Detaljerad miljöinformation

Physical properties

Solubility at pH 7: 5 430 000 µg/L⁴

pKa: 8.13 for the azalide ring and 9.82 for the desosamine nitrogen⁵

Vapor pressure: < 1 x 10^-7 mmHg

Molecular weight: 785 Da

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 = 0.0095 μg/L

Where:

A =	69.34 kg (total sold amount API in Sweden year 2020, data from IQVIA)3.
R =	0 % removal rate (worst-case scenario)
P =	number of inhabitants in Sweden = 10 * 106
V (L/day) =	wastewater volume per capita and day = 200 (ECHA default)1
D =	factor for wastewater dilution by surface water flow = 10 (ECHA default)1

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Microbial growth inhibition (guideline FDA 4.02)⁶

Aspergillus niger minimal inhibitory concentration = >1000 000 μg/L

Trichoderma viride minimal inhibitory concentration = >1000 000 μg/L

Clostridium perfringens minimal inhibitory concentration = 2 000 μg/L

Bacillus subtilis minimal inhibitory concentration = 2 000 μg/L

Nostoc sp. minimal inhibitory concentration = 400 μg/L

Activated sludge microorgansims (guideline OECD 209)⁷

EC₁₀ (respiration inhibition) = 1890 μg/L

EC₅₀ (respiration inhibition) = 269 000 μg/L

Green alga (Pseudokirchneriella subcapitata) (guideline OECD 201)⁸

NOEC 72 h (growth rate, acute toxicity) = 1.8 μg/L

EC₅₀ 72 h (growth rate, acute toxicity) = 8.4 μg/L

Blue-green alga (Microcystis aeruginosa) (guideline OECD 201)⁹

NOEC 72 h (growth rate, acute toxicity) = 0.19 μg/L

EC₅₀ 72 h (growth rate, acute toxicity) = 1.8 μg/L

NOEC 96 h (cell density, acute toxicity) = 0.19 μg/L

EC₅₀ 96 h (cell density, acute toxicity) = 0.68 μg/L

Daphnids (Daphnia magna) (guideline OECD 202)¹⁰

NOEC 48 hours (immobilization, acute toxicity) = 19 000 μg/L

EC₅₀ 48 hours (immobilization, acute toxicity) = 120 000 μg/L

Daphnids (Ceriodaphnia dubia) (guideline EPA 1002.0)¹¹

NOEC 7 days (reproduction, chronic toxicity) = 4.4 μg/L

LOEC 7 days (reproduction, chronic toxicity) = 15 μg/L

EC₅₀ 7 days (survival, chronic toxicity) = >1400 μg/L

Rainbow trout (Oncorhynchus mykiss) (guideline OECD 203)¹²

NOEC 96 hours (mortality, acute toxicity) = 84 000 μg/L

LC₅₀ 96 hours (mortality, acute toxicity) = > 84 000 μg/L

Fathead Minnow (Pimephales promelas) (guideline OECD 210)¹³

NOEC 32 days (early life stage, chronic toxicity) = 4600 μg/L

LOEC 32 days (early life stage, chronic toxicity) = >4600 μg/L

Based on the lowest NOEC for the species Microcystis aeruginosa and using the assessment factor² of 10, the PNEC is calculated to 0.19/10 = 0.019 µg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0095/0.019 = 0.50, i.e. PEC/PNEC ≤ 1 which justifies the phrase ”Use of azithromycin has been considered to result in low environmental risk.”

Adsorption (guideline OECD 106)¹⁴

Solid	Kd (L/Kg)	Koc (L/Kg)
Activated sludge (dewatered cationic polymer)	14.5-29.1	55.8-112
Activated sludge (not dewatered cationic polymer)	59.6-59.8	378-379
2.7% organic matter soil (California clay) – Aqueous phase 0.01 M CaCl2	948	59 600
2.7% organic matter soil (California clay) – Aqueous phase distilled, deionized water	585	36 800
2.7% organic matter soil (Kansas silt loam) – Aqueous phase 0.01 M CaCl2	660	41 500
2.7% organic matter soil (Kansas silt loam) – Aqueous phase distilled, deionized water	362	22 800
1.9% organic matter soil (Texas silt loam) – Aqueous phase 0.01 M CaCl2	526	47 100
1.9% organic matter soil (Texas silt loam) – Aqueous phase distilled, deionized water	444	39 600

HOM = high organic matter, LOM = low organic matter

Degradation

Biotic degradation

Ready degradability (guideline OECD 301D)⁷

18.8% degradation after 28 days. Azithromycin is therefore considered to be not readily biodegradable.

Water-sediment transformation simulation (guideline OECD 308)¹⁴

Length of study: 102 days

High organic sediment system: Turkey creek

Low organic sediment system: Choptank river

Sediment extraction solvent: Acetonitrile

Supplemental extraction solvents: Methyl alcohol and 10% methyl alcohol : 90% dichloromethane (v/v)

The results from the study are shown in the table below.

Data on day 102 at 20 °C	Turkey Creek		Choptank River
Total system
Half-life (days)	20.8	22.0
Total 14CO2 (% of AR)	0.5	0.3
Aerobic Water Layer
Extractables (% of AR)	4.8	5.1
Sediment Layer
Bound/NER (% of AR)	91.7	82.8
Extractables (% of AR)	2.6	6.5

ND = not detected, NER = non-extractable residues, AR = applied radioactivity

Justification of chosen degradation phrase

The DT₅₀ value (water-sediment transformation simulation, OECD 308) was calculated to 22 days, corresponding to the degradation phrase ”Azithromycin is degraded in the environment.”

Bioaccumulation

Partitioning coefficient (guideline OECD 107)¹⁵

pH	Log Kow
5	0.14
7	0.48
9	1.56

Justification of chosen bioaccumulation phrase

Since log D_ow < 4 at pH 7, azithromycin has low potential for bioaccumulation.

References

1. ECHA, European Chemicals Agency. 2016 Guidance on information requirements and chemical safety assessment chapter R16.

2. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment chapter R10.

3. IQVIA KG Consumption 2020 report.

4. Study report 2438.6151: Azithromycin – Determination of the Water Solubility Following FDA TAD 3.01. August 1991.

5. Study report 2438.6153: Azithromycin – Determination f the Dissociation Constant Following FDA TAD 3.04. September 1991

6. Study report 2438.6155: Azithromycin – Determination of microbial growth inhibition. FDA TAD 4.02. July 1991.

7. Study report 2438.6159: Azithromycin – Ready biodegradability by the closed bottle method. September 1991.

8. Study report 2438.6338: Azithromycin (CP-62,993-3) – Acute toxicity to the freshwater green alga (Pseudokirchneriella subcapitata). Aug 2004.

9. Study report 2438.6421: Azithromycin (CP-62,993-3) – Acute toxicity to the freshwater blue‑green alga, Microcystis aeruginosa. October 2005.

10. Study report 2438.6158.: Azithromycin – Acute toxicity to daphnids (Daphnia magna) under static conditions. July 1991.

11. Study report 2438.6419: Azithromycin (CP-62,993-3) – The life cycle toxicity test with daphnids, Ceriodaphnia dubia, under static renewl conditions. Aug 2004.

12. Study report 2438.6339: Azithromycin (CP-62,993-3) – Acute toxicity to rainbow trout (Oncorhynchus mykiss) under static conditions. November 2002.

13. Study report 2438.6420: Azithromycin (CP-62,993-3) – Early life-stage toxicity test with fathead minnow (Pimephales promelas). August 2004.

14. Study report 2438.6154: Azithromycin – Determination of the sorption and desorption properties following FDA technical assistance document 3.08. August 1991.

15. Study report 260E-134: Azithromycin: Aerobic and anaerobic transformation in aquatic sediment systems. September 2005.

16. Study report 2468.6152: Azithromycin – Determination of the n-octanol/water partition coefficient following FDA technical assistance document 3.02. August 1991.