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 = 0.160 µg/L

Where:

A = 1171.180 kg (total sold amount API in Sweden year 2022, 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 I)

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

Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata):

EC₅₀ 72 h (biomass) = >100 000 µg/L

EC₅₀ 72 h (growth rate) = >100 000 µg/L

NOEC = 100 000 µg/L

(OECD 201)
(Ref II)

Crustacean (Daphnia magna):

EC₅₀ 48 h (immobilization) = >100 000 µg/L

NOEC 48 h (immobilization) = >100 000 µg/L

(OECD 202)
(Ref III)

Chronic toxicity crustacean (Daphnia magna)

NOEC, EC₅₀, EC₁₀ 21 d (reproduction) ≥ 8870 µg/L
(OECD 211)

(Ref IV)

Fish (Danio rerio):

LC₅₀ 96 h (lethality) = 66 000 µg/L

(OECD 236)
(Ref V)

Chronic toxicity fish (Danio rerio)
NOEC 30 d (mortality) ≥ 10 200 µg/L
(OECD 210)
(Ref VI)

Other ecotoxicity data:

PNEC = 887 µg/L

The PNEC is calculated with the following formula: lowest EC₁₀ or NOEC/10 (Assessment factor justification: three long-term toxicity endpoints available for three trophic levels: algae, daphnia and fish)

EC₁₀ for Daphnia magna has been used for this calculation since it is the most sensitive of the tested species.

Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC = 0.160 µg/L / 887 µg/L = 0.00018, i.e. PEC/PNEC ≤ 0.1, which justifies the phrase "Use of valproic acid has been considered to result in insignificant environmental risk".

Biodegradation

Ready biodegradability:

Test showed 48 % degradation in 28 days.
(OECD 301)
(Ref VII)

Justification of chosen degradation phrase:

Valproic acid fails to pass the criteria for ready biodegradability. The phrase "Valproic acid is potentially persistent" is thus chosen.

Bioaccumulation

Partition coefficient

Log K_ow = 2.60 at pH 7
(OECD 107)
(Ref VIII)

Justification of chosen bioaccumulation phrase:

Since log K_ow < 4 at pH 7, valproic acid has low potential for bioaccumulation.

Excretion (metabolism)
Most drug is metabolized to glucuronide conjugates (30-50 %) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40 %). The remainder of metabolism (15-20 %) occurs through oxidation, hydroxylation, and dehydrogenation.

Most drug is eliminated through hepatic metabolism, about 30-50 %. The other major contributing pathway is mitochondrial β-oxidation, about 40 %. Other oxidative pathways make up an additional 15-20 %. Less than 3 % is excreted unchanged in the urine.

(Ref IX).

References

1. ECHA, European Chemicals Agency, 2008 Guidance on information requirements and chemical safety assessment . https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

2. Sanofi, Internal Report: Growth inhibition test with Sodium Valproate on Algae (Pseudokirchneriella subcapitata). OECD 201. Report # 11/157-022AL, March 2012.

3. Sanofi, Internal Report:Acute immobilization test with Sodium Valproate on Daphnia (Daphnia magna). OECD 202. Report #11/157-023DA, March 2012

4. ECHA, registration dossier on 2-propylvaleric acid, Long-term toxicity to aquatic invertebrates, Read across on Sodium Valproate. Available on (2021-08-24): https://echa.europa.eu/fr/registration-dossier/-/registered-dossier/14340/6/2/5

5. Sanofi, Internal report: Sodium Valproate: Fish Embryo Acute toxicity (FET) test. OECD 236. Report # 3200886, April 2015

6. ECHA, registration dossier on 2-propylvaleric acid, Long-term toxicity to fish, Read across on Sodium Valproate. Available on (2021-08-24): https://echa.europa.eu/fr/registration-dossier/-/registered-dossier/14340/6/2/5

7. Sanofi, Internal Report: Determination of the ready biodegradability CO2 evolution test. OECD 301B. Report # 32153 ECS, February 2007

8. Henczi, M., Nagy, J., Weaver, D.F., 1995. Determination of Octanol-water Partition Coefficients by an HPLC method for Anticonvulsant Structure-activity studies. Journal of Pharmacy and Pharmacology. 47, 345-347.

9. Drug Bank - Valproic acid - retrieved from drugbank.com 2021-08-24, find here.