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WORLD HEALTH ORGANIZATION

WHO/PCS/DS/96.84

ORGANISATION MONDIALE DE LA SANTE

Original: ENGLISH

FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS

Distr.: LIMITED

ORGANISATION DES NATIONS UNIES POUR L'ALIMENTATION ET L'AGRICULTURE

Date of issue: July 1996

WHO/FAO DATA SHEETS ON PESTICIDES

No. 84

NITROFEN

1.0 GENERAL INFORMATION
1.1 Common Name:
1.1.1 Identity:
1.2 Synopsis
1.3 Selected Properties
1.3.1 Physical characteristics:
1.3.2 Solubility:
1.3.3 Stability:
1.3.4 Vapour pressure:
1.4 Agriculture, Horticulture And Forestry
1.4.1 Common formulations:
1.4.2 Pests mainly controlled:
1.4.3 Use pattern:
1.4.4 Unintended effects:
1.5 Public Health Programmes:
1.6 Household Use:
2.0 Toxicology And Risks
2.1 Toxicology - Mammals
2.1.1 Absorption route:
2.1.2 Mechanism of action:
2.1.3 Excretion products:
2.1.4 Toxicity, single dose:
2.1.5 Toxicity, repeated doses:
2.1.6 Dietary studies:
2.1.7 Carcinogenicity:
2.1.8 Teratogenicity:
2.1.9 Reproduction:
2.1.10 Mutagenicity:
2.1.11 Other:
2.2 Toxicology - Man
2.2.1 Absorption Route:
2.2.2 Dangerous doses:
2.2.3 Observations on occupationally exposed workers:
2.2.4 Observations on exposure of the general population:
2.2.5 Observations on volunteers:
2.2.6 Reported mishaps:
2.3 Toxicity - Non-Mammalian Species
2.3.1 Fish:
2.3.2 Birds:
2.3.3 Bees:
3.0 FOR REGULATORY AUTHORITIES -
RECOMMENDATIONS ON REGULATION OF COMPOUND
3.1 Recommended Restrictions On Availability
3.2 Transportation And Storage
3.3 Handling
3.4 Disposal And/Or Decontamination Of Containers
3.5 Selection, Training And Medical Supervision Of Workers
3.6 Additional Regulations Recommended If Distributed By Aircraft
3.7 Labelling
3.8 Residues In Food
4.0 PREVENTION OF POISONING IN
MAN AND EMERGENCY AID
4.1 Precautions In Use
4.1.1 General:
4.1.2 Manufacture and formulation - TLV:
4.1.3 Mixers and applicators:
4.1.4 Other associated workers:
4.1.5 Other populations likely to be affected:
4.2 Entry Of Persons Into Treated Areas
4.3 Decontamination Of Spillage And Containers
4.4 Emergency Aid
4.4.1 Early symptoms of poisoning:
4.4.2 Treatment before person is seen by physician, if symptoms appear following exposure:
5.0 FOR MEDICAL AND LABORATORY PERSONNEL
5.1 Medical Diagnosis And Treatment In Case Of Poisoning
5.1.1 General information:
5.1.2 Symptoms and signs:
5.1.3 Laboratory:
5.1.4 Treatment:
5.1.5 Prognosis:
5.1.6 References to previously reported cases:
5.2 Surveillance Tests:
5.3 Laboratory Methods
5.3.1 Detection and assay of compound and residues:

It must be noted that the issue of a Data Sheet for a particular pesticide does not imply endorsement of the pesticide by WHO or FAO for any particular use, or exclude its use for other purposes not stated. While the information provided is believed to be accurate according to data available at the time when the sheet was compiled, neither WHO nor FAO are responsible for any errors or omissions, or any consequences therefrom.

The issue of this document does not constitute formal publication. It should not be reviewed, abstracted or quoted without the agreement of the Food and Agriculture Organization of the United Nations or of the World Health Organization.

Ce document ne constitue pas une publication. Il ne doit faire l'objet d'aucun compte rendu ou résumé ni d'aucune citation sans l'autorisation de l'Organisation des Nations Unies pour l'Alimentation et l'Agriculture ou de l'Organisation Mondiale de la Santé.

CLASSIFICATION:

Primary Use:

Herbicide

Secondary Use:

 

Chemical Group:

Diphenyl ether

1.0 GENERAL INFORMATION

1.1 Common Name:

nitrofen (BSI, E-ISO, WSSA), nitrofène (F-ISO), niclofen (Canada), NIP (JMAF), exception: Federal Republic of Germany.

1.1.1 Identity:

IUPAC name:

2,4-dichlorophenyl 4-nitrophenyl ether.

CAS name:

2,4-dichloro-1-(-4-nitrophenoxy)benzene.

CAS registry number:

1836-75-5

RTGCS number:

KN 8400000

Molecular formula:

C12H7Cl2NO3

Relative molecular mass:

284.1

Structural formula:

Structural Formula

Synonyms: 2,4-dichloro-4’nitrodiphenyl ether; 2,4-dichloro-4’-nitrophenyl ether; 4-(2,4-dichlorophenoxy)nitrobenzene; 4’-nitro-2,4-dichlorodiphenyl ether; 4-nitro-2’,4’-dichlorophenyl ether, nitrofen.

Trade names: MezotoxR; NiclofenR; NIPR; NIPDIAR; NIPDINR; NIPQ-P; NitrafenR; NitraphenR; NitrochlorR; TokR; Tok-E25R; TokWP-50R; TokkornR; TrizilinR; FW-925.

1.2 Synopsis

Nitrophen is a selective pre- and post-emergent herbicide. In rodents it is teratogenic following multiple dermal and oral exposures, or following a single oral exposure. Nitrofen is carcinogenic in rats and mice. The use of nitrofen has been prohibited in many countries, including the U.S.A., U.K., Federal Republic of Germany, Sweden and the Russian Federation, and severely restricted in many more.

1.3 Selected Properties

1.3.1 Physical characteristics:

The pure compound is a colourless, crystalline solid. The technical material is a brown, free flowing solid with a slight aromatic odour. The melting point of the technical material is 64-71 ºC and the density is 1.80 g/cm3 at 83 ºC.

1.3.2 Solubility:

22 ºC water 0.7 - 1.2 mg/litre

20 ºC ethanol 40 mg/litre

n-hexane 280 mg/litre

benzene 2000 mg/litre

Moderately soluble (approximately 250 g/litre) in methanol, acetone and xylene; soluble (approximately 600 g/litre) in methylene chloride and ethyl acetate.

1.3.3 Stability:

Stable to acids and alkalis. The colour darkens on ultra violet irradiation. Photo-decomposition occurs in thin films and in solutions. Formulations may have a shelf life of greater than two years.

1.3.4 Vapour pressure:

The vapour pressure is 1 mPa at 40 ºC.

1.4 Agriculture, Horticulture And Forestry

1.4.1 Common formulations:

Available as emulsifiable concentrate, wettable powder, and granule formulations. Also available in combination with other herbicides.

1.4.2 Pests mainly controlled:

Effective in the control of annual grasses and broadleaved weeds. Species controlled include goosefoot, lambsquarters, annual bluegrass, crabgrass, nightshade and nettle. Resistant species include ragweed, chickweed, mustard, nutgrass and Russian thistle.

1.4.3 Use pattern:

Used as a pre- or post-emergence contact herbicide. Moderate application rates give selective control in cereals, certain ornamentals, vegetable crops, sugar beet and paddy fields. Application as a thin layer on the soil surface provides a barrier for the penetration of weeds but soil incorporation decreases the efficacy. High application rates will give total vegetation control. Nitrofen requires adequate moisture for full effectiveness.

1.4.4 Unintended effects:

Crop injury may result following heavy rainfall when pools collect over the seed rows. Manufacturers instructions should be carefully followed to prevent exposure of susceptible crops. Nitrofen is toxic to fish.

1.5 Public Health Programmes:

No recommended usage reported.

1.6 Household Use:

No recommended usage reported.

2.0 Toxicology And Risks

2.1 Toxicology - Mammals

2.1.1 Absorption route:

Nitrofen is partially absorbed from the gastrointestinal tract in rats and sheeps. It is also absorbed from the skin to a significant extent. The wettable powder formulation is less efficiently absorbed than the emulsifiable concentrate formulation. Absorption may also occur from the lungs following inhalation.

2.1.2 Mechanism of action:

It has been postulated that nitrofen exerts its teratogenic effect (see 2.1.8) by altering the thyroid hormone status. Serum levels of thyroid-stimulating hormone are reduced in thyroidectomized and euthyroid rats exposed to nitrofen on day 11 of pregnancy. Nitrofen (or a metabolite) might have a thyroid hormone activity.

2.1.3 Excretion products:

Following oral exposure nitrofen is rapidly eliminated. In cows, rats and sheep no unchanged nitrofen in the urine was found. In the faeces unchanged nitrofen is a major excretion product. Urinary metabolites accounted for  20% of the dose in rats,  40% in sheep. The urinary metabolites identified included the hydroxylated and reduced derivatives, sulphate and glucuronide conjugates. In the rat faecal excretion of the acetylated derivative of the 4-aminophenyl ether was also observed. Dosing regimen, magnitude of dose, sex or strain of rat had little effect on the metabolic profile or pattern of excretion, although some differences in pancreas residues were observed (Section 2.1.11).

2.1.4 Toxicity, single dose:

Oral LD50

 

Rat (M)

2630 mg/kg b.w. (95% pure in corn oil)

Rat (M)

3580 mg/kg b.w. (100% pure in corn oil)

Rat (M)

2840 mg/kg b.w. (99% pure in peanut oil)

Rat (F)

2400 mg/kg b.w. (99% pure in peanut oil)

Mouse (M)

2390 mg/kg b.w. (unknown purity in corn oil)

Mouse (M)

3140 mg/kg b.w. (unknown purity in corn oil)

Dermal LD50

 

Rat (M&F)

5000 mg/kg b.w. (in xylene)

Rabbit

3270 mg/kg b.w. (in xylene)

Dermal LD50 - formulated product - 24 hour

Rabbit

> 2000 mg/kg b.w. (undiluted Tok E-25)

Inhalation LC50 - formulated product - 1 hour

Rat (M&F)

205 mg/litre (undiluted Tok E-25)

Deaths usually occurred 2 - 8 days after exposure. Post-mortem findings were unremarkable.

Primary irritation: A 24-hour occluded application of technical (95% pure) or pure (100%) nitrofen, in oil or as a moistened powder, did not cause irritation to clipped rabbit skin.

2.1.5 Toxicity, repeated doses:

Sensitization: No sensitization was observed in guinea pigs with technical nitrofen (95% pure).

2.1.6 Dietary studies:

Short-term: A 13-week feeding study was conducted in rats at doses of 100 - 50,000 mg/kg diet. All animals of the high dose died within a week. Survival was decreased at 12,500 mg/kg diet. The growth was depressed in males at  2500 mg/kg diet and in females at 12,500 mg/kg diet. Liver weights were increased at  100 mg/kg diet (females) and at  500 mg/kg diet (males). Other organs (kidney, testes, heart and spleen) were affected at higher doses.

An increased relative liver weight was observed in beagle dogs receiving 2000 mg/kg diet (95% pure nitrofen) for two years. No other adverse effects on clinical or histopathological parameters were found. The diet level of 200 mg/kg of diet was the NOEL.

2.1.7 Carcinogenicity:

An increased incidence of hepatocellular carcinoma was observed in both sexes of B6C3F1 mice receiving a 78 week time-weighted average of 2348 or 4696 mg (technical purity stated to be > 80%)/kg diet, followed by 12 weeks on control diet. The lungs showed a dose-related incidence of small foci of metastasized liver cells. In males, an increased incidence of haemangiosarcoma was observed at the higher dose level.

In a second study with B6C3F1 mice at doses of 3000 or 6000 mg/kg diet for 78 weeks followed by 13 weeks on control diet, an increased incidence of hepatocellular adenomas and carcinomas was observed. A low incidence of hepatoblastomas was observed in males at both dose levels and one case in females at the lower dose.

A dose-related incidence of a rare, highly invasive anaplastic adenocarcinoma of the exocrine pancreas was observed in female Osborne-Mendel rats receiving 1300 or 2600 mg (technical purity stated to be > 80%)/kg diet for 78 weeks, followed by 32 weeks on control diet. These findings correlate with the sex and strain dependent accumulation of nitrofen by the pancreas (see Section 2.1.11 - Other). All of the rats with pancreatic tumours showed metastases in the lungs. Poor survival prevented evaluation of the carcinogenic potential in males.

Nitrofen was not oncogenic in Fischer 344 rats receiving 3000 to 6000 mg (technical)/kg diet for 78 weeks, followed by 26 weeks on control diet.

2.1.8 Teratogenicity:

In rats, nitrofen given either orally or dermally causes neonatal mortality because of the induced malformations in the absence of maternal toxicity. Pups exposed in utero show signs of respiratory distress associated with morphological alterations of the lungs, cardiac malformations and diaphragmatic hernias. Day 11 of gestation was the most sensitive day. Other non-lethal malformations observed were hydronephrosis, alterations of Harderian glands, hydrocephaly and thyroid abnormalities. Hydronephrosis was observed at oral and dermal doses as low as 0.3 mg/kg b.w. per day. No differences were observed between technical (89% purity) and pure (> 99%) nitrofen.

In mice, nitrofen was teratogenic (mainly cleft palate and diaphragmatic hernias were observed) at 50 mg/kg b.w. per day and above. Decreased early and late neonatal survival, reduction of the Harderian gland and delayed puberty have been observed in pups whose mothers were treated pre- and post-natally with nitrofen. Some of these effects were seen at 6.25 mg/kg b.w. per day. A cross-fostering experiment demonstrated that these effects were induced by pre-natal exposure only.

Hamsters were less susceptible since teratogenic effects were observed at 100 but not at 50 mg/kg b.w. per day.

In rabbits, no teratogenic effect was observed when dams were treated with doses of nitrofen up to 80 mg/kg b.w. per day. A slight embryolethal effect was observed at this dose.

2.1.9 Reproduction:

Increased incidence of stillbirths and almost total pup mortality were observed in two multigeneration studies in rats given diets containing 500 or 1000 mg/kg diet of nitrofen. Pup mortality was also increased at 100 mg/kg diet but not at 20 mg/kg diet (equal to 1.1 mg/kg b.w. per day).

No effect on the reproductive performance or on the outcome of pregnancy was observed when male rats treated for 95 days with nitrofen at dietary levels up to 2500 mg/kg (equal to 186 mg/kg b.w. per day) were mated with untreated females.

2.1.10 Mutagenicity:

Nitrofen showed a weak mutagenic activity in several strains of Salmonella typhimurium, with and without metabolic activation. No dose response was obtained and both the pure and technical grades showed batch dependant effects.

Photolysis products of a pure sample of nitrofen were mutagenic in S. typhimurium TA100 and the mutagenic activity was increased by subsequent metabolic activation. The metabolite 2,4 dichlorophenyl 4-aminophenyl ether and a contaminant 4,4’-dichloroazobenzene have been shown to be mutagenic in microbial tests.

No evidence of chromosonal damage was found in vivo.

2.1.11 Other:

Distribution studies were conducted with 14C-labelled nitrofen, orally administered to rats following a four week exposure to 1300 mg/kg diet. Female Osborne-Mendel rats had higher pancreatic residues of nitrofen and its metabolites than the male rats of the same strain, or either sex of Fischer rats.

No preferential foetal accumulation or formation of a unique metabolite was observed following oral administration of 120 mg 14C-nitrofen/kg b.w. to Long Evans rats on gestation day 11. Foetal levels of radioactivity were proportionately greater following dermal dosing at 0.3 mg/kg b.w. than those at 27 mg/kg b.w.

2.2 Toxicology - Man

2.2.1 Absorption Route:

In vitro experiments with human skin showed that 14-25% of nitrofen is absorbed in six hours. In the same conditions rat skin absorbed 25-62% of the applied dose. Animal studies suggest that nitrofen may also be absorbed from the gastrointestinal tract, and possibly from the lungs.

2.2.2 Dangerous doses:

No published information available.

2.2.3 Observations on occupationally exposed workers:

Studies in applicators showed that maximum daily exposure levels were up to 78 μg/kg bw.

Nitrofen has been reported to have irritating effects on the skin and eyes of occupationally-exposed subjects.

2.2.4 Observations on exposure of the general population:

No published information available.

2.2.5 Observations on volunteers:

No published information available.

2.2.6 Reported mishaps:

There is only one reported incident in a man involved recycling barrels having contained a commercial formulation of nitrofen (TokR). He complained of specific symptoms such as upper respiratory tract irritation, headache, vertigo, abdominal pain, diarrhea and vomiting. Symptoms disappeared within a week.

2.3 Toxicity - Non-Mammalian Species

2.3.1 Fish:

Toxic to fish. No published quantitative information available.

2.3.2 Birds:

No published information available.

2.3.3 Bees:

Non-toxic. No quantitative data available.

3.0 FOR REGULATORY AUTHORITIES -
RECOMMENDATIONS ON REGULATION OF COMPOUND

3.1 Recommended Restrictions On Availability

[For definition of categories see the "Introduction to data sheets".]

All formulations: Category 1.

3.2 Transportation And Storage

All formulations: Should be transported and stored in clearly labelled, rigid and leak-proof containers well away from food and drink. Storage should be under lock and key, secure from access by children and other unauthorized persons.

3.3 Handling

All formulations: Women who are pregnant or may become pregnant should not handle nitrofen. All other workers should wear protective clothing at all times (see Section 4.1.3).

Adequate washing facilities should be available in the immediate area. Eating, drinking and smoking should be prohibited during handling and before washing after handling.

3.4 Disposal And/Or Decontamination Of Containers

Decontamination of containers should not be permitted. The container should either be burned or crushed and buried below topsoil. Keep clear of the smoke when the container is burned. Care must be taken to avoid subsequent contamination of water sources.

3.5 Selection, Training And Medical Supervision Of Workers

Workers who are pregnant or may become pregnant must be excluded from contact. Women of child bearing age should be informed of the teratogenic potential of nitrofen formulations. Training of all workers in techniques to avoid contact is essential. Account should be taken of the workers’ ability to comprehend and obey instructions.

3.6 Additional Regulations Recommended If Distributed By Aircraft

Application by aircraft cannot be recommended.

3.7 Labelling

All formulations

"DANGER - POISON"

(Skull and cross-bones insignia)

This formulation contains nitrofen which may cause birth abnormalities and tumours. Women who are pregnant, or who may become pregnant, should avoid all contact with this formulation. Nitrofen is poisonous following ingestion or skin contact or following inhalation of dust or spray-mists. Clean protective clothing, including gloves and a respirator must be worn. Keep formulations out of reach of children and well away from food and feedstuffs.

3.8 Residues In Food

Maximum residue limits (MRLs) or acceptable daily intake (ADI) have not been estabished by the FAO/WHO Joint Meeting on Pesticide Residues. Guidelines values for wheat have been set at 0.01 mg/kg.

4.0 PREVENTION OF POISONING IN
MAN AND EMERGENCY AID

4.1 Precautions In Use

4.1.1 General:

Nitrofen is of low acute toxicity but single and multiple doses have been shown to cause severe teratogenic effects in laboratory animals. Laboratory tests have also shown that nitrofen is a carcinogen at doses causing general toxicity. Nitrofen may be absorbed following dermal exposure, following inhalation of powder or spray-mists and following ingestion.

Women who are pregnant or may become pregnant should avoid all contact with nitrofen formulations including equipment or clothing contaminated with nitrofen.

4.1.2 Manufacture and formulation - TLV:

Closed systems and forced ventilation may be required to reduce as much as possible the exposure of workers to nitrofen.

4.1.3 Mixers and applicators:

Mixers and applicators should wear clean overalls, impermeable boots and a respirator. Mixing, if not mechanical should always be carried out with a paddle of appropriate length. Splashes should immediately be washed from the skin with large quantities of water. Before eating, drinking or smoking, hands and exposed skin should be thoroughly washed. Clothing, including the insides of gloves, should be thoroughly washed before re-use.

4.1.4 Other associated workers:

Persons associated with nitrofen application should wear a respirator, clean overalls and gloves and should obey the precautions listed in 4.1.3 above.

4.1.5 Other populations likely to be affected:

With good application practice the general public should not be exposed to hazardous amounts of nitrofen. Pregnant women should avoid contact with contaminated equipment or clothing.

4.2 Entry Of Persons Into Treated Areas

Unprotected persons should be kept out of the area until the application has dried.

4.3 Decontamination Of Spillage And Containers

Decontamination of containers for re-use should not be permitted. Residues in containers should be emptied in a diluted form into a deep pit, taking care to avoid contamination of water sources. Empty containers should be buried in a deep pit or burned. Avoid inhalation of the smoke.

Spillage of liquid formulations should be contained by adsorbent material. This material, or spillage of dry formulations, should be collected and buried or burned. Residual contamination should be removed by washing the site with water and detergent. Impermeable gloves and boots should be worn for all decontamination procedures.

When collecting powder or granule spillage a mask should additionally be worn. Care must be taken during all operations to avoid contamination of water sources.

4.4 Emergency Aid

4.4.1 Early symptoms of poisoning:

Non-specific gastrointestinal and respiratory symptoms.

4.4.2 Treatment before person is seen by physician, if symptoms appear following exposure:

The person should stop work immediately and remove contaminated clothing. Contaminated skin should be thoroughly washed with water (and soap if available). If the compound has entered the eyes they should be thoroughly flushed with clean water. Vomiting should only be induced following ingestion of large amounts of nitrofen formulations and only if the victim is fully conscious and if it can be ensured that the formulation did not contain organic solvents or oils.

5.0 FOR MEDICAL AND LABORATORY PERSONNEL

5.1 Medical Diagnosis And Treatment In Case Of Poisoning

5.1.1 General information:

Nitrofen is a herbicide of low acute toxicity which may be absorbed from the skin, gastrointestinal tract or lungs. Single and repeated doses have been shown to be teratogenic in rodents. In chronic exposure nitrofen is carcinogenic to laboratory animals.

5.1.2 Symptoms and signs:

Skin and eye irritation. Possible sensitization, upper respiratory tract irritation, diarrhea, vomiting, abdominal pain, headache, vertigo.

5.1.3 Laboratory:

No biochemical tests available.

5.1.4 Treatment:

If the pesticide has been ingested and unless the patient is vomiting, rapid gastric lavage should be performed and activated charcoal administered. Emulsifiable concentrate formulations contain hydrocarbons and measures to prevent pulmonary complications must be followed for these formulations. After contact, the skin should be thoroughly washed with soap. If the compound has entered the eyes, they should be washed with isotonic saline or water.

5.1.5 Prognosis:

The acute toxicity is low and the chances of complete recovery following accidental exposures are good. Nitrofen is an animal teratogen and acute or repeated exposures during pregnancy may cause irreversible effects on the human foetus.

5.1.6 References to previously reported cases:

No published information available.

5.2 Surveillance Tests:

No recommended procedures.

5.3 Laboratory Methods

5.3.1 Detection and assay of compound and residues:

Product analysis is made by GLC with FID. Gascromatographic/electron capture detection methods are available for determination of nitrofen in a variety of matrices.

REFERENCES

Alder IL and JONES BM (1978), Anal Methods Pestic Plant Growth Regul, 10:403-414.

The Pesticide Manual, A World Compendium (10th Edition 1994), Tomlin, C., ed., British Crop Protection Council, 20 Bridport Road, Thornton Heath, CR4 7QG, U.K.

Burke Hurt SS, Smith JM, Hayes AW (1983), Nitrofen: a review and perspective. Toxicology, 29:1-37.

FAO/WHO (1985), Pesticide Residues in Food: 1983 Evaluations. FAO Plant Production and Protection Paper 61, Rome, Food and Agriculture Organization of the United Nations.