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ochratoxin A
Editor	Juan Carlos Basilico
Entity code	OCA
CAS registry No.	303-47-9
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Last updated	30/7/2004

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Toxicology
-IDENTIFIERS
===========

*CATALOG ID NUMBER: 001318

*CAS NUMBER: 303-47-9

*BASE CHEMICAL NAME: OCHRATOXINA

*PRIMARY NAME: OCHRATOXIN A

*CHEMICAL FORMULA: C20H18ClNO6

*STRUCTURAL FORMULA: Not printable

*WLN: T66 BVOT&J D1 GG IVMYVQ1R& JQ

*SYNONYMS:
(-)-N-((5-CHLORO-8-HYDROXY-3-METHYL-1-OXO-7-ISOCHROMANYL)CARBONYL)-3-
PHENYLALANINE
ALANINE, N-((5-CHLORO-8-HYDROXY-3-METHYL-1-OXO-7-ISOCHROMANYL)CARBONYL)-3-
PHENYL-, (-)-
N-(((3R)-5-CHLORO-8-HYDROXY-3-METHYL-1-OXO-7-ISOCHROMANYL)CARBONYL)-3-
PHENYL-L-ALANINE
NCI-C56586


-PHYSICAL CHEMICAL DATA
======================

*PHYSICAL DESCRIPTION: LITERATURE: White crystalline powder
REPOSITORY: White powder

*MOLECULAR WEIGHT: 403.84

*SPECIFIC GRAVITY: Not available

*DENSITY: Not available

*MP (DEG C): 169 C [029,033,043]

*BP (DEG C): Not available

*SOLUBILITIES:
WATER : <1 mg/mL @ 19 C (RAD)

DMSO : >=100 mg/mL @ 19 C (RAD)

95% ETHANOL : 10-50 mg/mL @ 19 C (RAD)

METHANOL : Moderately soluble [395]

ACETONE : 50-100 mg/mL @ 19 C (RAD)

TOLUENE : Not available

OTHER SOLVENTS:
Chloroform: Moderately soluble [395]

*VOLATILITY:
Vapor pressure: Not available
Vapor density : Not available

*FLAMMABILITY(FLASH POINT):
Flash point data for this chemical are not available; however, it is
probably combustible. Fires involving this material can be controlled with
a dry chemical, carbon dioxide or Halon extinguisher.

*UEL: Not available LEL: Not available

*REACTIVITY:
This chemical is incompatible with strong oxidizing agents, strong acids
and strong bases [269].

*STABILITY:
This chemical is stable in the solid state [395]. UV spectrophotometric
stability screenings indicate that solutions of this chemical in acetone are
stable for at least 24 hours and that solutions of this chemical in 95% ethanol
are stable for less than two hours (RAD).

*OTHER PHYSICAL DATA:
Intensely fluorescent in ultraviolet light, emitting green and blue
fluorescence in acid and alkaline solutions, respectively [395]
Optical rotation: -118 degrees @ 20 C (concentration = 1.1 in chloroform)
[029,033,275,395]
Lambda max (in 95% ethanol): 332 nm, 212 nm (epsilon = 6300, 33070) [052]
Melting point also reported as 90 C (from benzene) [033]


-TOXICITY
========

*NIOSH REGISTRY NUMBER: AY4375000

*TOXICITY: (abbreviations)
typ. dose mode specie amount units other
LD50 orl rat 20 mg/kg
LD50 ipr rat 12600 ug/kg
LD50 ivn rat 12750 ug/kg
LD50 orl mus 46 mg/kg
LD50 ipr mus 22 mg/kg
LD50 ivn mus 25710 ug/kg
LD50 orl dog 200 ug/kg
LD50 orl pig 1 mg/kg
LD50 orl ckn 3300 ug/kg
LDLo scu ckn 11 mg/kg
LD50 ivn dom 1 mg/kg

*AQTX/TLM96: Not available

*SAX TOXICITY EVALUATION:
THR: Poison by ingestion, intraperitoneal, intravenous and subcutaneous
routes. An experimental carcinogen and teratogen. Experimental
reproductive effects. Mutation data.

*CARCINOGENICITY:
Tumorigenic Data:
TDLo: orl-mus 2216 mg/kg/44W-C
TD : orl-mus 1478 mg/kg/44W-C
TD : orl-mus 3504 mg/kg/2Y-C
TD : orl-mus 2 gm/kg/30W-C
Review: IARC Cancer Review: Animal Limited Evidence
IARC Cancer Review: Human Inadequate Evidence
IARC: Not classifiable as a human carcinogen (Group 3) [015,395,610]
Status: NTP Carcinogenesis Studies (Gavage); Clear Evidence: Male and Female
Rat [620]

*MUTATION DATA: See RTECS printout for data

*TERATOGENICITY: See RTECS printout for data

*STANDARDS, REGULATIONS & RECOMMENDATIONS:
OSHA: None
ACGIH: None
NIOSH Criteria Document: None
NFPA Hazard Rating: Health (H): None
Flammability (F): None
Reactivity (R): None

*OTHER TOXICITY DATA:
Review: Toxicology Review-2
Status: EPA Genetox Program 1988, Positive: S cerevisiae-homozygosis
EPA Genetox Program 1988, Negative: B subtilis rec assay
EPA Genetox Program 1988, Inconclusive: Histidine reversion-Ames test


-OTHER DATA (Regulatory)
=======================

*PROPER SHIPPING NAME (IATA): Poisonous solids, n.o.s.
(Ochratoxin A)

*UN/ID NUMBER: UN2811

*HAZARD CLASS: 6.1 SUBSIDIARY RISK: None PACKING GROUP: II

*LABELS REQUIRED: Poison

*PACKAGING: PASSENGER: PKG. INSTR.: 613, Y613 MAXIMUM QUANTITY: 25 kg, 1 kg
CARGO : PKG. INSTR.: 615 MAXIMUM QUANTITY: 100 kg

*SPECIAL PROVISIONS: None

*USES:
This compound is not used commercially.

*COMMENTS:
This compound is naturally occuring in molds [033,395]. It is produced
by some species of the Penicillin group [395].


-HANDLING PROCEDURES
===================

*ACUTE/CHRONIC HAZARDS:
This compound is highly toxic orally [029]. It may be fatal by ingestion
or inhalation [269]. When heated to decomposition it emits very toxic fumes
of chlorine and nitrogen oxides [043].

*MINIMUM PROTECTIVE CLOTHING: Not available

*RECOMMENDED GLOVE MATERIALS:
GlovES+ Expert System Glove Types For The Neat (Undiluted) Chemical:
This chemical has not been tested for permeation by Radian Corporation;
however, the GlovES+ expert system was used to extrapolate permeation test
information from compounds in the same chemical class. The GlovES+ system uses
permeation data from literature sources; therefore, extra safety margins should
be used with the estimated protection time(s). If this chemical makes direct
contact with your glove, or if a tear, puncture or hole develops, replace them
at once.
The GlovES+ expert system is a tool that can help people better manage
protection from chemicals, however this tool cannot replace sound judgment nor
make technical decisions. Our GlovES+ expert system is designed to offer
initial advice and assistance in glove selection while the final glove
selection should be made by knowledgeable individuals based on the specific
circumstances involved.

Glove Type Model Number Thickness Estimated Protection Time
Butyl rubber North B-174 0.63 mm 480 min
PE/EVAL/PE Safety4 4H 0.07 mm 240 min
Nitrile Edmont 37-155 0.32 mm 240 min

*RECOMMENDED RESPIRATOR:
Where the neat test chemical is weighed and diluted, wear a NIOSH-
approved half face respirator equipped with a combination filter cartridge,
i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid
gas, SO2 and a high efficiency particulate filter).

*OTHER:
Since this chemical is a known or suspected carcinogen you should contact
a physician for advice regarding the possible long term health effects and
potential recommendation for medical monitoring. Recommendations from the
physician will depend upon the specific compound, its chemical, physical and
toxicity properties, the exposure level, length of exposure, and the route
of exposure.

*STORAGE PRECAUTIONS:
You should store this material under freezer conditions.

*SPILLS AND LEAKAGE:
Should a spill occur while you are handling this chemical, FIRST REMOVE
ALL SOURCES OF IGNITION, then you should dampen the solid spill material with
60-70% ethanol and transfer the dampened material to a suitable container. Use
absorbent paper dampened with 60-70% ethanol to pick up any remaining material.
Seal the absorbent paper, and any of your clothes, which may be contaminated,
in a vapor-tight plastic bag for eventual disposal. Solvent wash all contamin-
ated surfaces with 60-70% ethanol followed by washing with a soap and water
solution. Do not reenter the contaminated area until the Safety Officer (or
other responsible person) has verified that the area has been properly cleaned.

*DISPOSAL AND WASTE TREATMENT: Not available


-EMERGENCY PROCEDURES
====================

*SKIN CONTACT:
IMMEDIATELY flood affected skin with water while removing and isolating
all contaminated clothing. Gently wash all affected skin areas thoroughly
with soap and water.
If symptoms such as redness or irritation develop, IMMEDIATELY call a
physician and be prepared to transport the victim to a hospital for treatment.

*INHALATION:
IMMEDIATELY leave the contaminated area; take deep breaths of fresh air.
IMMEDIATELY call a physician and be prepared to transport the victim to a
hospital even if no symptoms (such as wheezing, coughing, shortness of breath,
or burning in the mouth, throat, or chest) develop.
Provide proper respiratory protection to rescuers entering an unknown
atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA)
should be used; if not available, use a level of protection greater than or
equal to that advised under Respirator Recommendation.

*EYE CONTACT:
First check the victim for contact lenses and remove if present. Flush
victim's eyes with water or normal saline solution for 20 to 30 minutes while
simultaneously calling a hospital or poison control center.
Do not put any ointments, oils, or medication in the victim's eyes without
specific instructions from a physician.
IMMEDIATELY transport the victim after flushing eyes to a hospital even if
no symptoms (such as redness or irritation) develop.

*INGESTION:
If the victim is conscious and not convulsing, give 1 or 2 glasses of
water to dilute the chemical and IMMEDIATELY call a hospital or poison control
center.
Generally, the induction of vomiting is NOT recommended outside of a
physician's care due to the risk of aspirating the chemical into the victim's
lungs. However, if the victim is conscious and not convulsing and if medical
help is not readily available, consider the risk of inducing vomiting because
of the high toxicity of the chemical ingested. Ipecac syrup or salt water may
be used in such an emergency. IMMEDIATELY transport the victim to a hospital.
If the victim is convulsing or unconscious, do not give anything by mouth,
ensure that the victim's airway is open and lay the victim on his/her side with
the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport
the victim to a hospital.

*SYMPTOMS:
Symptoms of exposure to this compound may include irritation [269].
It can also interfere with the carbohydrate metabolism of eye lenses [099].
Symptoms of exposure to this compound in animals include necrosis of
the proximal tubular epithelium of the kidneys, necrosis of lymphoid tissues
and inhibition of nucleic acid and protein synthesis [395]. Other symptoms
in animals include pulmonary edema, congestion, weight loss, hepatitis and
hepatocellular necrosis [015].


-SOURCES
=======

*SOURCES:
[015] Lewis, R.J., Sr. and R.L. Tatken, Eds. Registry of Toxic Effects
of Chemical Substances. On-line Ed. National Institute for
Occupational Safety and Health. Cincinnati, OH. AY4375000.
April 10, 1990.

[029] Buckingham, J., Ed. Dictionary of Organic Compounds. 5th Ed. and
Supplements. Chapman and Hall. New York. 1988. Supplement 1,
pp. 437-438, #O-10006.

[033] Budavari, Susan, Ed. The Merck Index. 11th Ed. Merck and Co., Inc.
Rahway, NJ. 1989. p. 1068, #6660.

[043] Sax, N.I. and Richard J. Lewis, Sr. Dangerous Properties of Industrial
Materials. 7th Ed. Van Nostrand Reinhold. New York. 1989.
Vol. II, p. 833, #CHP250.

[052] Midwest Research Institute. MRI Report for Ochratoxin A.
Kansas City, MO. January 20, 1983.

[082] U.S. Environmental Protection Agency, Office of Toxic Substances.
Toxic Substances Control Act Chemical Substance Inventory: 1985
Edition. 5 Vols. U.S. Environmental Protection Agency.
Washington, D.C. January 1986. Not listed.

[099] Grant, W. Morton, M.D. Toxicology of the Eye. 3rd Ed. Charles
C. Thomas, Publisher. Springfield, IL. 1986. p. 646.

[110] Oak Ridge National Laboratory. Environmental Mutagen Information
Center (EMIC), Bibliographic Data Base. Oak Ridge National
Laboratory. Oak Ridge, TN. Listed.

[120] Oak Ridge National Laboratory. Environmental Teratogen Information
Center (ETIC), Bibliographic Data Base. Oak Ridge National
Laboratory. Oak Ridge, TN. Listed.

[269] Lenga, Robert E. The Sigma-Aldrich Library of Chemical Safety Data.
Edition 1. Sigma-Aldrich Corporation. Milwaukee, WI. 1985.
p. 1397, #B.

[275] Aldrich Chemical Company. Aldrich Catalog/Handbook of Fine
Chemical. Aldrich Chemical Co., Inc. Milwaukee, WI.
1988. p. 1141, #85,628-2.

[395] International Agency for Research on Cancer, World Health
Organization. IARC Monographs on the Evaluation of
Carcinogenic Risk of Chemicals to Man. International
Agency for Research on Cancer. Geneva. Vol. 31, pp. 191-
206; Supplement 7, pp. 271-272.

[610] Clansky, Kenneth B., Ed. Suspect Chemicals Sourcebook: A Guide to
Industrial Chemicals Covered Under Major Federal Regulatory and
Advisory Programs. Roytech Publications, Inc. Burlingame, CA.
1990. Update, p. xxxiv.

[620] United States National Toxicology Program. Chemical Status Report.
NTP Chemtrack System. Research Triangle Park, NC. November 6, 1990.
Listed.

CARCINOGENICITY

There is sufficient evidence for the carcinogenicity of ochratoxin A in
experimental animals. When administered by gavage, ochratoxin A
substantially increased the incidence of uncommon tubular cell adenomas
and of tubular cell carcinomas of the kidney in male and female rats.
Ochratoxin A also increased the incidence and multiplicity of fibroadenomas
of the mammary gland in female rats (NTP 358, 1989). When ochratoxin A
was administered in the diet, renal adenomas and carcinomas were
observed in male mice, and some hepatocellular carcinomas were observed
in female mice in one study. In another study, administration of ochratoxin A
in the diet induced hepatomas and renal cell tumors in male mice. Other
studies by dietary administration and studies by subcutaneous injection to
mice and rats were considered inadequate in terms of the numbers of
animals used and survival rates by an IARC Working Group. Based on
these observations, the IARC Working Group considered the evidence for
the carcinogenicity of ochratoxin A to be limited. The IARC Working group
had not yet evaluated the NTP data (IARC V.31, 1983; IARC S.7, 1987;
NTP 358, 1989). In view of a NCI/OTA correlative interpretation, the
evidence may be regarded as sufficient (Griesemer & Cueto, 1980; OTA,
1981).

An IARC Working Group reported that there were no adequate data
available to evaluate the carcinogenicity of ochratoxin A in humans.
Incidence of and mortality from urothelial urinary tract tumors have been
correlated with the geographical distribution of Balkan endemic nephropathy
in Bulgaria and Yugoslavia. A relatively high frequency of contamination of
cereals and bread with ochratoxin A has been reported in an area of
Yugoslavia where Balkan endemic nephropathy is present. No report of a
direct association between ochratoxin A and human cancer is available
(IARC V.10, 1976; IARC V.31, 1983; IARC S.7 1987).

PROPERTIES

Ochratoxin A is a toxic metabolite produced primarily by Aspergillus but
also by Penicillium and other molds. Recrystallized from xylene, it forms
crystals that emit green (acid solution) and blue (alkaline solution)
fluorescence in ultraviolet light; the melting point of these crystals is 169°C.
The free acid of ochratoxin A is soluble in polar organic solvents (IARC
V.31, 1983). The sodium salt is soluble in water. Ochratoxin A is unstable
to light and air, degrading and fading even after brief exposure to light
especially under humid conditions. Ethanol solutions are stable for longer
than 1 year if kept in the dark and cold. Ochratoxin A is fairly stable to heat;
in cereal products, up to 35% of the toxin survives autoclaving for up to 3
hours. When heated to decomposition, the toxin emits toxic fumes of
chlorine and NOx.

USE

The toxin has no known commercial use but is an experimental teratogen
and carcinogen (IARC V.31, 1983; Sax and Lewis, 1987).

PRODUCTION

Ochratoxin A is not produced commercially; however, it was previously
offered for sale by one foreign firm (IARC V.10, 1976).

EXPOSURE

Ochratoxin A is a naturally occurring mycotoxin. Its widespread occurrence
in food and animal feed results in probable human exposure. Mycotoxins
may well be among the world's most significant food contaminants
(Fischbach and Rodricks, 1973). Ochratoxin-producing fungi are included
in the Penicillium and Aspergillus genera (IARC V.10, 1976). In the colder
climates, ochratoxin A is formed by Penicillium strains and in tropical and
subtropical areas, by Aspergillus. Ochratoxin A is a natural contaminant on
corn, peanuts, storage grains, cottonseed, and decaying vegetation (Merck,
1989). It has been detected in moldy cereals including wheat, maize, rye,
barley, and oats; peanuts; coffee beans; bread; flour; rice; peas; and beans
(IARC V.31, 1983). Detected contamination levels in cereals range from
0.03 ppm to 27.5 ppm (Scott et al., 1972; Krogh et al., 1973). Although
the carryover from barley into beer is possible, one survey of all 130 U.S.
breweries did not detect ochratoxin A (up to 10 µg/kg) in beer or malted
barley (Fischbach and Rodricks, 1973; IARC V.31, 1983). The malting
process completely degrades the toxin in moderately contaminated barley,
but 2%-7% of the toxin was carried over to the final product from a heavily
contaminated lot (Krogh et al., 1974; IARC, 1983). Up to 28% of added
toxin was detected in a final beer product (Chu et al., 1975).

Residues of ochratoxin A have been detected in samples of meat from
animals slaughtered immediately after consuming contaminated feed (Krogh,
1977; IARC V.31, 1983). It has been detected at levels of 10-920 µg/kg in
sausage, ham, and bacon samples (IARC V.31, 1983).

No direct evidence of worker exposure has been reported. Potential worker
exposure exists for all personnel handling and storing grains, nuts, corn,
cereals, and animal feeds.

REGULATIONS

OSHA regulates ochratoxin A under the Hazard Communication Standard
and as a chemical hazard in laboratories.

Detection

Sampling

Methods

MRLs

Uses

Ochratoxin A is a naturally occurring fungal toxin that is a contaminant in
corn, peanuts, storage grains, cottonseed, meats, dried fish, and nuts.
Toxicology and carcinogenesis studies were conducted by administering
ochratoxin A (98% pure) in corn oil by gavage to groups of F344/N rats of each
sex for 16 days, 13 weeks, 9 months, 15 months, or 2 years. Only rats were
studied because ochratoxin A has been shown to be carcinogenic in mice.
Genetic toxicology tests were performed with bacterial and mammalian cells.
Urinalysis, hematologic and serum chemical analyses, and bone marrow
cellularity determinations were conducted at 9, 15, and 24 months in the
2-year
studies.

Notes

Bibliography

Mode of action

Ecotoxicology

Plant metabolism & residues

Notes

Notes

Notes

Notes