Theophylline

Theophylline	Last updated: 06/09/2025
(Also known as: armophylline; elixophylline; pseudotheophylline)

GENERAL INFORMATION

Description

A commonly used methylxanthine bronchodilator veterinary drug

Examples of veterinary uses

Drug used to relieve breathing problems related to heart failure, pulmonary edema, bronchial asthma and chronic obstructive pulmonary disease

Examples of species treated

Cat; Dogs

Approval status

VMR 2013/2033 approval status (GB/UK)

Approved - usually available as a prescription only medicine to be authorised by a veterinarian (POM-V)

EU Regulatory approval status

Approved

Chemical structure

Isomerism

Theophylline does not exhibit classical isomerism such as enantiomerism or geometric isomerism in its standard pharmaceutical form. Its structure is a rigid fused purine ring system that lacks chiral centres and so does not form stereoisomers under normal conditions. However, in specialised chemical contexts, such as when theophylline is part of a ylide compound, it can exhibit rotational isomerism. This involves restricted rotation around certain bonds, leading to Z and E isomers depending on the spatial arrangement of substituents around a double bond.

Chemical formula

C₇H₈N₄O₂

Canonical SMILES

CN1C2=C(C(=O)N(C1=O)C)NC=N2

Isomeric SMILES

No data

International Chemical Identifier key (InChIKey)

ZFXYFBGIUFBOJW-UHFFFAOYSA-N

International Chemical Identifier (InChI)

InChI=1S/C7H8N4O2/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13/h3H,1-2H3,(H,8,9)

2D structure diagram/image available?

Yes

Cambridge Crystallographic Data Centre diagrams

Common Name	Relationship	Link
theophylline	-

General status

Veterinary substance type

Muscle relaxant, Bronchodilator, Medicinal drug

Substance groups

Methylxanthine drug

Minimum active substance purity

Known relevant impurities

Substance origin

Synthetic

Mode of action

Works by inhibiting cellular enzymes promoting the dilation of smooth muscle in bronchial tubes and blood vessels.

Molecular targets

[Adenosine A1 receptor, Antagonist], [Adenosine A2a receptor, Antagonist], [Adenosine A2b receptor, anatgonist], [cAMP-specific 3',5'-cyclic phosphodiesterase 4B, Antagonist], [cGMP-specific 3',5'-cyclic phosphodiesterase, Antagonist], [cAMP-specific 3',5'-cyclic phosphodiesterase 4A, Antagonist], [cGMP-inhibited 3',5'-cyclic phosphodiesterase A, Antagonist]

CAS RN

58-55-9

EC number

200-385-7

CIPAC number

US EPA chemical code

PubChem CID

Therapeutic Class

Respiratory system: Drugs for obstructive airway diseases

ATCvet Code

QR03DA04

Controlled Drug?

Regulation 37/2010 MRL Classification

Molecular mass

180.16

PIN (Preferred Identification Name)

IUPAC name

1,3-dimethyl-7H-purine-2,6-dione

CAS name

1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurine

Forever chemical

Other status information

Relevant Environmental Water Quality Standards

Physical state

White crystalline powder

Commercial

Property

Value

Availability status

Current

Introduction & key dates

1888, first isolated

Example manufacturers & suppliers of products using this active now or historically

Elanco Europe Ltd

Example products using this active

Corvental D Hard Capsules

Formulation and application details

Usually supplied in tablet or capsule form for oral administration

Commercial production

The production of theophylline typically involves a synthetic route based on purine chemistry, most commonly using the Traube synthesis. This method begins with the reaction of N,N-dimethylurea and cyanoacetic acid ester, forming an intermediate that cyclizes into 6-amino-1,3-dimethyluracil. Subsequent steps include nitration, reduction, and formylation, ultimately yielding theophylline through ring closure and methylation. An alternative and more sustainable approach involves aerobic fermentation of caffeine-rich substrates, such as pu-erh tea, using specific fungi like Aspergillus sydowii, which convert caffeine into theophylline via enzymatic demethylation. This biotechnological method offers a greener pathway and has shown promising yields under optimised conditions of moisture, temperature, and inoculation rate.

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. However, for theophylline produced using green chemistry, the GHG emissions are likely to be considerably lower.

ENVIRONMENTAL FATE

Property

Value

Source; quality score; and other information

Interpretation

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

7360

High

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

Melting point (°C)

272

Boiling point (°C)

Degradation point (°C)

Flashpoint (°C)

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

9.55 X 10^-01

Calculated

Log P

-0.02

Low

Fat solubility of residues

Solubility

Data type

Density (g ml⁻¹)

Dissociation constant pKa) at 25 °C

8.81

Vapour pressure at 20 °C (mPa)

6.81 X 10^-04

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)

CT₅₀ (days)

Known soil and groundwater metabolites

None

Other known metabolites

Metabolite name and reference

Aliases

Formation medium / Rate

Estimated maximum occurrence fraction

1-methylxanthine

Human (Liver)

3-methylxanthine

Human (Liver)

1,3-dimethyluric acid

Human (Liver)

ECOTOXICOLOGY

Terrestrial ecotoxicology

Property

Value

Source; quality score; and other information

Interpretation

Mammals - Acute oral LD₅₀ (mg kg⁻¹)

225

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 dw soil)

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

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)

> 100

Leuciscus idus

Low

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)

178

Daphnia magna

Low

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

4504

Danio rerio Larva

Low

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)

> 100

Desmodesmus subspicatus

Low

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

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)

225

Rat

Moderate

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

Mammals - Inhalation LC₅₀ (mg l⁻¹)

Other Mammal toxicity endpoints

Subcutaneous LD₅₀ = 325 mg kg⁻¹

Rat

Intraperitoneal LD₅₀ = 150 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

Extensively metabolised in the liver, only 10% excreted unchanged in the urine

Health issues

Specific human health issues (hazard-based)

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

Possible kidney toxicant
May cause vomiting

Handling issues

Property

Value and interpretation

General

IMDG Transport Hazard Class 6.1

CLP classification 2013

WHO Classification

Not listed (Not listed)

UN Number

UN1544

Waste disposal & packaging

Packaging Group III (minor danger)

Shelf-life, storage, stability and reactivity

TRANSLATIONS

Language

Name

English

theophylline

French

German

Danish

Italian

Spanish

Greek

Polish

Swedish

Hungarian

Dutch

Norwegian

Record last updated:	06/09/2025
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