Pyrimethamine

Pyrimethamine	Last updated: 08/09/2025
(Also known as: daraprim; ethylpyrimidine)

GENERAL INFORMATION

Description

A systemic antiprotozoal medication used to treat parasitic infections

Examples of veterinary uses

Used to treat Hepatozoon americanum infections as well as toxoplasmosis (Toxoplasma gondii)

Examples of species treated

Dogs; Cats; Horses; Sheep; Birds

Approval status

VMR 2013/2033 approval status (GB/UK)

Not approved

EU Regulatory approval status

Not approved

Chemical structure

Isomerism

While pyrimethamine itself, in its final pharmaceutical form, is generally considered a single, stable compound without stereocentres, some synthetic intermediates or analogues used during its production may exhibit E/Z isomerism. In the case of pyrimethamine, certain precursors or derivatives can exist as E or Z isomers depending on the spatial arrangement of their functional groups. These isomers may be relevant during synthesis or in structural studies, but they are not present in the final active drug used clinically. However, pyrimethamine can form different solid-state forms, such as salts, solvates, and cocrystals, depending on the crystallisation conditions and coformers used. These variations are not isomers in the traditional chemical sense but represent polymorphism, distinct crystalline arrangements of the same molecule, which can influence solubility, stability, and bioavailability. So while pyrimethamine itself is structurally stable and non-isomeric, its formulation landscape is rich with solid-state diversity.

Chemical formula

C₁₂H₁₃ClN₄

Canonical SMILES

CCC1=C(C(=NC(=N1)N)N)C2=CC=C(C=C2)Cl

Isomeric SMILES

No data

International Chemical Identifier key (InChIKey)

WKSAUQYGYAYLPV-UHFFFAOYSA-N

International Chemical Identifier (InChI)

InChI=1S/C12H13ClN4/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7/h3-6H,2H2,1H3,(H4,14,15,16,17)

2D structure diagram/image available?

Yes

Cambridge Crystallographic Data Centre diagrams

Common Name	Relationship	Link
pyrimethamine	-

General status

Veterinary substance type

Antiparasitic, Antiprotozoic, Medicinal drug

Substance groups

Unclassified substance

Minimum active substance purity

Known relevant impurities

Substance origin

Synthetic

Mode of action

Interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR)

Molecular targets

[Dihydrofolate reductase, Inhibitor], [Bifunctional dihydrofolate reductase-thymidylate synthase, inhibitor]

CAS RN

58-14-0

EC number

200-364-2

CIPAC number

US EPA chemical code

PubChem CID

Therapeutic Class

ATCvet Code

None allocated

Controlled Drug?

Regulation 37/2010 MRL Classification

Molecular mass

248.71

PIN (Preferred Identification Name)

IUPAC name

5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine

CAS name

2,4-diamino-5-p-chlorophenyl-6-ethylpyrimidine

Forever chemical

Other status information

Evidence of use in third world countries

Relevant Environmental Water Quality Standards

Physical state

White solid

Related substances & organisms

sulfadiazine

Commercial

Property

Product

Manufacturer

Authorisation Route

Legal Class (GB/UK)

Availability status

Introduction & key dates

Example products (past and present) using this active

Formulation and application details

Commercial production

The synthesis of pyrimethamine involves a multi-step chemical process beginning with 4-chlorobenzyl cyanide, which undergoes condensation with a methyl ester of propionic acid in the presence of sodium methoxide to form a beta-ketonitrile intermediate. This intermediate is then reacted with ethyl orthoformate to produce a methoxymethylene derivative, which sets the stage for heterocyclisation. The final ring closure is achieved using guanidine, a binucleophile that facilitates the formation of the 2,4-diaminopyrimidine core, the pharmacologically active structure of pyrimethamine.

Impact on climate of production and use

Published GHG data is not available for most pharmaceuticals. However, according to industry, global averages suggest producing 1 kg of a typical active pharmaceutical ingredient can range from 10 to 100 kg CO₂e for small molecule drugs and potentially up to 1000 kg CO₂e for complex biologicals such as vaccines, depending on the drug type, its formulation, complexity of synthesis, solvent recovery, and energy sources used.

ENVIRONMENTAL FATE

Property

Value

Source; quality score; and other information

Interpretation

Solubility - In water at 20 °C (mg l⁻¹)

100

Moderate

Solubility - In organic solvents at 20 °C (mg l⁻¹)

Melting point (°C)

233

Boiling point (°C)

Degradation point (°C)

Flashpoint (°C)

Octanol-water partition coefficient at pH 7, 20 °C

4.90 X 10⁰²

Calculated

Log P

2.69

Low

Fat solubility of residues

Solubility

Data type

Density (g ml⁻¹)

Dissociation constant pKa) at 25 °C

7.34

Weak base

Vapour pressure at 20 °C (mPa)

8.29 X 10^-03

Low volatility

Henry's law constant at 25 °C (Pa m³ mol⁻¹)

Volatilisation as max % of applied dose lost

From plant surface

From soil surface

Maximum UV-vis absorption L mol⁻¹ cm⁻¹

Surface tension (mN m⁻¹)

Refractive Index

Environmental release

Degradation

Property

Value

Source; quality score; and other information

Interpretation

Soil degradation (days) (aerobic)

DT₅₀ (typical)

DT₅₀ (lab at 20 °C)

DT₅₀ (field)

DT₉₀ (lab at 20 °C)

DT₉₀ (field)

Note

Manure DT₅₀ (days)

Aqueous photolysis DT₅₀ (days) at pH 7

Value

Note

Aqueous hydrolysis DT₅₀ (days) at 20 °C and pH 7

Value

Note

Water-sediment DT₅₀ (days)

Water phase only DT₅₀ (days)

Sediment phase only DT₅₀ (days)

Air degradation

As this parameter is not normally measured directly, a surrogate measure is used: ‘Photochemical oxidative DT₅₀’. Where data is available, this can be found in the Fate Indices section below.

Decay in stored produce DT₅₀

Soil adsorption and mobility

Property

Value

Source; quality score; and other information

Interpretation

Linear

K_d (mL g⁻¹)

K_oc (mL g⁻¹)

Notes and range

Freundlich

K_f (mL g⁻¹)

K_foc (mL g⁻¹)

¹/_n

Notes and range

pH sensitivity

Fate indices

Property

Value

Source; quality score; and other information

Interpretation

GUS leaching potential index

Bio-concentration factor

BCF (l kg⁻¹)

Low risk

Based on LogP < 3

Low risk

CT₅₀ (days)

Known metabolites

None

ECOTOXICOLOGY

Terrestrial ecotoxicology

Property

Value

Source; quality score; and other information

Interpretation

Mammals - Acute oral LD₅₀ (mg kg⁻¹)

440

Rat

Moderate

Mammals - Short term dietary NOEL

(mg kg⁻¹)

(ppm diet)

Mammals - Chronic 21d NOAEL (mg kg⁻¹ bw d⁻¹)

Birds - Acute LD₅₀ (mg kg⁻¹)

Birds - Short term dietary (LC₅₀/LD₅₀)

Birds - Chronic 21d NOEL (mg kg⁻¹ bw d⁻¹)

Earthworms - Acute 14 day LC₅₀ (mg kg⁻¹)

Earthworms - Chronic NOEC, reproduction (mg kg⁻¹)

Soil micro-organisms

Collembola

Acute LC₅₀ (mg kg⁻¹)

Chronic NOEC (mg kg⁻¹)

Non-target plants

Vegetative vigour ER₅₀ (g ha⁻¹)

Seedling emergence ER₅₀ (g ha⁻¹)

Honeybees (Apis spp.)

Contact acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg bee⁻¹)

Oral acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg bee⁻¹)

Unknown mode acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg bee⁻¹)

Chronic

Notes

Bumblebees (Bombus spp.)

Contact acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg bee⁻¹)

Oral acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg bee⁻¹)

Mason bees (Osmia spp.)

Contact acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg bee⁻¹)

Oral acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg bee⁻¹)

Other bee species (1)

Acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg insect⁻¹)

Mode of exposure

Other bee species (2)

Acute LD₅₀ (worst case from 24, 48 and 72 hour values - μg insect⁻¹)

Mode of exposure

Beneficial insects (Ladybirds)

Beneficial insects (Lacewings)

Beneficial insects (Parasitic wasps)

Beneficial insects (Predatory mites)

Beneficial insects (Ground beetles)

Aquatic ecotoxicology

Property

Value

Source; quality score; and other information

Interpretation

Temperate Freshwater Fish - Acute 96 hour LC₅₀ (mg l⁻¹)

Temperate Freshwater Fish - Chronic 21 day NOEC (mg l⁻¹)

Tropical Freshwater Fish - Acute 96 hour LC₅₀ (mg l⁻¹)

Temperate Freshwater Aquatic invertebrates - Acute 48 hour EC₅₀ (mg l⁻¹)

Temperate Freshwater Aquatic invertebrates - Chronic 21 day NOEC (mg l⁻¹)

Tropical Freshwater Aquatic invertebrates - Acute 48 hour EC₅₀ (mg l⁻¹)

Aquatic crustaceans - Acute 96 hour LC₅₀ (mg l⁻¹)

Sediment dwelling organisms - Acute 96 hour LC₅₀ (mg l⁻¹)

Sediment dwelling organisms - Chronic 28 day NOEC, static, water (mg l⁻¹)

Sediment dwelling organisms - Chronic 28 day NOEC, sediment (mg kg⁻¹)

Aquatic Plants (free-floating, fonds growth, fresh) - 7 day (mg l⁻¹)

Aquatic plants (rooted, growth rate, fresh) - 14 day (mg l⁻¹)

Algae - Acute (growth rate, fresh; mg l⁻¹) (EC₅₀)

5.06

Raphidocelis subcapitata

Moderate

Algae - Chronic (growth rate, fresh; mg l⁻¹) (NOEC)

0.752

Raphidocelis subcapitata

Moderate

Mesocosm study data

NOEAEC mg l⁻¹

Marine bivalves

HUMAN HEALTH AND PROTECTION

General

Property

Value

Source; quality score; and other information

Interpretation

Threshold of Toxicological Concern (Cramer Class)

High (class III)

Mammals - Acute oral LD₅₀ (mg kg⁻¹)

440

Rat

Moderate

Mammals - Dermal LD₅₀ (mg kg⁻¹ body weight)

Mammals - Inhalation LC₅₀ (mg l⁻¹)

Other Mammal toxicity endpoints

Intraperitoneal LD₅₀ = 70 mg kg⁻¹

Rat

Subcutaneous LDLo = 160 mg kg⁻¹

Rat

ADI - Acceptable Daily Intake (mg kg⁻¹ bw day⁻¹)

ARfD - Acute Reference Dose (mg kg⁻¹ bw day⁻¹)

AAOEL - Acute Acceptable Operator Exposure Level (mg kg⁻¹ bw day⁻¹)

AOEL - Acceptable Operator Exposure Level - Systemic (mg kg⁻¹ bw day⁻¹)

Dermal penetration studies (%)

Dangerous Substances Directive 76/464

Exposure Routes

Public

Occupational

Mammalian dose elimination route and rate

Principally lost via the urine as metabolites

Health issues

Specific human health issues

Carcinogen

Genotoxic

Endocrine disruptor

No data found

; ; ; ;

No data found

Reproduction / development effects

Acetyl cholinesterase inhibitor

Neurotoxicant

No data found

Respiratory tract irritant

Skin irritant

Skin sensitiser

No data found

Eye irritant

Phototoxicant

No data found

General human health issues

May cause hypersensitivity, megaloblastic anemia & thrombocytopenia
May cause gastrointestinal problems

Handling issues

Property

Value and interpretation

General

IMDG Transport Hazard Class 6.1

CLP classification 2013

WHO Classification

Not listed (Not listed)

UN Number

UN3249

Waste disposal & packaging

Packaging Group III (minor danger)

Shelf-life, storage, stability and reactivity

TRANSLATIONS

Language

Name

English

pyrimethamine

French

German

Danish

Italian

Spanish

pirimetamina

Greek

Polish

Swedish

Hungarian

Dutch

Norwegian

Record last updated:	08/09/2025
Contact:	aeru@herts.ac.uk
Please cite as:	Lewis, K.A., Tzilivakis, J., Warner, D. and Green, A. (2016) An international database for pesticide risk assessments and management. Human and Ecological Risk Assessment: An International Journal, 22(4), 1050-1064. DOI: 10.1080/10807039.2015.1133242