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Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Esketamin

Miljörisk: Användning av esketamin har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Esketamin är potentiellt persistent.
Bioackumulering: Esketamin har låg potential att bioackumuleras.


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Detaljerad miljöinformation

1. PREDICTED ENVIRONMENTAL CONCENTRATION (PEC):

The Predicted Environmental Concentration is calculated according to the following formula:

PEC (µg/L)

=

A x 109 x (100 - R) / 365 x P x V x D x 100

Where:

A (kg/year)

=

204.5008 kg (total amount API in the sales forecast for Sweden (2020))

R (%)

=

removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)


=

0% (worst-case scenario: no removal)

P

=

number of inhabitants in Sweden (9 x 106)

V (L/day)

=

volume of waste water per capita and day


=

200 (ECHA default) [1]

D

=

factor for dilution of waste water by surface water flow


=

10 (ECHA default) [1]

PEC (µg/L)

=

0.03112645 µg/L


2. PREDICTED NO EFFECT CONCENTRATION (PNEC)

2.1. Ecotoxicological studies

2.1.1. Algae

Algal growth inhibition test with the green alga (Pseudokirchneriella subcapitata) (OECD 201) [2]:

EγC50 72 h (yield) = 48.0 mg/L

NOECγ (yield) = 14.7 mg/L

ErC50 72 h (growth) = - (the values were greater than the highest concentration)

NOECr (growth) = 14.7 mg/L


2.1.2. Crustacean

Acute

Acute toxicity in the water-flea (Daphnia magna) (OECD202) [3]:

EC50 48 h = 106.7 mg/L


Chronic

Reproduction test with water-flea (Daphnia magna) (OECD 211) [4]:

NOEC 21 days = 3.31 mg/L


2.1.3. Fish

Acute

Acute toxicity in fish (Oncorhynchus mykiss) (OECD 203) [5]:

LC50 96 h = 77.5 mg/L


Chronic

Fish early life stage test with Zebrafish (Danio rerio) (OECD 210) [6]:

It is concluded that the NOEC of (S)-Ketamine for fry length and weight was 1.12 and

0.341 mg/L, respectively. Mortality in the 0.341 mg/L group was found to be significantly higher than that seen in the control group. There were no significant differences in mortality in any of the other test-item treated groups compared with the control.

The duration of the test was 30 days, post hatch.


NOEC 30 days (early-life stage development - length) = 1,12 mg/L

NOEC 30 days (early-life stage development - length) = 0,341 mg/L


2.1.4. Other ecotoxicity data

Activated sludge respiration inhibition test (OECD 209) [7]:

EC50 3h = no value was reported because the value was estimated to be greater than 1000 mg/L

NOEC for (S)-Ketamine to activated sludge was estimated to be 100 mg/L.


2.2. Calculation of Predicted No Effect Concentration (PNEC)

PNEC (µg/l) = lowest (NOEC)/10, where 10 is the assessment factor used. NOEC for the Zebrafish (Danio rerio) of 0.341 mg/L has been used for this calculation since it is the most sensitive of the three tested species.


PNEC = 0.341 mg/L/10 = 0.0341 mg/L = 34.1 µg/L


2.3. Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.03112645 /34.1 = 0.000912799 i.e. PEC/PNEC ≤ 0.1


Conclusion for environmental risk:

Use of S-ketamine has been considered to result in insignificant environmental risk.


3. DEGRADATION

3.1. Biotic degradation

3.1.1. Ready biodegradation

Test results in 1.4 % degradation in 28 days (Guideline OECD 301) [8]:

Result: (S)-Ketamine was not biodegradable


3.1.2. Simulation study: Aerobic degradation in aquatic sediment systems:

S-ketamine was investigated for its aerobic degradation in a 100-day aquatic sediment test, according to OECD 308 [9]:


Dissipation and degradation from the surface water, sediment and total system was observed following application of [14C]-S-Ketamine to sand and silt loam sediment-water systems. Kinetic modelling yielded values of 11.4 and 20.4 days, respectively, for dissipation from the sand and silt loam surface waters. Dissipation from the total system yielded DT50 values of 138 days for the sand system and 230 days for the silt loam system.


Kinetic analysis of degradation in the sediment compartment of each system yielded DegT50 values of 252 days for the sand sediment system and 346 days for the silt loam sediment system. These are longer than the calculated DT50 values for the total system, and as the sediment is the major degradation compartment, the overall test system dissipation half-lives of 138 and 230 days may be a better indication of degradation rates in sediment. There is evidence to suggest that degradation occurs by incorporation into sediment organic matter followed by mineralisation to CO2.


The dissipation of S-Ketamine was fitted to single first-order (SFO) and bi-phasic model kinetics using CAKE version 3.1. The kinetic modelling results are summarized in the following table:

Bild 1


For all samples pooled extract was prepared by combining 70% of each of Extracts 1-4 (Extracts 1-3 where appropriate). Duplicate aliquots (1 mL) of the pooled sample were analysed by LSC and 50% of the pooled extract concentrated under nitrogen (TurboVap) until ca 1.0 mL of liquid remained. The concentrate was transferred to a centrifuge tube, the concentration vessel washed/sonicated with Milli-Q water (2 mL) and the wash transferred to the centrifuge tube. This process was repeated with 2 mL of acetonitrile. The centrifuge tube containing the concentrated extract was sonicated for ca 5 minutes, centrifuged at ca 2000 rpm for ca 15 minutes and the supernatant transferred to a 5 mL volumetric flask. Acetonitrile (1 mL) was added to the centrifuge tube and solid residue, sonicated for ca 5 minutes and centrifuged at ca 2000 rpm for ca 15 minutes. The supernatant was transferred to the volumetric flask and the volume adjusted to 5 mL with Milli-Q water. Duplicate aliquots (100 μL) were analysed by LSC to confirm recovery of radioactivity.


Conclusion for degradation:

S-ketamine is potentially persistent.


4. BIOACCUMULATION

4.1. Partition coefficient octanol/water

The partition coefficient octanol/water was determined using OECD Test Guideline 107. [10]


The mean apparent log POW (distribution coefficient at a specific pH) for each n-octanol / aqueous media system was determined as follows:

Milli-RO water: Log D = -0.72 ± 0.06

pH 4 buffer: Log D = -0.72± 0.02

pH 7 buffer: Log D = 1.63 ± 0.22

pH 9 buffer: Log D = 2.06 ± 0.05


The true log POW (partition of non-ionised molecule only) was calculated from the following equation based on a dissociation constant of 7.45 for (S)-Ketamine:

Log Pow= Log D + Log(1+10(pKa-pH))

Milli-RO water: Log POW = 2.66 ± 0.41

pH 4 buffer: Log POW = 2.55 ± 0.04

pH 7 buffer: Log POW = 1.70 ± 0.24

pH 9 buffer: Log POW = 2.08 ± 0.05


Log POW values calculated from the pH 9 buffer test are expected to be most accurate since at this pH (S)-Ketamine was closest to a non-ionised state and therefore the correction calculation was most accurate.


4.2. Bioconcentration

No data available.

Conclusion for bioaccumulation:

S-ketamine has low potential for bioaccumulation.


5. PBT-ASSESSMENT


PBT-criteria

Results for S-ketamine

Persistence

Half-life in freshwater: DT50 > 40 days
Half-life in sediment: DT50 > 120 days

Half-life in sediment: DT50 = 138days (Charles River – Sand sediment)

Half-life in sediment: DT50 = 230 days (Charles River – Silt Loam sediment)

Bioaccumulation

BCF > 2000

No data available.

Toxicity

Chronic NOEC < 10 µg/L

NOEC algae = 14.7 mg/L

NOEC daphnia = 3.31 mg/L

NOEC fish = 0,341 mg/L


Conclusion for PBT-assessment:

S-ketamine contains no components considered to be persistent.


6. 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. Hugill E, Freshwater Alga, Growth Inhibition Test with (S)-Ketamine, Following OECD Guideline #201; Charles River laboratories Edinburgh Ltd No. 224219; JNJ Study No. RMD 1215; July 27, 2016.

  3. Hugill E, (S)-Ketamine: Determination of Acute Toxicity (EC50) to Daphnia magna, Following OECD Guideline #202; Charles River laboratories Edinburgh Ltd No. 224224; JNJ Study No. RMD 1216; July 1, 2016.

  4. Hugill E, (S)-Ketamine: Daphnia Reproduction Test, Following OECD Guideline #211; Charles River laboratories Edinburgh Ltd No. 224250; JNJ Study No. RMD 1218; August 8, 2016.

  5. Hugill E, (S)-Ketamine: Determination of Acute Toxicity (LC50) to Rainbow Trout, Following OECD Guideline #203; Charles River laboratories Edinburgh Ltd No. 224245; JNJ Study No. RMD 1217; July 1, 2016.

  6. Hugill E, Zebrafish, Early Life-Stage Test (Continuous Flow) in (S)-Ketamine, Following OECD Guideline #210; Charles River laboratories Edinburgh Ltd No. 224266; JNJ Study No. RMD 1219; July 26, 2016.

  7. Hugill E, Zebrafish, (S)-Ketamine: Activated Sludge Respiration Inhibition, Following OECD Guideline #209; Charles River laboratories Edinburgh Ltd No. 224203; JNJ Study No. RMD 1214; November 5, 2015.

  8. Hugill E, Determination of Ready Biodegradability of (S)-Ketamine by the CO2Evolution (Modified Sturm) Test, Following OECD Guideline #301; Charles River laboratories Edinburgh Ltd No. 224198; JNJ Study No. RMD 1212; November 5, 2015.

  9. McCorquodale G, The Aerobic Transformation of [14C]-S-Ketamine in Aquatic Sediment Systems, Following OECD Guideline #308; Charles River laboratories Edinburgh Ltd No. 812599; JNJ Study No. RMD 1213; December 8, 2016.

  10. Clipston A S, Determination of Partition Coefficient (n-octanol/water) of (S)-Ketamine, Following OECD Guideline #107; Charles River laboratories Edinburgh Ltd No. 224177; JNJ Study No. RMD 1210; September 23, 2015.