Milbemycin A4

Milbemycin A4	Last updated: 20/05/2025
(Not known by any other names)

Data alerts

The following alerts are based on the data in the tables below. An absence of an alert does not imply the substance has no implications for human health, biodiversity or the environment but just that we do not have the data to form a judgement.

Environmental fate	Ecotoxicity	Human health
Environmental fate Moderate alert: Potential for particle bound transport: Medium	Ecotoxicity High alert: Fish acute ecotoxicity: High; Fish chronic ecotoxicity: High; Daphnia acute ecotoxicity: High; Daphnia chronic ecotoxicity: High; Bees acute contact ecotoxicity: High; Bees acute oral ecotoxicity: High	Human health High alert: Reproduction/development effects

GENERAL INFORMATION

Description

An active and the most dominant component of milbemectin with acaricidal activity and is used as an antibiotic drug.

Example pests controlled

Spider mites; Tarsonemid mites; Leaf miners

Example applications

Soft fruit including strawberry, blackberry, currants, raspberry, gooseberry; Apple, Pear, Cherry, Plum; Orange; Aubergine; Ornamentals

Efficacy & activity

Efficacy proven via field trials and extensive use

Appearance and life cycle

Availability status

Current

Introduction & key dates

1960, introduced Japan

Taxonomic classification

GB regulatory status

GB COPR regulatory status

Not approved

Date COPR inclusion expires

Withdrawn

GB LERAP status

No UK approval for use as a plant protection agent

EC Regulation 1107/2009 (repealing 91/414)

EC Regulation 1107/2009 status

Approved

Dossier rapporteur/co-rapporteur

Germany/Netherlands

Date EC 1107/2009 inclusion expires

31/05/2026

EU Candidate for substitution (CfS)

Listed in EU database

Yes

Approved for use (✓) under EC 1107/2009 in the following EU Member States

ATAustria	BEBelgium	BGBulgaria	CYCyprus	CZCzech Republic	DEGermany	DKDenmark	EEEstonia	ELGreece
✓	✓	✓	✓	✓	✓	✓		✓
ESSpain	FIFinland	FRFrance	HRCroatia	HUHungary	IEIreland	ITItaly	LTLithuania	LULuxembourg
✓		✓		✓		✓		✓
LVLatvia	MTMalta	NLNetherlands	PLPoland	PTPortugal	RORomania	SESweden	SISlovenia	SKSlovakia
		✓	✓		✓	✓	✓

Approved for use (✓) under EC 1107/2009 by Mutual Recognition of Authorisation and/or national regulations in the following EEA countries

ISIceland	NONorway

Additional information

Known to be also used in the following countries

Australia, USA

Chemical structure

Isomerism

Milbemectin is a complex molecule with 10 chiral features.

Chemical formula

C₃₂H₄₆O₇

Canonical SMILES

CCC1C(CCC2(O1)CC3CC(O2)CC=C(CC(C=CC=C4COC5C4(C(C=C(C5O)C)C(=O)O3)O)C)C)C

Isomeric SMILES

CCC1C(CC[C@@]2(O1)C[C@@H]3C[C@H](O2)C/C=C(/CC(/C=C/C=C/4\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)\C)C

International Chemical Identifier key (InChIKey)

VOZIAWLUULBIPN-DFYAAVTESA-N

International Chemical Identifier (InChI)

InChI=1S/C32H46O7/c1-6-27-21(4)12-13-31(39-27)17-25-16-24(38-31)11-10-20(3)14-19(2)8-7-9-23-18-36-29-28(33)22(5)15-26(30(34)37-25)32(23,29)35/h7-10,15,19,21,24-29,33,35H,6,11-14,16-18H2,1-5H3/b8-7+,20-10+,23-9+/t19?,21?,24-,25+,26+,27?,28-,29-,31-,32-/m1/s1

2D structure diagram/image available?

Yes

General status

Biopesticide type

Insecticide; Acaricide

Substance groups

Micro-organism derived substance

Minimum active substance purity

617.5 g A4/kg milbemectin

Known relevant impurities

EU 2017 dossier: None declared

Substance origin

Natural

Mode of action

Not applicable

Substance source

Isolated from the soil bacterium Streptomyces hygroscopicus (Jensen) Waks and henrici subsp. aureolacrimosus.

Substance production

Milbemycin A4 is produced commercially through a fermentation process involving the bacterium Streptomyces spp. The bacterium is cultured in a fermentation broth, where it produces milbemycins, including A4. The fermentation broth is processed to extract the milbemycins, purified to isolate milbemycin A4 from other components and formulated.

Uses

Crop protection

Target pests

Spider mites; Tarsonemid mites; Leaf miners

Target host

Soft fruit including strawberry, blackberry, currants, raspberry, gooseberry; Apple, Pear, Cherry, Plum; Orange; Aubergine; Ornamentals

Farming system suitability

CAS RN

51596-11-3

EC number

CIPAC number

660

US EPA chemical code

Not applicable

PubChem CID

Molecular mass

542.7

PIN (Preferred Identification Name)

IUPAC name

(10E,14E,16E,22Z)-(1R,4S,5’S,6R,6’R,8R,13R,20R,21R,24S)-6-ethyl-21,24-dihydroxy-5’,11,13,22-tetramethyl-3,7,19-trioxatetracyclo[15.6.1. 14.8020,24]pentacosa-10,14,16,22-tetraene-6-spiro-2’-tetrahydropyran-2-one

CAS name

(6R,25R)-5-O-demethyl-28-deoxy-6,28-epoxy-25-ethylmilbemycin B

Other status information

Relevant Environmental Water Quality Standards

Herbicide Resistance Class (HRAC MoA class)

Not applicable

Herbicide Resistance Class (WSSA MoA class)

Not applicable

Insecticide Resistance Class (IRAC MoA class)

Fungicide Resistance Class (FRAC MOA class)

Not applicable

Examples of recorded resistance

Physical state

White crystalline solid

Formulations

Property

Product

Manufacturer

Example products

MilbeKNOCK miticide

Belchim Crop protection

Formulation and application details

ENVIRONMENTAL FATE

Property

Value

Source; quality score; and other information

Interpretation

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

4.55

Low

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

203000

Acetone for milbemectin

3450

n-Octanol for milbemectin

25900

o-Xylene for milbemectin

251000

Methanol

Melting point (°C)

191

Boiling point (°C)

Decomoposes before boiling

Degradation point (°C)

275

Flashpoint (°C)

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

1.00 X 10⁰⁷

Calculated

Log P

7.0

at 25 °C

High

Fat solubility of residues

Solubility

Data type

Density (g ml⁻¹)

1.2

Dissociation constant pKa) at 25 °C

Not applicable

No dissociation

Vapour pressure at 20 °C (mPa)

1.3 X 10^-02

at 25 °C

Low volatility

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

1.59 X 10^-03

Non-volatile

Volatilisation as max % of applied dose lost

From plant surface

From soil surface

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

Neutral pH: 238nm=27400, 244nm=30100, 252nm=19500
Acid pH: 238nm=28500, 244nm=31300, 252nm=20300
Basic pH: 238nm=28500, 244nm=31200, 252nm=20200

Surface tension (mN m⁻¹)

49.4

Degradation

Property

Value

Source; quality score; and other information

Interpretation

General biodegradability

Not readily biodegradable

Soil degradation (days) (aerobic)

DT₅₀ (typical)

36.1

Moderately persistent

DT₅₀ (lab at 20 °C)

36.1

Moderately persistent

DT₅₀ (field)

11.5

Non-persistent

DT₉₀ (lab at 20 °C)

143

Persistent

DT₉₀ (field)

DT₅₀ modelling endpoint

Note

EU 2023 dossier lab studies DT₅₀ range 20.3-81.8 days, DT₉₀ range 70.1-275 days, Soils =4; EU 2002 dossier field studies DT₅₀ range 10.0-12.9 days, soils =2

Dissipation rate RL₅₀ (days) on plant matrix

Value

Note

Dissipation rate RL₅₀ (days) on and in plant matrix

Value

Note

Aqueous photolysis DT₅₀ (days) at pH 7

Value

2.6

Moderately fast

Note

pH variable: 0.93 days at pH5, 4.1days at pH9

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

Value

260

as milbemectin

Persistent

Note

pH variable: 12 days at pH5, 226 days at pH9 as milbemectin

Water-sediment DT₅₀ (days)

Moderately fast

Water phase only DT₅₀ (days)

2.9

Moderately fast

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)

Non-mobile

K_oc (mL g⁻¹)

70636

Notes and range

Estimated

Freundlich

K_f (mL g⁻¹)

60.6

Slightly mobile

K_foc (mL g⁻¹)

2817

¹/_n

0.97

Notes and range

EU 2023 dossier K_f range 12.2-138 g/Kg, K_foc range 1370-4059 g/Kg, ¹/_n range 0.875-1.04, Soils =4

pH sensitivity

Known soil metabolites

Metabolite

Major/Minor fraction

$Click here for further information on Major/Minor fraction$

Estimated maximum occurrence fraction

Notes

27-hydroxy-milbemycin A4

Major fraction

0.341

27-keto-milbemycin A4

Major fraction

0.118

Known groundwater metabolites

None

Other known metabolites

None

ECOTOXICOLOGY

Terrestrial ecotoxicology

Property

Value

Source; quality score; and other information

Interpretation

Mammals - Acute oral LD₅₀ (mg kg⁻¹)

340

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)

347

Anas platyrhynchos as milbemectin

Moderate

Birds - Short term dietary (LC₅₀/LD₅₀)

1922 mg kg feed⁻¹

Anas platyrhynchos as milbemectin

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

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

28.5

Moderate

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

0.217

Eisenia foetida

Moderate

Soil micro-organisms

Nitrogen mineralisation: No significant adverse effect
Carbon mineralisation: No significant adverse effect

Dose: 0.1 mg kg⁻¹ soil Milbemectin

Collembola

Acute LC₅₀ (mg kg⁻¹)

Chronic NOEC (mg kg⁻¹)

Non-target plants

Honeybees (Apis spp.)

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

0.026

Apis mellifera as milbemectin

High

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

0.40

Apis mellifera as milbemectin

High

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)

> 9.7

Bombus terrestris as milbemectin

Moderate

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

> 10

Bombus terrestris as milbemectin

Moderate

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) as Mortality LR₅₀ g ha⁻¹

> 1.0

Coccinella septempunctata as milbemectin

Beneficial insects (Lacewings) as Mortality LR₅₀ g ha⁻¹

> 27.9

Chrysoperla carnea as milbemectin Larva

Beneficial insects (Parasitic wasps) as Mortality 48 hr LR₅₀

< 25

Aphidius rhopalosiphi as milbemectin

Beneficial insects (Predatory mites) as Mortality 48 hr LR₅₀

< 25

Typhlodromus pyri as milbemectin

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)

0.044

Oncorhynchus mykiss as milbemectin

High

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

0.00065

Oncorhynchus mykiss as milbemectin 88days

High

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

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

0.011

Daphnia magna as milbemectin

High

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

0.000012

Daphnia magna as milbemectin

High

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, growth) - Acute 7 day EC₅₀, biomass (mg l⁻¹)

> 0.62

Lemna gibba IC50

Moderate

Aquatic plants (rooted, growth) - Acute 14 day EC₅₀, biomass (mg l⁻¹)

Algae - Acute 72 hour EC₅₀, growth (mg l⁻¹)

> 2.0

Selenastrum capricornutum as milbemectin

Moderate

Algae - Chronic 96 hour NOEC, growth (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)

340

Rat

Moderate

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

2000

Rat

Mammals - Inhalation LC₅₀ (mg l⁻¹)

1.9

Rat 4 hr (whole body) as Milbemycin

Other Mammal toxicity endpoints

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

0.007

Rat SF=100 as milbemectin

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

0.03

Dog SF=100 as milbemectin

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

0.014

Dog SF=100 as milbemectin

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

0.014

Dog SF=100 as milbemectin

Dermal penetration studies (%)

2-19

concentration dependent as milbemectin

Dangerous Substances Directive 76/464

Exposure Routes

Public

No acceptable risks identified

Occupational

No unacceptable risks identified when using PPE/PPC

Mammalian dose elimination route and rate

Extensively metabolised and elimination is mainly faecal (85-100%) with some urinary: (5-9) % in 24 hrs

Health issues

Specific human health issues

Carcinogen

Genotoxic

Endocrine disruptor

; ; ; ;

No data found

Reproduction / development effects

Acetyl cholinesterase inhibitor

Neurotoxicant

Respiratory tract irritant

Skin irritant

Skin sensitiser

Eye irritant

Phototoxicant

No data found

General human health issues

Possible liver, kidney, adrenals and uterus toxicant especially in vulnerable groups
Possible CNS toxicant
CLP data - suspected carcinogen

Handling issues

Property

Value and interpretation

General

Not oxidising or explosive
Not expected to auto-ignite; Not highly flammable

CLP classification 2013

Health: H302, H332, H351, H361d, H373
Environment: H400, H410

WHO Classification

Not listed (Not listed)

UN Number

Waste disposal & packaging

Shelf-life, storage, stability and reactivity

TRANSLATIONS

Language

Name

English

milbemycin A4

French

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Italian

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Polish

Swedish

Hungarian

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Record last updated:	20/05/2025
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