total system	4.0	1.5
M1
Total system	>2123	>2123
M2
Total system	73.5	78.3

Hydrolysis:

Not determined

Justification of chosen degradation phrase

Degradation was determined in two freshwater sediment systems. The parent, apremilast is degraded rapidly in the environment. However, the half-lives of apremilast and metabolites M1 and M2 in the total systems were > 120 days. Therefore, the phrase ‘degraded in the environment’ should be used.

Bioaccumulation

Since the log₁₀Pow at pH 7 was 1.77 ± 0.04, apremilast has a low potential for bioaccumulation (log₁₀Pow < 4).

Excretion (metabolism) (Investigator’s Brochure; Ref IX)

Following dosing in healthy humans with [¹⁴C]-apremilast, 90% of the radioactive dose was recovered as up to 23 metabolites. Apremilast was primarily eliminated as metabolites formed via both CYP-mediated oxidative metabolism (and subsequent glucuronidation) and non-CYP-mediated hydrolysis, with less than 3% excreted unchanged in urine. A pharmacologically inactive glucuronide conjugate of O- demethylated apremilast was the major circulating metabolite and its urinary excretion represented approximately 34% of the total administered dose. Other minor metabolic routes included O-deethylation, N-deacetylation, hydroxylation (oxidative), hydrolysis of the imide ring, and a combination of these pathways. The O- demethylated and O-deethylated metabolites in the plasma and urine were predominantly glucuronide conjugates.

PBT/vPvB ASSESSMENT

Apremilast does not fulfil the criteria to be classified as PBT or vPvB.

REFERENCES

1. FASS, (2021). Environmental classification of pharmaceuticals at www.fass.se– Guidance for pharmaceutical companies 2012 v 3.0.

2. SCB Statistics Sweden Population Statistics. February 2022.

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

4. Migchielsen MHJ (2012a). Fresh water algal growth inhibition test with apremilast. NOTOX Project No. 498810.

5. Migchielsen MHJ (2012b). Daphnia magna, reproduction test with apremilast (flow-through). NOTOX Project No. 498809.

6. Migchielsen MHJ (2012c). Fish early-life stage toxicity test with apremilast (flow-through). NOTOX Project No. 498811.

7. Desmares-Koopmans MJE (2012a). Determination of “ready” biodegradability: carbon dioxide(CO2) evolution test (modified Sturm test) of apremilast. NOTOX Project No. 498812.

8. Brands CMJ (2013b). Aerobic degradation of apremilast in two water/sediment systems. WIL Research Project No. 500300.

9. Investigator’s Brochure Amgen Inc. Apremilast Edition: 23.0. Date: 07 May 2020.