Classification
Introduction
The environmental classification of human pharmaceuticals on Janusinfo consists of two components:
- Environmental hazard (hazard): This refers to the environmentally harmful properties of a substance—its persistence (P: ability to resist degradation), bioaccumulation (B: ability to accumulate in fatty tissue), and toxicity (T: toxicity to aquatic organisms).
- Environmental risk (risk): This refers to the likelihood of toxic effects on aquatic organisms, i.e., a comparison between exposure and toxicity. The environmental risk is assessed in relation to the use of a pharmaceutical. Currently, no data are available regarding environmental risk during the manufacturing phase.
When using the classification, both environmental hazard and environmental risk should be taken into account. In environmental risk assessments of pharmaceuticals, additional information should also be considered when available—for example, removal efficiency in wastewater treatment plants, occurrence in water and fish, observed effects in aquatic organisms, and the risk of antibiotic resistance development.
The environmental criteria of the knowledge support in relation to EMA’s regulatory framework
The knowledge support Pharmaceuticals and Environment uses the term environmental hazard with classifications to describe individual properties of substances. However, this differs from the regulatory context outlined in the Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (EMEA/CHMP/SWP/4447/00 Rev. 1 [1]). Within the regulatory framework, there are no formal classifications for the individual criteria P/vP (v = very), B/vB, or T. Only the combination of these criteria leads to a formal environmental hazard classification—namely, PBT (Persistent, Bioaccumulative and Toxic) or vPvB (very Persistent and very Bioaccumulative). Similarly, being identified as an endocrine-active substance (EAS) does not constitute a formal environmental classification, but rather a technical note that may influence the environmental risk assessment (ERA). The knowledge support Pharmaceuticals and Environment applies its own environmental criteria, which differ from the formal ERA system used by EMA/CHMP, and therefore cannot be directly applied in regulatory authorisation processes.
Data sources for the knowledge support Pharmaceuticals and Environment
The knowledge support Pharmaceuticals and Environment presents environmental information for each active substance based on a worst-case scenario. The data in the database are sourced from three main origins:
- Environmental information (Environmental Risk Assessment: ERA) from the European Medicines Agency’s (EMA) assessment reports (European Public Assessment Report: EPAR) [2]
- Environmental information from fass.se (LIF: the trade association for the research-based pharmaceutical industry in Sweden) [3]
- Environmental risk assessments for certain substances based on concentrations measured in the Swedish environment and effect studies.
As noted in point 3 above, for some substances, risk assessments have been conducted using concentrations measured in the Swedish environment and effect studies considered to be of high quality (see example in [4]). The PEC (Predicted Environmental Concentration) values used for risk calculations in the environmental information on fass.se are based on the total sales of an active substance in Sweden during a given year. In contrast, the PEC values used in manufacturers’ assessment reports are based on the estimated use of the specific medicinal product under evaluation, plus potentially other products from the same company—not all products containing the same active substance [1]. In general, we accept the hazard and risk assessments provided by EMA and LIF, but we are aware that shortcomings in the submitted data have been noted [5,6,7].
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).
Data on persistence, bioaccumulation, and toxicity are described in the text for each active substance. Previously, each property was assigned a numerical value from 0 to 3. The sum of the P, B, and T values for a substance constituted the hazard score (formerly referred to as the PBT index; see section “Previous Hazard Score” below). The hazard score could therefore range from 0 to 9. The higher the score, the greater the environmental hazard of the substance. Work is currently underway to phase out the use of the hazard score.
Risk
Risk refers to the likelihood of toxic effects on aquatic organisms, that is, a comparison between exposure and toxicity (Phase IIA environmental study). According to the new, updated and more comprehensive environmental risk assessment guidelines from 2024, if a pharmaceutical substance exceeds certain threshold values, a risk assessment should also be conducted for soil, groundwater, and/or secondary poisoning [4].
Exposure can be estimated either based on the current use of a pharmaceutical or on the expected use of a newly registered medicinal product. Thus, the risk depends on how much of the pharmaceutical is used and reaches the environment. An increase or decrease in usage could therefore lead to a change in risk. The risk can be stated as:
- Insignificant
- Low
- Moderate
- High
- Cannot be excluded
- Exempt.
The use of certain pharmaceuticals within the categories of vitamins, electrolytes, amino acids, peptides, proteins, carbohydrates, and lipids is generally not considered to pose an environmental risk. In such cases, the environmental risk assessment (ERA) may consist of a justification for not submitting ERA studies [1]. Vaccines without adjuvants are also unlikely to pose an environmental risk. However, adjuvants present in vaccines may require additional justification for the absence of ERA studies. If an approved justification is provided, the substance is marked as “exempt” in the database. Nevertheless, some researchers argue that environmental risk assessments should not be based solely on the natural origin of the products, and that the categorical exclusion of such pharmaceuticals in the European Medicines Agency’s scientific committee (CHMP) guidelines is problematic [8].
Environmental risk assessments on fass.se are presented per medicinal product, not per active substance, similar to the environmental information in the assessment reports published on EMA’s website. The environmental information on fass.se is updated every three years, and new documents are added for new substances or for substances previously lacking environmental documentation [9]. However, complete environmental information is still missing for many pharmaceuticals listed on fass.se.
Description of the classification process in more detail
Hazard
The assessment of the hazard of pharmacologically active substances is based on the characteristics:
Persistence – ability to resist degradation.
Bioaccumulation – accumulation in adipose tissue of aquatic organisms.
Toxicity – the potential to poison aquatic organisms.
Persistence is assessed based on criteria for ready biodegradability according to OECD Test Guideline 301 [1].
Bioaccumulation is assessed using the n-octanol/water partition coefficient, typically reported as log Kow (OECD Test 107 or 123), or log Dow. If log Kow ≥ 3—the threshold for secondary poisoning—the bioconcentration factor (BCF) in fish must be determined (OECD 305) [4]. BCF is the ratio between the concentration in aquatic organisms and the concentration in water at steady state. If log Kow > 4.5, a PBT/vPvB assessment must be conducted. PBT (Persistent, Bioaccumulative and Toxic) and vPvB (very Persistent and very Bioaccumulative) substances are considered to have particularly hazardous environmental properties under the regulatory framework.
BCFFISH ≥ 100 L/kg is the threshold for further assessment of secondary poisoning. If BCFFISH > 2,000 L/kg, further evaluation is required to determine whether the substance may be classified as a PBT substance, and if BCF > 5,000 L/kg, whether it meets the criteria for vPvB.
Acute toxicity to aquatic organisms is assessed based on the results of toxicity tests on species from three trophic levels: algae, crustaceans, and fish (OECD Test Guidelines 201, 202, and 203, or equivalent). Data from the most sensitive organism are 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 |
According to the environmental risk assessment guidelines, companies are required to submit information on chronic toxicity (OECD Test Guidelines 201, 210, and 211) for aquatic organisms [1]. A categorisation has been made in accordance with European chemicals legislation [12,13], using data from the most sensitive organism as the basis for the 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 |
When selecting an algal test for antibiotics, testing with blue-green algae (cyanobacteria) is recommended [1].
In the environmental assessment document for each pharmaceutical in the database, it is indicated whether the data refer to acute or chronic toxicity.
Lack of data
In the absence of data, for example regarding persistence, the database states:
"It cannot be ruled out that substance X is persistent, due to lack of data."
For the previous hazard scoring, a property was classified as follows, with reference to the precautionary principle (Chapter 2, Section 3 of the Swedish Environmental Code) [14]:
If data on persistence is lacking, the active substance is classified as potentially persistent.
If data on bioaccumulation is lacking, the active substance is classified as having a high potential for bioaccumulation.
If toxicity data is entirely lacking, the active substance is assessed as having very high toxicity. If toxicity data is missing for one or two trophic levels, the available data is adjusted using a safety factor as follows:
- Toxicity data missing for one trophic level is adjusted by a factor of 2.
- Toxicity data missing for two trophic levels is adjusted by a factor of 5.
For antibiotics lacking toxicity data from tests on cyanobacteria (blue-green algae), when such testing is appropriate based on the mode of action, the toxicity is classified as very high.
Previous hazard score
Work is currently underway to phase out the hazard score, as it is considered a coarse measure. Instead, data on persistence, bioaccumulation, and toxicity are now described in text.
The hazard score was previously referred to as the PBT index. In light of the existence of PBT/vPvB substances under the European regulatory framework [1], the name was changed from PBT index to hazard score.
The hazard score can range from 0 to 9 and serves as an indication of the intrinsic environmental hazard of the active substance. For example, when comparing two substances with the same hazard score, it may be necessary to examine the underlying data in more detail, in addition to other available information used in environmental assessments.
Since substances with incomplete data may receive a higher score (see Lack of Data), the hazard score also serves as a compensation for data gaps. In such cases, the score is marked with an asterisk (*).
The hazard score is obtained by summing the numerical values for the active substance based on the assessment criteria described 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 |
A substance is considered hazardous if the active substance accumulates in water due to its persistence, or if it becomes concentrated in biological material (biota) through bioaccumulation. A substance is also considered hazardous if it poses a risk of harmful environmental effects due to its toxicity, especially when combined with persistence and/or bioaccumulation.
For substances that have been identified under European regulations as having particularly hazardous environmental properties (PBT/vPvB substances), this is indicated in the database for the substance in question.
Environmental risk assessment
The environmental risk refers to the toxic risk to the aquatic environment and is based on the ratio between: the Predicted Environmental Concentration (PEC) of the pharmaceutical in Swedish watercourses under current usage levels or expected usage for newly registered medicinal products in Europe, and the Predicted No Effect Concentration (PNEC), which is the concentration expected to be harmless to aquatic animals and plants [1,9,11].
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 |
Information on environmental risk is obtained from fass.se or EPAR. In recent years, risk assessments have increasingly been based on measured environmental concentrations of several pharmaceuticals—see, for example, [4]. Such information is presented in the documentation for each substance in the database and serves as an important complement to the theoretical risk assessments from fass.se or EPAR.
For antibiotics that have not been toxicity-tested on cyanobacteria (blue-green algae)—despite the mode of action indicating that such testing would be appropriate—the environmental risk is assessed as "cannot be excluded".
According to the new updated guidelines for environmental risk assessments from 2024, if any compartment—such as sediment, soil, or groundwater—is classified as a risk (i.e., PEC/PNEC > 1), the overall conclusion is that there is generally an environmental risk [1]. The updated guidelines also include specific assessment strategies for endocrine-active substances, antibacterial, and antiparasitic pharmaceuticals.
Lack of data
If there are insufficient ecotoxicological data to calculate the PEC/PNEC ratio, the environmental risk for the active substance is stated as "cannot be excluded."
Additional Information
A pharmaceutical may have undergone only a Phase I study in accordance with regulatory requirements for environmental risk assessments [1]. A Phase I environmental study includes data on bioaccumulation and an estimation of the Predicted Environmental Concentration in surface water (PECsurface water). If the specified threshold values are not exceeded, the company is not required to conduct a Phase II environmental study, which would include data on toxicity and persistence, as well as a risk assessment based on the PEC/PNEC ratio.
References
- 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 September 2024.
- European Medicines Agency (EMA). European public assessment reports (EPAR).
- Läkemedelsindustriföreningen (Lif). Fass. Miljöinformation för läkemedel.
- Prioritering av läkemedel med miljörisk inom SLL. Stockholm: Goodpoint; 2016. Rapport LS 2016–0634Pdf, 714 kB..
- Caneva L, Bonelli M, Papaluca-Amati M, Vidal JM (2014) Critical review on the environmental risk assessment of medicinal products for human use in the centralised procedure. Regul Toxicol Pharmacol 68(3):312–316.
- Ågerstrand M, Ruden C (2010) Evaluation of the accuracy and consistency of the Swedish environmental classification and information system for pharmaceuticals. Sci Total Environ 408(11):2327–2339.
- Oelkers K, Floeter C. The accessibility of data on environmental risk assessment of pharmaceuticals: Is the marketing authorisation procedure in conflict with the international right of access to environmental information? Environ Sci Eur (2019) 31:58.
- Bruun Rasmussen AS et al. Definition, categorization, and environmental risk assessment of biopharmaceuticals. Science of the Total Environment 789 (2021) 147884.
- Läkemedelsindustriföreningen (Lif). Environmental classification of pharmaceuticals at www.fass.se. Guidance for pharmaceutical companies 2012.
- 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.
- 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.
- 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.
- ECHA (European Chemicals Agency). Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.11: PBT/vPvB assessment. Version 4.0 December 2023.
- Sveriges Riksdag. Svensk författningssamling. Miljöbalk (SFS 1998:808).
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