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Classification

Introduction

The environmental classification of pharmaceutical substances contains two parts: environmental hazard (hazard) and environmental risk (risk). When using the classification, consideration should be given to both hazard and risk. In the case of environmental risk assessments of pharmaceuticals, other information should also be considered as far as possible, for example, purification in wastewater treatment plants, measured levels in water and fish, changes in aquatic organisms and risk of resistance to antibiotics.

Hazard

Environmental hazard expresses the inherent, environmentally harmful characteristics of the pharmaceutical substance, such as resistance to degradation (P = persistence), ability to accumulate in adipose tissue (B = bioaccumulation), and its toxicity to aquatic organisms (T = toxicity).

Each characteristic is assigned a numerical value, 0–3. The sum of the values constitutes the hazard score (formerly referred to as the PBT index, see below under the heading “Hazard score"). The hazard score can assume values in the range 0–9. The higher the value, the greater the substance's danger to the environment.

Environmental classification is made by Stockholm County Council and is based on data from pharmaceutical companies [1]. For newly approved pharmaceutical products, such information may be obtained from the European Public Assessment Report (EPAR) by the European Medicines Agency (EMA) [2].

Risk

The risk relates to the likelihood of toxic effects on aquatic organisms, i.e. a comparison between exposure and toxicity. Exposure can either be based on the current use of a pharmaceutical substance or on the expected use for a newly registered pharmaceutical. The risk depends on how much of a pharmaceutical we use and how much reaches nature. An increased or decreased use of a pharmaceutical could mean a change in risk. The risk can be stated as:

  • Insignificant
  • Low
  • Moderate
  • High
  • Cannot be excluded
  • See the document
  • Exempt.

In the case, See the document, the risk assessment may have been carried out by the environmental consulting firm Goodpoint AB in cooperation with Joakim Larsson, Professor of Environmental Pharmacology [3], and the risk deviated from that indicated by the pharmaceutical companies on Fass.se.

The use of certain pharmaceuticals, products containing vitamins, electrolytes, amino acids, peptides, proteins, carbohydrates, lipids, vaccines and herbal medicinal products, that are not expected to have an environmental impact according to the European Medicines Agency scientific committee’s (CHMP) guidelines [4] are not classified. For the risk assessment, Exempt is given.

Environmental risk assessments from Fass.se are conducted by the association for the research based pharmaceutical Industry in Sweden (Lif) according to a model developed in cooperation with Stockholm County Council, Apoteket AB, the Swedish Medical Products Agency and the Swedish Association of Local Authorities and Regions (SKL). The environmental information on Fass.se is updated every three years and documents for new pharmaceuticals and pharmaceuticals that previously lacked environmental documents are added [5]. It is voluntary for manufacturers to provide information on the environmental impact on Fass.se. Full environmental information is missing for many drugs on Fass.se.

Hazard – description of the classification process

The assessment of the hazard of pharmacologically active substances is based on the characteristics:

Persistence – ability to resist degradation in the aquatic environment.

Bioaccumulation – accumulation in adipose tissue of aquatic organisms.

Toxicity – the potential to poison aquatic organisms.

Persistence is based on criteria for degradability according to OECD Test Guidelines (Test 301, 308) or other similar degradability tests [4]. For pharmaceuticals that have environmental information in EPAR [2], the assessment of persistence is taken from there. For pharmaceuticals that lack EPAR, we use information from Fass [6].

Bioaccumulation is assessed on the partition coefficient (n-octanol/water), usually reported as log Kow (also log Pow) where substances with log Kow ≥ 4.5 are assessed as having a high potential for bioaccumulation (OECD test 107 or 117) [4]. However, there is a gray area between log Kow 3.0 and 4.5 [6,7,8]. If bioaccumulative simulation or test data are available, these can be reported as an alternative. If the partition coefficient (n-octanol/water) indicates that the substance has the potential to bioaccumulate, the bioconcentration factor (BCF) should be determined. “BCF is measured as the concentration in the organism relative to the concentration in water under steady-state conditions and/or estimated from the uptake rate constant and the elimination rate constant” [7]. Different regulations specify different thresholds for BCF. The CLP Regulation states that a substance has a high potential for bioaccumulation when BCF ≥ 500 L/kg [7]. According to the REACH Regulation, a substance fulfills the criterion for bioaccumulation when BCF is > 2,000 L/kg [9]. In case of uncertainty about the interpretation of data, an expert assessment is made.

Acute toxicity for aquatic organisms is assessed based on the results of toxicity tests on species from three different trophic levels in the food chain: algae, crustaceans and fish (OECD Test Guidelines 201, 202 and 203, or equivalent). Data for the most sensitive organism is used in the assessment, which is divided into four categories [10,11] as follows:

Classification of acute toxicity

LC/EC/IC50

<1 mg/L

Very high toxicity

LC/EC/IC50

1–< 10 mg/L

High toxicity

LC/EC/IC50

10–100 mg/L

Moderate toxicity

LC/EC/IC50

>100 mg/L

Low toxicity

Since more and more pharmaceuticals, not least newly approved, now have information on chronic toxicity (OECD Test Guidelines 201, 210 and 211) a classification has been made according to the European Chemicals Guidelines [7,12], taking into account data for the most sensitive organism used for assessment:

Classification of chronic toxicity

NOEC/EC10

<0.01 mg/L

Very high toxicity

NOEC/EC10

0.01–< 0.1 mg/L

High toxicity

NOEC/EC10

0.1–1 mg/L

Moderate toxicity

NOEC/EC10

>1 mg/L

Low toxicity

Blue-green algae (Cyanophyta) are recommended for effects testing of antimicrobials by the European Medicines Agency, EMA [4].

The environmental assessment document for each pharmaceutical in the database shows if T refers to acute or chronic toxicity in the hazard score.

Criteria for substances with especially hazardous properties, PBT-/vPvB (Persistent, Bioaccumulative and Toxic/very Persistent and very Bioaccumulative) substances, see reference [13].

Lack of Data

If data is missing entirely for one of the three characteristics persistence, bioaccumulation or toxicity, the missing characteristic is classified as below, referring to the the precautionary principle (Environmental Code 2 chap. 3) [14].

If persistence data is missing, the active substance is classified as potentially persistent.

If bioaccumulation data is missing, the active substance is classified as having a high potential for bioaccumulation.

If toxicity data is not available, the active substance is expected to have very high toxicity. If toxicity data is missing for one or two trophic levels, the available data is recalculated with a security factor as follows:

  • Toxicity data where one trophic level is missing, is recalculated by a factor of 2.
  • Toxicity data where two levels are missing, is recalculated by a factor of 5.

For those antibiotics lacking data on toxicity for blue-green algae (Cyanophyta) tests when such tests were appropriate based on mechanism of action, toxicity is indicated as very high.

Hazard score

Hazard score was referred to as the previous PBT index. In view of the existence of PBT/vPvB substances according to the European Regulatory Regulations [13], we have chosen to rename PBT index to hazard score.

The hazard score may vary between 0 and 9, and expresses the inherent environmentally damaging characteristics of the active substance. Successively, underlying data to P, B and T will be added to the substance documents because the hazard score is a rough measure. For example, when comparing two substances with the same hazard score, there may be a reason to compare the underlying data in more detail, in addition to other available information in environmental assessments. Since substances with incomplete data can get a higher score (see Lack of data), the hazard score also include a compensation for missing data. In these cases, the score is marked with a * (asterisk).

The hazard score is obtained by summarizing the following numerical values for the active substance based on the assessment criteria listed above:

Persistence

Is degraded slowly or is potentially persistent

3

Is degraded

0

Bioaccumulation

Has high potential for bioaccumulation

3

Has low potential for bioaccumulation

0

Toxicity

Very high toxicity

3

High toxicity

2

Moderate toxicity

1

Low toxicity

0

An active substance that is easily degradable, does not have the potential to bioaccumulate and has low toxicity obtains the score 0. A substance that is persistent, is potentially bioaccumulative and has very high toxicity, achieves the score 9.

Hazard can exists if the active substance is accumulated in water by persistence or if it is concentrated in biota (biological material) by bioaccumulation. Hazard can also exist if the active substance through toxicity, especially in combination with persistence and/or bioaccumulation, poses a risk of harmful effects in the environment.

For substances that, according to the European Regulatory Regulations, have been assessed to have particularly hazardous properties (PBT/vPvB substance), we indicate this in the environmental assessment document.

The model of hazard was drawn up in 2003 by Stockholm County Council and Apoteket AB. Information about persistence, bioaccumulation and toxicity has been collected since 2006 from Fass.se, but in recent years we also take such information from other sources, such as EPAR [2] and scientific publications.

Environmental risk assessment

Environmental risk refers to toxic risk to the aquatic environment. It is based on the ratio of expected concentration of the pharmaceutical in Swedish waterscapes when used to the present extent or the expected use for newly registered pharmaceuticals in Europe (PEC, Predicted Environmental Concentration) and the concentration expected to be harmless to aquatic animals and plants (PNEC, Predicted No Effect Concentration) [4,5,11].

The risk is stated as follows:

Risk classification

Insignificant

if PEC/PNEC

≤0,1

Low

if PEC/PNEC

>0,1–≤1

Moderate

if PEC/PNEC

>1–≤10

High

if PEC/PNEC

>10

Risk information is retrieved from Fass.se or EPAR.

Environmental risk for those antibiotics that have not been toxicity tested on cyanobacteria (blue-green algae), although the mechanism of action means that tests on cyanobacteria are appropriate, are assessed as Cannot be excluded.

In recent years, risk assessments have been carried out based on measured levels in the environment of several pharmaceuticals [3]. Such information is then presented in the document text for each substance and is an important complement to the theoretical risk assessments from Fass.se or EPAR.

Lack of Data

If there is insufficient ecotoxicity data to calculate PEC/PNEC, we indicate for the active substance that environmental risk Cannot be excluded. If the risk assessment from Fass.se or EPAR differs from that based on measured levels in the environment and toxic effects [3], we refer to the document text, i.e., See the document.

References

  1. Läkemedelsindustriföreningen (Lif). Fass. Environmental information.
  2. European Medicines Agency (EMA). European public assessment reports (EPAR).
  3. Prioritering av läkemedel med miljörisk inom SLL. Stockholm: Goodpoint; 2016. Rapport LS 2016–0634.
  4. European Medicines Agency, EMA: Committee for Medicinal Products for Human Use (CHMP). Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006.
  5. Läkemedelsindustriföreningen (Lif). Läkemedel och miljö.
  6. Läkemedelsindustriföreningen (Lif). Environmental classification of pharmaceuticals at www.fass.se. Guidance for pharmaceutical companies 2012.
  7. ECHA (European Chemicals Agency). Guidance on the Application of the CLP Criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. Version 5.0 July 2017.
  8. Birger Scholz, Swedish Medical Products Agency, email 2018-06-21
  9. Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC.
  10. Wennmalm Å, Gunnarsson B. Public health care management of water pollution with pharmaceuticals: Environmental classification and analysis of pharmaceutical residues in sewage water. Drug Information Journal. 2005;39:291–297.
  11. Gunnarsson B, Wennmalm Å. Mitigation of the pharmaceutical outlet into the environment – Experience from Sweden. In: Kümmer K, editor. Pharmacueticals in the environment. 3 ed. Berlin Heidelberg: Springer-Verlag; 2008. p. 475–487.
  12. ECHA (European Chemicals Agency). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.11: PBT/vPvB assessment. Version 3.0 June 2017.
  13. Institute for Health and Consumer Protection. European Chemical Bureau. Technical Guidance Document on Risk Assessment in support of Commission Directive 93/67/EEC on Risk assessment for new notified substances. Commission Regulation (EC) No 1488/94 on Risk assessment for existing substances. Directive 98/8/EC of the European Parliament and of the Council concerning the placing of biocidal products on the market. Part II. EUR 20418 EN/2. 2003.
  14. Sveriges Riksdag. Svensk författningssamling. Miljöbalk (SFS 1998:808).

Senast ändrad 2019-07-23