LIMONENE
CASRN: 138-86-3
For other data, click on the Table of Contents
Human Health Effects:
Evidence for Carcinogenicity:
Evaluation: No data were available on the carcinogenicity of d-limonene
to humans. Overall evaluation: d-Limonene is not
classifiable as to its carcinogenicity to humans (Group 3).
Human Toxicity Excerpts:
NO TOXIC REACTIONS HAVE BEEN DESCRIBED OTHER THAN MILD LOCAL IRRITATION & SKIN
SENSITIZATION, BUT ALBUMINURIA & HEMATURIA ARE PROBABLE IF INGESTED IN SUFFICIENT
QUANTITY.
DIPENTENE TESTED /AS IRRITATION TEST/ AT 20%
IN PETROLATUM PRODUCED NO IRRITATION AFTER A 48 HR CLOSED PATCH TEST IN 25 HUMAN SUBJECTS.
A MAXIMIZATION TEST ... WAS CARRIED OUT ON 25 VOLUNTEERS. THE MATERIAL WAS TESTED @ CONCN
OF 20%, IN PETROLATUM & PRODUCED NO SENSITIZATION REACTIONS.
FOLLOWING DENTAL SURGERY, PATIENT PRESENTED WITH INTENSE SWELLING OF HIS TONGUE, LIPS,
& GINGIVAL MUCOSA. TESTING REVEALED HYPERSENSITIVITY TO PEPPERMINT OIL (A DENTAL
PREPN), DUE TO SENSITIZING PROPERTIES OF INGREDIENTS SUCH AS LIMONENE.
THREE CASES OF ALLERGIC CONTACT DERMATITIS FROM DIPENTENE
IN SAME BRAND OF HONING OIL REPORTED. MANUFACTURER HAS SINCE REPLACED IT WITH AN
ALTERNATIVE.
The toxicokinetics of d-limonene were studied
in human volunteers exposed by inhalation (2 hr, work load 50 W) in an exposure chamber on
three different occasions. The exposure concn were approximately 10, 225, and 450 mg/cu m
d-limonene. The relative pulmonary uptake was
high, approximately 70% of the amount supplied. A decrease in vital capacity was observed
after exposure to d-limonene at a high exposure
level. The subjects did not experience any irritative symptoms or symptoms related to the
CNS.
Skin, Eye and Respiratory Irritations:
Skin irritant.
Liquid irritates eyes; ingestion causes irritation of GI tract.
Probable Routes of Human Exposure:
Occupational exposure to limonene may occur
by inhalation or dermal contact during its production, formulation, transport or use.
Exposure to the general population may occur by inhalation due to its presence in the
atmosphere as a result of its release from natural sources(1,2), its presence in household
products, or by ingestion of food in which it occurs either naturally or has been added as
a flavor or fragrance(SRC).
NIOSH (NOES Survey 1981-83) has statistically estimated that 94,910 workers are exposed
to limonene in the USA(1). Limonene
was detected in the air of the vulcanization area of a shoe-sole factory at a concn of
25-130 ug/cu m, and at 5-1700 ug/cu m in the vulcanization area of a tire retreading
factory(2). Limonene was detected indoors in an
office building, 1987, at a concn ranging from 43-63 ug/cu m(3). Limonene
was qualitatively detected in air samples taken at 2 Stockholm preschools, 1981-2(4).
Body Burden:
Limonene has been identified in the expired
air of urban volunteers(1). Limonene was
qualitatively detected in 8 of 8 samples of mother's milk obtained from residents of urban
centers in PA, NJ, and LA(2).
Emergency Medical Treatment:
Emergency Medical Treatment:
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replication or redistribution of all or part of the POISINDEX(R) database is a violation
of Micromedex' copyrights and is strictly prohibited. The following Overview, *** LIMONENE ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted.
|
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o HUMAN - Limonene is most likely of low toxicity. Mild
dermal irritation and skin sensitization may occur.
Hematuria and albuminuria might occur if large amounts
are ingested.
o MICE - Somnolence and hypothermia have been noted in
mice. Gastric epithelial irritation was caused by oral
administration in mice.
o CATS completely wetted with a limonene-containing
insecticidal dip developed skin excoriation,
hypersalivation, transient blepharospasm in directly
exposed eyes, hypothermia, muscle tremors, and ataxia.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Aspiration might produce lipoid pneumonitis.
GENITOURINARY
0.2.10.1 ACUTE EXPOSURE
o Hematuria and albuminuria might occur.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Dermal irritation and sensitization may occur.
Percutaneous absorption may occur.
|
| Laboratory: |
o Monitor urinalysis, urine output, and renal function tests
in patients with significant exposure.
|
| Treatment Overview: |
SUMMARY EXPOSURE
o Inducing emesis should be avoided if gastric irritation
occurs. If somnolence and ataxia occur, adequate
respirations and oxygenation should be assured. Monitor
temperature and instituted warming measures for
hypothermia. Urinalysis, urine output, and renal
function tests should be monitored in significant
exposures.
o Dermal irritation and skin sensitization may require
treatment with standard topical therapies.
ORAL EXPOSURE
o DILUTION: Following ingestion and/or prior to gastric
evacuation, immediately dilute with 4 to 8 ounces (120
to 240 mL) of milk or water (not to exceed 15 mL/kg in a
child).
o GASTRIC LAVAGE: Consider after ingestion of a
potentially life-threatening amount of poison if it can
be performed soon after ingestion (generally within 1
hour). Protect airway by placement in Trendelenburg and
left lateral decubitus position or by endotracheal
intubation. Control any seizures first.
1. CONTRAINDICATIONS: Loss of airway protective reflexes
or decreased level of consciousness in unintubated
patients; following ingestion of corrosives;
hydrocarbons (high aspiration potential); patients at
risk of hemorrhage or gastrointestinal perforation; and
trivial or non-toxic ingestion.
o ACTIVATED CHARCOAL: Administer charcoal as slurry (240
mL water/30 g charcoal). Usual dose: 25 to 100 g in
adults/adolescents, 25 to 50 g in children (1 to 12
years), and 1 g/kg in infants less than 1 year old.
o Observe patients with ingestion carefully for the
possible development of esophageal or gastrointestinal
tract irritation or burns. If signs or symptoms of
esophageal irritation or burns are present, consider
endoscopy to determine the extent of injury.
o Carefully observe patients for the development of any
systemic signs or symptoms and administer symptomatic
treatment as necessary.
INHALATION EXPOSURE
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
o If aspiration occurs, monitor temperature, WBC, arterial
blood gases, and chest x-ray. Administer oxygen as
required.
EYE EXPOSURE
o DECONTAMINATION: Irrigate exposed eyes with copious
amounts of tepid water for at least 15 minutes. If
irritation, pain, swelling, lacrimation, or photophobia
persist, the patient should be seen in a health care
facility.
DERMAL EXPOSURE
o DECONTAMINATION: Remove contaminated clothing and wash
exposed area thoroughly with soap and water. A
physician may need to examine the area if irritation or
pain persists.
o Treat dermal irritation or burns with standard topical
therapy. Patients developing dermal hypersensitivity
reactions may require treatment with systemic or topical
corticosteroids or antihistamines.
o Some chemicals can produce systemic poisoning by
absorption through intact skin. Carefully observe
patients with dermal exposure for the development of any
systemic signs or symptoms and administer symptomatic
treatment as necessary.
|
| Range of Toxicity: |
o Minimum lethal human exposure is unknown. |
Animal Toxicity Studies:
Evidence for Carcinogenicity:
Evaluation: No data were available on the carcinogenicity of d-limonene
to humans. Overall evaluation: d-Limonene is not
classifiable as to its carcinogenicity to humans (Group 3).
Non-Human Toxicity Excerpts:
D-LIMONENE SOLUTION INJECTED AS BOLUS INTO
BILIARY TRACT OF CATS PRODUCED HEPATOBILIARY TISSUE DAMAGE, DEPENDING ON CONTACT TIME,
VOLUME AND FLOW DIRECTION OF THE SOLUTION. /D-LIMONENE/
STUDY OF CHROMATOGRAPHIC DATA OF GLC PROFILES FROM TOTAL PARTICULATE MATTER OF 8 EXPTL
CIGARETTES. D-LIMONENE WAS 1 PEAK IDENTIFIED
THAT CORRELATED WITH CARCINOGENIC ACTIVITY WHEN PAINTED ON MICE SKIN. D-LIMONENE
IS BEST INDICATOR THUS FAR OF TOBACCO SMOKE BIOLOGICAL ACTIVITY. /D-LIMONENE/
2363 MG/KG GIVEN ORALLY TO MICE FOR 6 DAYS FROM DAY 7 TO DAY 12 OF GESTATION DECR BODY
WT GAIN & INCR INCIDENCE OF ABNORMAL BONE FORMATION IN FETUSES. ALSO DECR BODY WT GAIN
IN MALE OFFSPRING. TOXICITY WAS NOT SEVERE.
ADMIN TO DOGS @ 1.2-3.6 ML/KG/DAY FOR 6 MONTHS CAUSED FREQUENT VOMITING & NAUSEA
& DECR IN BODY WT, BLOOD SUGAR & CHOLESTEROL. NO SIGNIFICANT CHANGE OBSERVED IN
ORGANS EXCEPT IN THE KIDNEY.
AMINOPYRINE DEMETHYLASE & ANILINE HYDROXYLASE INCR 26 & 22% BY REPEATED ORAL
ADMIN OF 400 MG/KG FOR 30 DAYS TO RATS. DECR PLASMA & LIVER CHOLESTEROL & ALTERED
FATTY ACIDS OF LIVER PHOSPHOLIPIDS. ENZYMES NOT AFFECTED AFTER SINGLE DOSE OF 200-1200
MG/KG.
ORALLY 227-1385 MG/KG/DAY CAUSED SLIGHT DECR IN BODY WEIGHT, LITTLE OR NO CHANGE IN
WATER & FOOD CONSUMPTION IN RATS. NO HISTOPATHOLOGICAL CHANGES, EXCEPT GRANULAR CASTS
IN KIDNEY OF SOME MALE RATS.
LIMONENE WAS INHIBITORY /HEPATIC HMGCoA
(HYDROXY-3-METHYLGLUTARYL-CoA) REDUCTASE/ WHEN ADMIN INTRAGASTRICALLY @ 3 MMOL/KG TO RATS.
Naturally occurring compounds belonging to two chemical groups were studied for their
capacities to inhibit N-nitrosodiethylamine-induced carcinogenesis in female A/ mice. One
group consisted of D-limonene and D-carvone. ...
Test compounds were given orally either 15 min or 1 hr prior to NDEA. Under these
conditions, D-limonene and D-carvone reduced
forestomach tumor formation by about 60% and pulmonary adenoma formation by about 35%. /D-limonene/
Adult male and female Sprague Dawley rats were given single oral doses of 0, 0.1, 0.3,
1, or 3 mmol d-limonene/kg (0, 14, 41, 136, or
409 mg/kg) in corn oil. A dose response relationship for acute exacerbation of hyaline
droplets by d-limonene treatment was observed.
Hyaline droplets were graded according to size, eosinophilic intensity, and the number of
tubules loaded with droplets. Control rats received a mean score of 3. At 3 mmol/kg, admin
of d-limonene resulted in a score of 10. At 0.1
mmol/kg, no effect on hyaline droplet accumulation was seen in male rats. 24 hr after
admin of 3 mmol d-limonene/kg, the renal
concentration of d-limonene equivalents was
approximately 2.5 times higher in male rats than in female rats. Equilibrium dialysis in
the presence or absence of sodium dodecyl sulfate indicated that approximately 40% of the
d-limonene equivalents in male rat kidney
associated with proteins in a reversible manner, whereas no significant association was
observed between d-limonene equivalents and
female rat kidney proteins. Gel filtration HPLC indicated that d-limonene
in male rat kidney is associated with a protein fraction having a mol wt of approximately
20,000. Using reverse phase HPLC, d-limonene was
shown to be associated with alpha-2u-globulin which was identified by amino acid
sequencing. The major metabolite associated with alpha-2u-globulin was d-limonene-1,2-oxide.
Parent d-limonene was also identified as a minor
component in the alpha-2u-globulin fraction. /D-limonene/
d-Limonene was not mutagenic in four strains
of Salmonella typhimurium (TA98, TA100, TA1535, or TA1537), did not significantly increase
the number of trifluorothymidine resistant cells in the mouse L5178Y/TK + or - assay, and
did not induce chromosomal aberrations or sister chromatid exchanges in cultured chinese
hamster ovary cells. All assays were conducted in the presence and absence of exogenous
metabolic activation (S9).
Inhibition of cholesterol biosynthesis occurred in the small intestine of rats after
administration of d-limonene for 7 days, but no
significant effect on the secretion of radiolabeled cholesterol into bile and feces was
observed. d-Limonene increased the perfusion
pressure of the sphincter of Oddi in dogs when injected iv or directly into the common
bile duct. d-Limonene has also been used
successfully for the postoperative dissolution of retained cholesterol gallstones. /D-limonene/
There is a diverse group of hydrocarbons that induce a specific spectrum of
nephropathic alterations. Examples include d-limonene,
an aromatic hydrocarbon. Only male rats develop kidney alterations upon exposure. Other
mammals such as female rats, mice, guinea pigs, dogs and monkeys evidently are refractory
to kidney injury upon exposure. The male rat hydrocarbon nephropathy should not be
predictive of a normal human renal response.
The role of alpha2-microglobulin in xenobiotic induced nephropathy was examined in
rats. Male NCI Black Reiter rats were administered various cmpd including 1650 mg/kg d-limonene by gavage daily for 4 days. Twenty four hours
after the last dose, the animals were killed and the kidneys were removed and sectioned.
Nephrotoxicity was assessed by examining the sections for the presence of hyaline droplets
and other histological changes. The sections were assayed for alpha2-microglobulin using a
histochemical technique. Lindane induced hyaline droplet formation in male, but not
female, F344 rats. d-Limonene did not induce
hyaline droplet formation or alpha2-microglobulin production in male NCI Black Reiter
rats. It was concluded that the presence of alpha2-microglobulin is necessary for the
development of kidney disease in male rats exposed to d-limonene.
The monocyclic monoterpenoid compounds limonene
and sobrerol have anticarcinogenic activity when fed during the initiation stage of
dimethylbenz(a)anthracene induced rat mammary carcinogenesis. The potential roles of
hepatic glutathione-S-transferase and uridine diphosphoglucuronosyl transferase were
studied in monoterpene-mediated chemoprevention. Diets containing the isoeffective
anticarcinogenic terpenes, 5% limonene or 1%
sobrerol, elevated hepatic glutathione-S-transferase activity > 2 fold when measured
using the general substrate 1-chloro-2,4-dinitrobenzene and 3,4-dichloronitrobenzene for
the glutathione-S-transferase dimer 3-3. However, there were no significant changes in
hepatic glutathione-S-transferase activity when 1,2-epoxy-3-(p-nitrophenoxy)propane was
used. Liver glutathione-S-transferase subunit 3 had the greatest increase followed by 1
and 4 with no change in subunit 2. Both terpene diets significantly increased the activity
of the methylcholanthrene inducible and the phenobarbital inducible uridine
diphosphoglucuronosyl transferase isozymes. It was proposed that much of the
anticarcinogenic activity of these monocyclic monoterpenes during the initiation phase of
dimethylbenz[a]anthracene carcinogenesis is mediated through the induction of the hepatic
detoxification enzymes glutathione-S-transferase and uridine diphosphoglucuronosyl
transferase.
The nephrotoxicity of d-limonene was studied
in rats and mice. Kidney sections taken from male rats, strain not specified, that had
been part of a 91 day oral dosing study of limonene
in rats and mice, were examined by light microscopy. The study showed that renal
alterations were induced only in male rats. Dose related decreases in absolute weight gain
and relative weight gain (expressed as a percentage of the control weight gain) also
occurred. The 2400 mg/kg dose killed nine of ten female rats. Kidney sections of male rats
showed that limonene caused cytoplasmic
basophilia of proximal convoluted tubule cells, tubular hyperplasia or atrophy, fibrosis
of Bowman's capsule, and an interstitial fibrolymphocytic response. The severity of the
lesions was dose related except in rats given 2400 mg/kg limonene.
The severity of the lesions in the 2400 mg/kg group was similar to those seen in rats
given 150 mg/kg. Occasional foci of proximal convoluted tubule epithelial cell necrosis of
degeneration were seen in all treated rats. Granular casts were seen in the outer medulla
of animals that survived to the end of the study except for one rat in the 2400 mg/kg
group. No hyaline droplet accumulation within the cytoplasm of proximal convoluted tubule
epithelial cells was seen. Except for the absence of hyaline droplet formation, the
changes induced by limonene are similar to those
seen in male rats exposed to decalin.
The allergenic potential of d-limonene
oxidation products was examined. Samples of d-limonene
were exposed to air or unexposed in a preliminary experiment. The concn of d-limonene decreased after 8 wk air exposure. Carvone,
cis and trans limonene oxide, and cis and trans
carveal were the major oxidation products detected. Only slight decomposition was seen in
nonexposed d-limonene. Dunkin-Hartley guinea
pigs were induced by topical application of (+)-limonene
oxide, (R)-(-)-carvone, (-)-carveal, or air exposed d-limonene.
(+)-Limonene oxide and (-)-carveal consisted of
mixtures of cis and trans isomers of the two compounds. The sensitizing potential of the
compounds was assessed by the Freund complete adjuvant test after challenge with (+)-limonene oxide. Other guinea pigs were induced with
air exposed d-limonene. The sensitizing
potential of air exposed or nonexposed d-limonene,
(+)-limonene oxide, or (R)-(-)-carvone was
evaluated by the guinea pig maximization test. Air exposed d-limonene
was a strong sensitizer in both the Freund complete adjuvant test and guinea pig
maximization test. d-Limonene that was not air
exposed exhibited no sensitizing potential. (+)-Limonene
oxide and R-(-)-carvone, but not (-)-carveal, were potent sensitizers. Air oxidation of d-limonene is necessary for its sensitizing potential.
Air oxidation produces potent allergens such as limonene
oxide and carvone.
d-Limonene, a monocyclic monoterpenoid with
known insecticidal properties, was assayed (by a standard method of cutaneous exposure)
for general lethality effects as well as neurotoxic effects on escape reflex pathways in
earthworms, Eisenia fetida (Savigny). Neurotoxicity was assessed by noninvasive
electrophysiological techniques involving (a) quantification of the impacts of chronic and
acute sublethal exposures on impulse conduction in the worms' medial and lateral giant
nerve fiber pathways, (b) determination of whether such effects were generalized or
localized within various body regions, and (c) determination of the reversibility of
neurotoxic effects. The LD50 value for d-limonene
alone was 6.0 ppm, and the LT50 value for exposure to 12.6 ppm was 4.9 hr. Effects on
lethality were not synergized significantly by either piperonyl butoxide or sesame oil.
Generally, chronic and acute intoxication involved a rapid and predictable cascade of
behavioral and morphological symptoms, including increased mucus secretion, writhing,
clitellar swelling, and elongation of the body. In addition, chronic d-limonene
exposures induced significant weight loss, but there was no effect on median giant nerve
fiber and lateral giant nerve fiber conduction velocities, even though abnormal rebounding
of median giant nerve fiber impulses and spontaneous lateral giant nerve fiber spiking
were often evident. Acute exposures, however, induced significant decreases in conduction
velocity in both the median giant nerve fiber and lateral giant nerve fiber, but the
effects were regionally specific; for example, lateral giant nerve fiber velocities were
significantly reduced in the posterior half of the body but not in the anterior half. The
magnitude of conduction velocity decreases was directly related to both concn and duration
of exposure. Decreases in conduction velocities after acute exposures were reversed once
d-limonene exposure ceased.
The anticarcinogenic effects of monocyclic monoterpenes such as limonene
were demonstrated when given during the initiation phase of 7,12-dimethylbenz[a]anthracene
induced mammary cancer in Wistar-Furth rats. The possible mechanisms for this
chemoprevention activity including limonene's
effects on 7,12-dimethylbenz(a)anthracene-DNA adduct formation and hepatic metabolism of
7,12-dimethylbenz[a]anthracene were investigated. Twenty four hours after carcinogen
administration, there were approx 50% decreases in 7,12-dimethylbenz(a)anthracene-DNA
adducts found in control animals formed in the liver, spleen, kidney and lung of limonene fed animals. While circulating levels of
7,12-dimethylbenz(a)anthracene and/or its metabolites were not different in control and limonene fed rats, there was a 2.3 fold increase in
7,12-dimethylbenz(a)anthracene and/or 7,12-dimethylbenz(a)anthracene derived metabolites
in the urine of the limonene fed animals. Limonene and sobrerol, a hydroxylated monocyclic
monoterpenoid with increased chemoprevention activity, modulated cytochrome p450 and
epoxide hydrolyase activity. The 5% limonene
diet increased total cytochrome p450 to the same extent as phenobarbital treatment, while
1% sobrerol (isoeffective in chemoprevention to 5% limonene)
did not. However, both 5% limonene and 1%
sobrerol diets greatly increased the levels of microsomal epoxide hydrolyase protein and
associated hydrating activities towards benzo[a]pyrene 4,5-oxide when compared to control
and phenobarbital treatment. These changes also modified the rate and regioselectivity of
in vitro microsomal 7,12-dimethylbenz(a)anthracene metabolism when compared to
phenobarbital treatment or control. Identification of the specific isoforms of cytochrome
p450 induced by these terpenoids was performed with antibodies to cytochrome p450 isozymes
in Western blot analysis and inhibition studies of microsomal
7,12-dimethylbenz(a)anthracene metabolism. Five percent limonene
was more effective than 1% sobrerol at increasing the levels of members of the cytochrome
p450 2B and 2C families but was equally effective at increasing epoxide hydrolyase.
Furthermore, both terpenoid diets caused increased formation of the proximate carcinogen,
7,12-dimethylbenz(a)anthracene 3,4-dihydrodiol.
National Toxicology Program Studies:
Two year studies of d-limonene /more than 99%
pure/ were conducted by administering 0, 75, or 150 mg/kg d-limonene
in corn oil by gavage to groups of 50 F344/N male rats, 5 days per week for 103 weeks;
groups of 50 female F344/N rats were administered 0, 300, or 600 mg/kg. Mean body weights
of rats dosed with d-limonene were similar to
those of vehicle controls throughout the studies. Survival of the high dose female rats
after week 39 and of the vehicle control male rats after week 81 was significantly reduced
(survival at week 104--male: vehicle control, 29/50; low dose, 33/50; high dose, 40/50;
female: 42/50; 40/50; 26/50). The kidney was confirmed as the primary target organ for
chemically related lesions. No lesions were observed in female rats. For males, the
nonneoplastic lesions included exacerbation of the age-related nephropathy, linear
deposits of mineral in the renal medulla and papilla, and focal hyperplasia of the
transitional epithelium overlying the renal papilla. Uncommon tubular cell adenomas and
adenocarcinomas of the kidney also occurred in dosed male rats, and this effect was
supported by a dose-related increased incidence of tubular cell hyperplasia. ... There was
clear evidence of carcinogenic activity of d-limonene
for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia,
adenomas, and adenocarcinomas of the kidney. There was no evidence of carcinogenic
activity of d-limonene for female F344/N rats
that received 300 or 600 mg/kg. /D-Limonene/
Groups of 50 male B6C3F1 mice were administered 0, 250, 500 mg/kg, ... /5 days per week
for 103 weeks/; groups of 50 female B6C3FI mice were administered 0, 500, or 1000 mg/kg.
Mean body weights of dosed and vehicle control male mice were similar throughout the
studies. Mean body weights of high dose female mice were notably lower than those of the
vehicle controls after week 28. Survival of the low dose group-of male mice was
significantly lower than that of vehicle controls at the end of the study (33/50; 24/50;
39/50). No difference in survival was observed between vehicle control and dosed female
mice (43/50; 44/50; 43/50). ... No chemically related increases in neoplasms were
observed. The incidence of neoplasms of the anterior pituitary gland in high dose female
mice was lower than that in vehicle controls (adenomas or carcinomas, combined: vehicle
control, 12/49; high dose, 2/48). Cells with an abnormal number of nuclei (8/49; 32/50)
and cytomegaly (23/49; 38/50) were observed in the liver of high dose male mice. There was
no evidence of carcinogenic activity of d-limonene
for male B6C3Fl mice that received 250 or 500 mg/kg. There was no evidence of carcinogenic
activity of d-limonene for female B6C3Fl mice
that received 500 or 1000 mg/kg.
Non-Human Toxicity Values:
LD50 Mouse oral 5.6-6.6 g/kg
LD50 Mouse ip 1.3 g/kg
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
AFTER ORAL ADMIN, MAJOR METABOLITE IN URINE WAS PERILLIC ACID 8,9-DIOL IN RATS &
RABBITS, PERILLYL-BETA-D-GLUCOPYRANOSIDURONIC ACID IN HAMSTERS, P-MENTH-1-ENE-8,9-DIOL IN
DOGS, & 8-HYDROXY-P-MENTH-1-EN-9-YL-BETA-D-GLUCOPYRANOSIDURONIC ACID IN GUINEA PIGS
AND MAN.
Adult male and female Sprague Dawley rats were given single oral doses of 0, 0.1, 0.3,
1, or 3 mmol d-limonene/kg (0, 14, 41, 136, or
409 mg/kg) in corn oil. Gel filtration HPLC indicated that d-limonene
in male rat kidney is associated with a protein fraction having a mol wt of approximately
20000. Using reverse phase HPLC, d-limonene was
shown to be associated with alpha-2u-globulin which was identified by amino acid
sequencing. The major metabolite associated with alpha-2u-globulin was d-limonene-1,2-oxide.
Parent d-limonene was also identified as a minor
component in the alpha-2u-globulin fraction. /d-Limonene/
The major urinary metabolites of d-limonene
were identified as perillic acid-8,9-diol in rats and rabbits,
perillyl-beta-D-glucopyranosiduronic acid in hamsters, p-menth-l-ene-8,9-diol in dogs, and
8-hydroxy-p-menth-1-ene-9-yl-beta-D-glucopyranosiduronic acid in guinea pigs andhumans.
... Five new metabolites /were isolated/ from dog and rat urine after oral administration
of radiolabeled d-limonene:
2-hydroxy-p-menth-8-en-7-oic acid, perillylglycine , perillyl-beta-D-glucopyranosiduronic
acid, p-mentha-1,8-diene-6-ol, and probably p-menth-1-ene-6,8,9-triol. /d-Limonene/
Absorption, Distribution & Excretion:
THE DATA SUGGEST THAT MONOTERPENES ARE POORLY RESORBED IN THE GI TRACT. THE RESORBED
PORTION OF HYDROCARBONS ACCUMULATES IN THE LIPOPHILIC BODY COMPARTMENTS & IS
METABOLIZED & THEN EXCRETED BY THE KIDNEYS.
AFTER ORAL ADMIN OF (14)C-LABELED D-LIMONENE
TO ANIMALS & MAN, 75-95 & LESS THAN 10% OF THE RADIOACTIVITY WAS EXCRETED IN THE
URINE & FECES RESPECTIVELY WITHIN 2-3 DAYS. /D-LIMONENE/
PERCUTANEOUS ABSORPTION OF RADIOACTIVE LIMONENE
FROM FOAM BATH WAS MEASURED IN ANIMALS. MAXIMUM BLOOD LEVEL REACHED AFTER 10 MIN OF
EXPOSURE & THE CONCN WAS PROPORTIONAL TO THE SKIN EXPOSED.
The toxicokinetics of d-limonene were studied
in human volunteers exposed by inhalation (2 hr, work load 50 W) in an exposure chamber on
three different occasions. The exposure concn were approximately 10, 225, and 450 mg/cu m
d-limonene. The relative pulmonary uptake was
high, approximately 70% of the amount supplied. The blood clearance of d-limonene
observed in this study, 1.1 l/kg/hr, indicates that d-limonene
is metabolized readily. About 1% of the total uptake was eliminated unchanged in the
expired air after the end of exposure, while approximately 0.003% was eliminated in the
urine. A long half-time in blood was observed in the slow elimination phase, which
indicates accumulation in adipose tissues.
Interactions:
RAUSCHER MURINE LEUKEMIAVIRUS INFECTED F344 RAT EMBRYO CELLS WERE NOT TRANSFORMED
TREATED WITH SUBEFFECTIVE DOSES OF 3-METHYLCHOLANTHRENE. THESE CELLS TREATED WITH LIMONENE SHOWED CARCINOGENIC TRANSFORMATION.
The monoterpene d-limonene has been shown to
an effective, non-toxic chemopreventive agent in mammary and other rodent tumor models.
The studies reported here investigated structure activity relationships among limonene and three hydroxylated derivatives in the
prevention of dimethylbenz[a]anthracene induced mammary cancer. Rats were fed control or
1% limonene, carveol, uroterpenol or sobrerol
diets from 2 wk before to one week after carcinogen administration. Carveol, uroterpenol
and sobrerol significantly prolonged tumor latency and decreased tumor yield. Sobrerol was
the most potent of the monoterpenes tested, decreasing tumor yield to half that of the
control, a level previously achieved with 5% limonene
diets. Excretion of radioactivity from (3)H dimethylbenz(a)anthracene was doubled in rats
fed 5% limonene and nearly tripled in rats fed
1% sobrerol. Sobrerol is thus 5 fold more potent than limonene
in both enhancing carcinogen excretion and in preventing tumor formation. These data
demonstrate that hydroxylation of monoterpenes affects chemopreventive potential, with 2
hydroxyl groups greater than 1 greater than 0. Sobrerol, carveol and uroterpenol are novel
cancer chemopreventive agents with little or no toxicity.
To identify possible hazards of combined exposure to chemicals with the same target
organ, a 24 hr single dose experiment was carried out in which the renal toxicity of
mercuric chloride, potassium dichromate, d-limonene
and hexachloro-1:3-butadiene administered simultaneously was compared with the
nephrotoxicity of the individual compounds in 12 wk old male Wistar rats. The dose levels
used were based on the results of a range finding study with the individual compounds in
the same strain of rats kept under similar experimental conditions, and comprised the
'Minimum Nephrotoxic Effect Level' and the 'No Nephrotoxic Effect Level' of each of the
four compunds alone and in combination. A group of vehicle treated rats served as
controls. At the 'Minimum Nephrotoxic Effect Level' of the combinations, antagonism of
effects was encountered, seen for example as less severely increased activity of
gamma-glutamyl transferase in the urine. Synergism of effects was also observed, for
example increased severity of renal tubular necrosis, and more markedly increased activity
of urinary lysozyme, lactate dehydrogenase, alkaline phosphatase and
N-acetyl-beta-glucosaminidase. More importantly, however, at the 'No Nephrotoxic Effect
Level' of the combination no signs of impaired renal function or renal damage were
observed, suggesting absence of both dose additivity and potentiating interaction at the
tested subeffective levels of the individual nephrotoxicants.
Mouse mammary glands respond to carcinogen stimulus to form mammary lesions in organ
culture. In this study it was determined whether the effective chemopreventive agents are
active against initiation or the promotion phase of lesion development. Mammary glands
were subjected to 24 hr exposure to 2 mg/ml dimethylbenz(a)anthracene followed by a 5 day
exposure to 7,12-tetradecanoyl phorbol-13-acetate. This treatment protocol allows the
study of initiation and promotion aspects of lesion development. Chemopreventive agents
effective when present prior to the carcinogen were considered as anti-initiators, whereas
agents effective when present after the dimethylbenz[a]anthracene treatment along with
7,12-tetradecanoyl pherbol-13-acetate were considered as anti-promoters. Within the
chemopreventive agents evaluated limonene was an
anti-initiator.
The effects of D-limonene and citrus fruit
oils, ie orange oil and lemon oil, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
induced neoplasia of the lungs and forestomach of female A/J mice were investigated. D-Limonene and the citrus fruit oils given orally 1 hr
prior to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, also administered orally,
inhibited pulmonary adenoma formation and the occurrence of forestomach tumors. In an
additional experiment, D-limonene given orally 1
hr prior to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone administered ip again showed
pronounced inhibition of pulmonary adenoma formation.
Pharmacology:
Interactions:
RAUSCHER MURINE LEUKEMIAVIRUS INFECTED F344 RAT EMBRYO CELLS WERE NOT TRANSFORMED
TREATED WITH SUBEFFECTIVE DOSES OF 3-METHYLCHOLANTHRENE. THESE CELLS TREATED WITH LIMONENE SHOWED CARCINOGENIC TRANSFORMATION.
The monoterpene d-limonene has been shown to
an effective, non-toxic chemopreventive agent in mammary and other rodent tumor models.
The studies reported here investigated structure activity relationships among limonene and three hydroxylated derivatives in the
prevention of dimethylbenz[a]anthracene induced mammary cancer. Rats were fed control or
1% limonene, carveol, uroterpenol or sobrerol
diets from 2 wk before to one week after carcinogen administration. Carveol, uroterpenol
and sobrerol significantly prolonged tumor latency and decreased tumor yield. Sobrerol was
the most potent of the monoterpenes tested, decreasing tumor yield to half that of the
control, a level previously achieved with 5% limonene
diets. Excretion of radioactivity from (3)H dimethylbenz(a)anthracene was doubled in rats
fed 5% limonene and nearly tripled in rats fed
1% sobrerol. Sobrerol is thus 5 fold more potent than limonene
in both enhancing carcinogen excretion and in preventing tumor formation. These data
demonstrate that hydroxylation of monoterpenes affects chemopreventive potential, with 2
hydroxyl groups greater than 1 greater than 0. Sobrerol, carveol and uroterpenol are novel
cancer chemopreventive agents with little or no toxicity.
To identify possible hazards of combined exposure to chemicals with the same target
organ, a 24 hr single dose experiment was carried out in which the renal toxicity of
mercuric chloride, potassium dichromate, d-limonene
and hexachloro-1:3-butadiene administered simultaneously was compared with the
nephrotoxicity of the individual compounds in 12 wk old male Wistar rats. The dose levels
used were based on the results of a range finding study with the individual compounds in
the same strain of rats kept under similar experimental conditions, and comprised the
'Minimum Nephrotoxic Effect Level' and the 'No Nephrotoxic Effect Level' of each of the
four compunds alone and in combination. A group of vehicle treated rats served as
controls. At the 'Minimum Nephrotoxic Effect Level' of the combinations, antagonism of
effects was encountered, seen for example as less severely increased activity of
gamma-glutamyl transferase in the urine. Synergism of effects was also observed, for
example increased severity of renal tubular necrosis, and more markedly increased activity
of urinary lysozyme, lactate dehydrogenase, alkaline phosphatase and
N-acetyl-beta-glucosaminidase. More importantly, however, at the 'No Nephrotoxic Effect
Level' of the combination no signs of impaired renal function or renal damage were
observed, suggesting absence of both dose additivity and potentiating interaction at the
tested subeffective levels of the individual nephrotoxicants.
Mouse mammary glands respond to carcinogen stimulus to form mammary lesions in organ
culture. In this study it was determined whether the effective chemopreventive agents are
active against initiation or the promotion phase of lesion development. Mammary glands
were subjected to 24 hr exposure to 2 mg/ml dimethylbenz(a)anthracene followed by a 5 day
exposure to 7,12-tetradecanoyl phorbol-13-acetate. This treatment protocol allows the
study of initiation and promotion aspects of lesion development. Chemopreventive agents
effective when present prior to the carcinogen were considered as anti-initiators, whereas
agents effective when present after the dimethylbenz[a]anthracene treatment along with
7,12-tetradecanoyl pherbol-13-acetate were considered as anti-promoters. Within the
chemopreventive agents evaluated limonene was an
anti-initiator.
The effects of D-limonene and citrus fruit
oils, ie orange oil and lemon oil, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
induced neoplasia of the lungs and forestomach of female A/J mice were investigated. D-Limonene and the citrus fruit oils given orally 1 hr
prior to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, also administered orally,
inhibited pulmonary adenoma formation and the occurrence of forestomach tumors. In an
additional experiment, D-limonene given orally 1
hr prior to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone administered ip again showed
pronounced inhibition of pulmonary adenoma formation.
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Limonene is both a naturally occurring and a
synthetic terpene which is used in flavors and fragrances, as a solvent and for numerous
other commercial uses. If released to soil, limited data indicate that limonene
is expected to be resistant to biodegradation under aerobic conditions. Limonene
is expected to exhibit low to slight mobility in soil. It is expected to rapidly
volatilize from both dry and moist soil to the atmosphere although adsorption to soil may
attenuate the rate of this process. If released to water, limited data indicate that limonene is expected to be resistant to biodegradation
under aerobic conditions. Limonene may
bioconcentrate in fish and aquatic organisms and it may significantly adsorb to sediment
and suspended organic matter. It is expected to rapidly volatilize from water to the
atmosphere. The estimated half-life for volatilization of limonene
from a model river is 3.4 hr, although adsorption to sediment and suspended organic matter
may attenuate the rate of this process. If released to the atmosphere, limonene
is expected to rapidly undergo gas-phase oxidation reactions with photochemically produced
hydroxyl radicals, ozone, and at night with nitrate radicals. Calculated lifetime for
these processess in a clean and moderately polluted atmosphere are 2.0 hr and 30 min, 36
min and 11 min, and 9 min and 0.9 min, respectively. Occupational exposure to limonene may occur by inhalation or dermal contact
during its production, formulation, transport or use. Exposure to the general population
my occur by inhalation due to its presence in the atmosphere as a result of release from
natural sources, its presence in household products, or by ingestion of food in which it
is contained. (SRC)
Probable Routes of Human Exposure:
Occupational exposure to limonene may occur
by inhalation or dermal contact during its production, formulation, transport or use.
Exposure to the general population may occur by inhalation due to its presence in the
atmosphere as a result of its release from natural sources(1,2), its presence in household
products, or by ingestion of food in which it occurs either naturally or has been added as
a flavor or fragrance(SRC).
NIOSH (NOES Survey 1981-83) has statistically estimated that 94,910 workers are exposed
to limonene in the USA(1). Limonene
was detected in the air of the vulcanization area of a shoe-sole factory at a concn of
25-130 ug/cu m, and at 5-1700 ug/cu m in the vulcanization area of a tire retreading
factory(2). Limonene was detected indoors in an
office building, 1987, at a concn ranging from 43-63 ug/cu m(3). Limonene
was qualitatively detected in air samples taken at 2 Stockholm preschools, 1981-2(4).
Body Burden:
Limonene has been identified in the expired
air of urban volunteers(1). Limonene was
qualitatively detected in 8 of 8 samples of mother's milk obtained from residents of urban
centers in PA, NJ, and LA(2).
Natural Pollution Sources:
Limonene is a naturally occurring compound
and it is found in many natural oils including orange, lemon, grapefruit, berry, leaf,
caraway, dill, bergamot, peppermint and spearmint oils(1,2,3,4). Limonene
emissions to the environment are associated with wax myrtle, sweet acacia, oranges,
tomatoes, grasses, and California western sagebrush(5). Emissions of limonene
are also associated with balsam poplar, European larche, European fir, scots pine,
Siberian pine, silver fir, common juniper, zeravshan juniper, pencil cedar, evergreen
cypress, northern white cedar, chinese arbor vitae, marsh tea and deciduous moss(6).
Artificial Pollution Sources:
0.2-0.3 OF THE SMOKE CONDENSATE FROM BOTH BRIGHT (FLUE-CURED) BURLEY TOBACCO & A
COMMERCIAL BLEND OF BRIGHT, BURLEY, TURKISH & MARYLAND TOBACCO.
Limonene is used as a flavor and
fragrance(1,2). It is also used as a solvent, wetting agent, in resins, and as a monomer
and copolymer(2,3). Limonene may be released to
the environment as a fugitive emission during its production, use or transport, from
volatilization during its use as a solvent, from landfills, and in industrial
effluent(4,5,SRC). Limonene emissions have been
associated with effluent from the following industries: extraction of pine gum, paper and
pulp mills, plastics materials-synthetic resins and non vulcanizable elastomers, perfumes,
cosmetics and other toilet preparations, organic solvents and lubricating oils and
greases(6). Limonene may be emitted to household
environments from furniture polishes and room fresheners(7).
Environmental Fate:
TERRESTRIAL FATE: If released to soil, limited data indicate that limonene
is expected to be resistant to biodegradation under aerobic conditions(1,2). Based on limonene's water solubility, 13.8 mg/l at 25 deg C(3)
and an estimated log octanol/water partition coefficient of 4.232(4,SRC), soil adsorption
coefficients ranging from 1030-4780 can be calculated using an appropriate regression
equation(5,SRC) indicating that it will display low to slight mobility in soil(6). Its
vapor pressure, 20 mm Hg at 68.2 deg C(7) and a calculated Henry's Law constant of 0.380
atm cu m/mole at 25 deg C(8,SRC) indicate that limonene
will rapidly volatilize from both dry and moist soil to the atmosphere although strong
adsorption to soil may significantly attenuate the rate of this process(SRC).
AQUATIC FATE: If released to water, limited data indicate that limonene
is expected to be resistant to biodegradation under aerobic conditions(1,2). Based on limonene's water solubility, 13.8 mg/l at 25 deg C(3)
and an estimated log octanol/water partition coefficient of 4.232(4,SRC) bioconcentration
factors ranging from 246-262 can be calculated using an appropriate regression
equation(5,SRC) indicating that it may bioconcentrate in fish and aquatic organisms(SRC).
Estimated soil adsorption coefficients ranging from 1030 to 4780(3,4,5,SRC) indicate that limonene may significantly adsorb to sediment and
suspended organic matter. A calculated Henry's Law constant of 0.380 atm cu m/mole at 25
deg C(7,SRC) suggests that limonene will rapidly
volatilize from water to the atmosphere. The estimated half-life for volatilization of limonene from a model river 1 m deep flowing at 1
m/sec with a wind speed of 3 m/sec is 3.4 hr(4,SRC), although adsorption to sediment and
suspended matter may attenuate the rate of this process(SRC).
ATMOSPHERIC FATE: If released to the atmosphere, limonene
is expected to rapidly undergo gas-phase oxidation reactions with photochemically produced
hydroxyl radicals, ozone, and at night with nitrate radicals. Based on experimental rate
constants, calculated lifetimes for the gas-phase reaction between limonene
and photochemically produced hydroxyl radicals are 2.0 hrs in a clean atmosphere and 30
mins in a moderately polluted atmosphere(1). Corresponding values for the gas-phase
reaction with ozone are 36 min and 11 min, respectively(1). Calculated lifetimes, based on
experimentally determined rate constants, for the night time reaction of alpha-pinene with
nitrate radicals of 9 min in a clean atmosphere and 0.9 min in a moderately polluted
atmosphere have been reported(1). The atmospheric lifetime of limonene
was estimated at 0.2-0.8 hr depending on both the local hydroxyl radical and ozone
concn(2).
Environmental Biodegradation:
Organisms isolated from soil and water were, in general, unable to oxidize limonene in laboratory experiments(1). Limonene was listed as a compound difficult to
biodegrade and was classified in level 3 (difficult to biodegrade) in a 5 tiered rating
system on ease of biodegradability(2). The concn of limonene
between the influent and effluent of aerated treatment lagoons was found to decrease
significantly which the author ascribed to a biological removal process although complete
documentation was not provided(3).
Environmental Abiotic Degradation:
An experimental rate constant for the gas-phase reaction of limonene
with photochemically produced hydroxyl radicals of 1.49X10-10 atm/cu m molec at 32 deg
C(1) translates to a half-life of 2.6 hr using an average atmospheric hydroxyl radical
concn of 5X10+5 molec/cu m(2,SRC). A calculated lifetime for the reaction of limonene with photochemically produced hydroxyl
radicals in a clean atmosphere is 2.0 hr or 30 min in a moderately polluted atmosphere(3).
Limonene was classified as group V in a 5 tiered
rating system of relative reactivities towards photochemically produced hydroxyl radicals
(methane =1, limonene=18,800), indicating a
atmospheric half-life of <0.24 hr(4). An experimental rate constant for the gas-phase
reaction of limonene with ozone of 6.5X10-16
atm/cu m molec(1) translates to a half-life of 25 min using an average atmospheric ozone
concn of 7X10+11 molec/cu cm(3,SRC). A calculated lifetime for the reaction of limonene with ozone in a clean atmosphere is 36 min or
11 min in a moderately polluted atmosphere(3).
A calculated lifetime for the reaction of limonene
with nitrate radicals in a clean atmosphere is 9 min or 0.9 mins in a moderately polluted
atmosphere(1). Limonene was listed as a compound
amenable to direct photochemical degradation in the presence of nitrogen oxides(2).
Photolysis of limonene in the presence of
nitrogen oxides produces formaldehyde, formic acid, carbon monoxide, carbon dioxide,
acetaldehyde, peroxyacetyl nitrate and acetone(5). The daytime atmospheric lifetime of limonene was estimated at 0.2-0.8 hr depending on both
the local hydroxyl radical and ozone concn(4).
Environmental Bioconcentration:
Based on limonene's water solubility of 13.8
mg/l at 25 deg C(1), and an estimated log octanol/water partition coefficient of
4.232(2,SRC), bioconcentration factors of 246 and 262, respectively, can be calculated
using an appropriate regression equation(3,SRC). These values indicate that limonene may bioconcentrate in fish and aquatic
organisms(SRC).
Soil Adsorption/Mobility:
Based on its water solubility of 13.8 mg/l at 25 deg C(1) and an estimated log
octanol/water partition coefficient of 4.232(2,SRC), soil adsorption coefficients of 1030
and 4780, respectively, can be calculated for limonene
using an appropriate regression equation(3,SRC). These values indicate that limonene is expected to display slight to low mobility
in soil(4).
Volatilization from Water/Soil:
Based on its vapor pressure, 20 mm Hg at 68.2 deg C(1), limonene
may volatilize rapidly from dry soil to the atmosphere(SRC). A calculated Henry's Law
constant of 0.380 atm cu m/mole(2,SRC) indicates that limonene
will rapidly volatilize from both water and moist soil to the atmosphere(3,SRC). The
estimated half-life for volatilization of limonene
from a model river 1 m deep flowing at 1 m/sec with a wind speed of 3 m/sec is 3.4
hr(3,SRC).
Environmental Water Concentrations:
SURFACE WATER: The concn of limonene in
seawater samples from Resurrection Bay, AK, was 84 ng/l in June 1985 and 0.47 ng/l in
June, 1986(1). Limonene has been qualitatively
detected in the Black Warrior River, near Tuscaloosa, AL, 1975(2). Limonene
was identified in the River Glatt, Switzerland, 1975(3). It was detected, but not
quantified, in water samples taken from the River Lee, in the UK, date not given(4).
GROUNDWATER: Limonene was detected in
contaminated groundwater in The Netherlands at a maximum concn of 10 ug/l(1). Limonene was detected in 11 of 11 ground water samples
at the site of a former pine tar manufacturer in Gainsville, FL, at concn ranging from 1
ug/l to 130 ug/l(2).
DRINKING WATER: Limonene was listed as a
compound identified in U.S. drinking water supplies(1,2). It was qualitatively detected in
treated drinking water supplies in the U.K., 1976(3).
Effluent Concentrations:
Limonene was detected as a component of
landfill gases from sites in the UK at measured concns of 21-84 mg/cu m in probes buried
underground and 7.4 mg/cu m at above ground vents(1). It was qualitatively detected in 2
of 46 U.S. industrial effluent samples(2). Limonene
was detected in 6 of 7 samples of kraft pulp mill wastewater at concns ranging from 10-220
ppb in 2 Canadian mills monitored in 1973(3). It was qualitatively detected in landfill
leachate(4). Limonene was qualitatively
identified in the effluent gas from refuse waste obtained from a food center in an
experiment designed to determine the gases emitted from decaying waste matter at refuse
sites, landfills, and trash transfer sites(5). Limonene
has been associated with effluent from the following industries: extraction of pine gum,
paper and pulp mills, plastics materials-synthetic resins and non vulcanizable elastomers,
perfumes, cosmetics and other toilet preparations, organic solvents and lubricating oils
and greases(6).
Sediment/Soil Concentrations:
Limonene was detected in soil samples at the
site of a former pine-tar manufacturer in Gainsville, FL, at concn ranging from not
detected to 920 ug/g(1).
Atmospheric Concentrations:
URBAN/SUBURBAN: Limonene was detected in 97%
of 17 indoor air samples taken at residences in Ruston, WA, 1985-6, at a concn ranging
1.6-78 ug/cu m (mean and median 18 ug/cu m and 11 ug/cu m, respectively), outdoor concns
were typically 12 times lower(1). It was detected in 37 indoor and 12 outdoor samples from
36 houses (50 total measurements) in the Chicago area, concn not provided, indoor/outdoor
ratio 3.1(2). The concn of limonene in the air
above Moscow Mountain, ID, 1976-1977, ranged from <10 ppt to 50 ppt(3). The mean and
maximum concn of limonene in 40 homes in Oak
Ridge/Knoxville, TN, 1982-3, was 16 ug/cu m and 77.5 ug/cu m, respectively(4). The concn
of limonene in Houston, TX, ranged from not
detected to 5.7 ppb(5). Limonene was detected
indoors in an office building, 1987, at a concn ranging 43-63 ug/cu m(6). It was listed as
a compound typically identified in both indoor and outdoor air(7).
URBAN/SUBURBAN: Limonene was qualitatively
detected in the air of Leningrad, 1976, and 5 other Russian cities(1,2). It was detected
in suburban air samples in Germany, 1985, at concns ranging from not detected-2.0 ng/cu
m(3,4). Limonene was qualitatively detected in
air samples taken at 2 Stockholm preschools, 1981-2(5). Limonene
was detected in indoor and outdoor air in Northern Italy, 1983-8, at mean concns of 140
ug/cu m and 2 ug/cu m, respectively(6).
RURAL/REMOTE: The concn of limonene in the
air over a forest in Soviet Georgia, July, 1979, ranged from 0.004 ug/cu m to 0.010 ug/cu
m in 8 samples(1). The concn of limonene 1.7 m
above a maple forest in Quebec ranged from approximately 100-1750 parts per trillion over
a two day period in June, 1989(2). Limonene was
detected in forest air samples in southern black forest region, Germany, 1985, at concns
ranging from 1.0-89 ng/cu m(3,4). Traces of limonene
were found in the air over the Landes Forest, France, 1984, which consists mainly of
maritime pines(5).
Food Survey Values:
Limonene has been identified as a volatile
component of fried chicken(1), chickpea seed(2), orange juice essence(3), mangos(4),
roasted filberts(5), Beaufort (Gruyere) cheese(6) and baked potatoes(7). It has been
detected in a headspace analysis of intact, tree ripened nectarines, but not in an
analysis of the blended fruit(8).
Plant Concentrations:
Limonene was identified as a volatile
constituent of Kiwi fruit flowers(1).
Milk Concentrations:
Limonene was qualitatively detected in 8 of 8
samples of mother's milk obtained from residents of urban centers in PA, NJ, and LA(1).
Environmental Standards & Regulations:
FDA Requirements:
Synthetic flavoring substances and adjuvants that are generally recognized as safe
(GRAS) for their intended use include limonene.
Chemical/Physical Properties:
Molecular Formula:
C10-H16
Molecular Weight:
136.23
Color/Form:
COLORLESS MOBILE LIQUID
Odor:
PLEASANT, LEMON-LIKE ODOR FREE FROM CAMPHORACEOUS & TURPENTINE-LIKE NOTES
CITRUS ODOR
Taste:
SWEET, CITRUS TASTE
Boiling Point:
175.5-176.5 DEG C @ 763 MM HG
Melting Point:
-95.5 DEG C
Density/Specific Gravity:
0.8402 @ 20.85 DEG C/4 DEG C
Heat of Combustion:
-19,520 Btu/lb = -10,840 cal/g = -454x10+5 J/kg
Heat of Vaporization:
140 Btu/lb = 77 cal/g = 3.2x10+5 J/kg
Octanol/Water Partition Coefficient:
log Kow= 4.232 (est)
Solubilities:
MISCIBLE WITH ALCOHOL
Miscible in ... ether.
Water solubility: 13.8 mg/l at 25 deg C
Spectral Properties:
INDEX OF REFRACTION: 1.4727 @ 20 DEG C/D; MAX ABSORPTION (ISOOCTANE): 220 NM (LOG E=
2.41); 250 NM (LOG E= 1.36)
MASS: 318 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63)
Surface Tension:
26 dynes/cm = 0.026 N/m at 20 deg C
Vapor Density:
4.7 (AIR= 1)
Vapor Pressure:
20 mm Hg at 68.2 deg C
Other Chemical/Physical Properties:
IS THE OPTICALLY INACTIVE FORM OF LIMONENE
WT/GAL: 7.15 LB @ 15.5 DEG C
WITH DRY HYDROGEN CHLORIDE OR HYDROGEN BROMIDE IT FORMS MONOHALIDES, & WITH AQ
HYDROGEN CHLORIDE OR HYDROGEN BROMIDE, THE DIHALIDE.
Henry's Law constant= 0.380 atm cu m/mole at 25 deg C (calc)
PEROXIDE VALUE: NOT MORE THAN 2.0
LIQUID; BP: 175.5-176.5 DEG C @ 763 MM HG; DENSITY: 0.8407 @ 20.5 DEG C/4 DEG C;INDEX
OF REFRACTION: 1.474 @ 21 DEG C/D; SPECIFIC OPTICAL ROTATION: -101.3 DEG C @ 19.5 DEG C/D
/L-LIMONENE/
BP: 177-8 DEG C @ 755 MM HG, 64.4 DEG C @ 15 MM HG; DENSITY: 0.8422 @ 20 DEG C/4DEG C;
INDEX OF REFRACTION: 1.4746 @ 20 DEG C/D; MAX ABSORPTION (ISOOCTANE): 220 NM (LOG E= 2.4),
250 NM (LOG E= 1.1); SPECIFIC OPTICAL ROTATION: -122.1 DEG @ 20 DEG C/D (UNDILUTED) /L-LIMONENE/
MP: 95.5 DEG C; BP: 178 DEG C @ 760 MM HG, 64.4 DEG C @ 15 MM HG; DENSITY: 0.8402 @ 21
DEG C/4 DEG C; MAX ABSORPTION (ISOOCTANE): 220 NM (LOG E= 2.41), 250 NM (LOG E= 1.36);
INDEX OF REFRACTION: 1.4727 @ 20 DEG C/D /DL-LIMONENE/
LIQUID; PLEASANT LEMON-LIKE ODOR; PRACTICALLY INSOL IN WATER; MISCIBLE WITH ALCOHOL;
BP: 175.5-176.5 DEG C @ 763 MM HG; DENSITY: 0.8402 @ 20.85 DEG C/4 DEG C; INDEX OF
REFRACTION: 1.4744; WITH DRY HYDROGEN CHLORIDE OR HYDROGEN BROMIDE IT FORMS MONOHALIDES,
& WITH AQ HYDROGEN CHLORIDE OR HYDROGEN BROMIDE, DIHALIDES /DL-LIMONENE/
IR: 4996 (Coblentz Society Spectral Collection) /DL-Limonene/
NMR: 400 (Johnson and Jankowski, Carbon-13 NMR Spectra, John Wiley & Sons, New
York) /DL-Limonene/
MASS: 704 (Atlas of Mass Spectral Data, John Wiley & Sons, New York) /DL-Limonene/
IR: 4996 (Coblentz Society Spectral Collection) /L-Limonene/
NMR: 400 (Johnson and Jankowski, Carbon-13 NMR Spectra, John Wiley & Sons, New
York) /L-Limonene/
MASS: 704 (Atlas of Mass Spectral Data, John Wiley & Sons, New York) /L-Limonene/
Chemical Safety & Handling:
DOT Emergency Guidelines:
Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames.
Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and
flash back. Most vapors are heavier than air. They will spread along ground and collect in
low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors
or in sewers. Some may polymerize (P) explosively when heated or involved in a fire.
Runoff to sewer may create fire or explosion hazard. Containers may explode when heated.
Many liquids are lighter than water. Substance may be transported hot.
Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire
may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or
suffocation. Runoff from fire control or dilution water may cause pollution.
Public safety: CALL Emergency Response Telephone Number on Shipping Paper first. If
Shipping Paper not available or no answer, refer to appropriate telephone number listed on
the inside back cover. Isolate spill or leak area immediately for at least 25 to 50 meters
(80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep
out of low areas. Ventilate closed spaces before entering.
Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA).
Structural firefighters' protective clothing will only provide limited protection.
Evacuation: Large spill: Consider initial downwind evacuation for at least 300 meters
(1000 feet). Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800
meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2
mile) in all directions.
Fire: Caution: All these products have a very low flash point: Use of water spray when
fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular
foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move
containers from fire area if you can do it without risk. Fire involving tanks or
car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or
monitor nozzles. Cool containers with flooding quantities of water until well after fire
is out. Withdraw immediately in case of rising sound from venting safety devices or
discoloration of tank. Always stay away from the ends of tanks. For massive fire, use
unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and
let fire burn.
Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in
immediate area). All equipment used when handling the product must be grounded. Do not
touch or walk through spilled material. Stop leak if you can do it without risk. Prevent
entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be
used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible
material and transfer to containers. Use clean non-sparking tools to collect absorbed
material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may
reduce vapor; but may not prevent ignition in closed spaces.
First aid: Move victim to fresh air. Call emergency medical care. Apply artificial
respiration if victim is not breathing. Administer oxygen if breathing is difficult.
Remove and isolate contaminated clothing and shoes. In case of contact with substance,
immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with
soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the
material(s) involved, and take precautions to protect themselves.
Skin, Eye and Respiratory Irritations:
Skin irritant.
Liquid irritates eyes; ingestion causes irritation of GI tract.
NFPA Hazard Classification:
Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond
that of ordinary combustible material.
Flammability: 2. 2= Includes materials that must be moderately heated before ignition
will occur and includes Class II and IIIA combustible liquids and solids and semi-solids
that readily give off ignitible vapors. Water spray may be used to extinguish fires in
these materials because the materials can be cooled below their flash points.
Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure
conditions, and that do not react with water. Normal fire fighting procedures may be used.
Flammable Limits:
UPPER LIMIT: 6.1%; LOWER LIMIT: 0.7% (IN AIR: % BY VOLUME, @ 302 DEG C)
Flash Point:
113 DEG F (45 DEG C) CLOSED CUP
Autoignition Temperature:
458 DEG F
Hazardous Reactivities & Incompatibilities:
The inhibitor monomer will explode if ignited. Liquid tetrafluoroethylene, being
collected in an liquid nitrogen-cooled trap open to air, formed a peroxidic polymer which
exploded.
... Tetrafluoroethylene gas supply system with iodine pentafluoride caused a violent
explosion in the cylinders. Exothermic reaction of the limonene
inhibitor with the contaminant present in the gas cylinders may have depleted the
inhibitor and initiated explosive polymerization.
Hazardous Decomposition:
When heated to decomp it emits acrid smoke and fumes.
Preventive Measures:
SRP: The scientific literature for the use of contact lenses in industry is
conflicting. The benefit or detrimental effects of wearing contact lenses depend not only
upon the substance, but also on factors including the form of the substance,
characteristics and duration of the exposure, the uses of other eye protection equipment,
and the hygiene of the lenses. However, there may be individual substances whose
irritating or corrosive properties are such that the wearing of contact lenses would be
harmful to the eye. In those specific cases, contact lenses should not be worn. In any
event, the usual eye protection equipment should be worn even when contact lenses are in
place.
Shipment Methods and Regulations:
No person may /transport,/ offer or accept a hazardous material for transportation in
commerce unless that person is registered in conformance ... and the hazardous material is
properly classed, described, packaged, marked, labeled, and in condition for shipment as
required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./
The International Air Transport Association (IATA) Dangerous Goods Regulations are
published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and
constitute a manual of industry carrier regulations to be followed by all IATA Member
airlines when transporting hazardous materials.
The International Maritime Dangerous Goods Code lays down basic principles for
transporting hazardous chemicals. Detailed recommendations for individual substances and a
number of recommendations for good practice are included in the classes dealing with such
substances. A general index of technical names has also been compiled. This index should
always be consulted when attempting to locate the appropriate procedures to be used when
shipping any substance or article.
Occupational Exposure Standards:
Other Occupational Permissible Levels:
Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 30 ppm.
Manufacturing/Use Information:
Major Uses:
PAINT BRUSH CLEANSER & PRESERVATIVE.
MONOMER IN TERPENE RESINS; SOLVENT FOR OLEORESINOUS PRODUCTS; GENERAL WETTING AND
DISPERSING AGENT; CHEMICAL INTERMEDIATE FOR VARIOUS ORGANIC COMPOUNDS; FLAVOR INGREDIENT
(ORANGE-LIKE).
d-Limonene is used to synthesize l-carvone.
/D-Limonene/
Limonene ... has been utilized to produce
carvacrol.
Gallstone solubilizer
Manufacturers:
International Paper Co, Hq, Subsidiary: Arizona Chemical Co, 1001 E Business Highway
98, Panama City, FL 32401, (904) 785-6700; Production sites: Panama City, FL 32402;
Pensacola, FL 32596
Tecnal Ltd Partnership, Hq, 708 North Texas Rd, Anacortes, WA 98221, (206) 293-3200;
Production site: Anacortes, Wa 98221
Union Camp Corp, Hq, 1600 Valley Rd, Wayne, NJ 07470, (201) 628-2000; Terpene Division;
Production site: Jacksonville, FL 32236
SMC Corp, Glidco Organics, PO Box 389, Jacksonville, FL 32201, (904) 768-5800
Methods of Manufacturing:
EXTRACTION FROM SOUTHEASTERN PINE STUMPS, AND CITRUS FRUITS (ESPECIALLY FROM THE PEELS
OF ORANGES AND LEMONS); FROM PYROLYSIS OF ALPHA-PINENE
ISOLATION OF D-LIMONENE FROM MANDARIN PEEL
OIL (CITRUS RETICULATA BLANCO, RUTACEAE).
AS A BY-PRODUCT IN THE MANUFACTURE OF TERPINEOL AND IN VARIOUS SYNTHETIC PRODUCTS MADE
FROM ALPHA-PINENE OR TURPENTINE OIL.
General Manufacturing Information:
CONCN IN FINAL PRODUCT (%): AS USUAL TO MAXIMUM RANGE IS 0.05-0.75 IN SOAP; 0.05-0.075
IN DETERGENT; 0.5-2.0 IN PERFUME AND 0.25 MAXIMUM IN CREAMS & LOTIONS. /FROM TABLE/
FEMA NUMBER 2633 (DL-FORM); NON-ALCOHOLIC BEVERAGES 31 PPM; ICE CREAM, ICES, ETC 68
PPM; CANDY 49 PPM; BAKED GOODS 120 PPM; GELATINS & PUDDINGS 48-400 PPM; CHEWING GUM
2,300 PPM.
USE IN FRAGRANCES IN THE USA AMOUNTS TO LESS THAN 1000 LB/YR.
DIPENTENE (DL-LIMONENE)
WAS GRANTED GRAS STATUS BY FLAVOR AND EMOLLIENT MANUFACTURING ASSOCIATION (1965) ... . THE
COUNCIL OF EUROPE (1970) INCLUDED DIPENTENE (DL-LIMONENE) IN THE LIST OF ADMISSIBLE ARTIFICIAL
FLAVORING SUBSTANCES, WITH A TECHNOLOGICAL LIMIT EXCEPT FOR CHEWING GUM. /DL-LIMONENE/
WIDELY DISTRIBUTED OPTICALLY ACTIVE TERPENE, CLOSELY RELATED TO ISOPRENE. IT OCCURS
NATURALLY IN BOTH D- & L-FORMS. RACEMIC MIXTURE OF 2 ISOMERS IS KNOWN AS DIPENTENE.
FLAVORS USEFUL IN: CITRUS FLAVOR, ARTIFICIAL ESSENTIAL OILS /FROM TABLE/
ONE OF THE TERPENE HYDROCARBONS FOUND IN TURPENTINE.
Formulations/Preparations:
GRADES: STEAM-DISTILLED; DESTRUCTIVELY DISTILLED.
Laboratory Methods:
Analytic Laboratory Methods:
The analyte can be GC as determined by Athens-ERL or S-Cubed.
Some citrus essential oils were analyzed by HPLC with both microbore and std columns in
reversed and normal phase. Volatile and non-volatile fraction were investigated. In the
non-volatile fraction some coumarins were identified. Fractions are detected
spectrophotometrically at 220 and 320 nm before and after evap of samples.
Graphpac was investigated to see if carbon was a better GC support than silica for
columns of 3% of the liq crystal bismethoxybenzylidenebitoluidine or (MBT)2. Six volatile
oil component solutes exhibited the same elution sequence as from silica, but with lower
relative retention times with respect to linalool - about 50% for some aroms., reflecting
the much lower polarity of the carbon-supported packing indicated by cuminal/caryophyllene
ratio. Caryophyllene had greatly increased relative retention, and this was further raised
if a low-loading of 0.3% (MBT)2 was used on Graphpac, indicating even lower polarity. This
column was not reliable below 200 deg C, but an initial period at 203 deg C, followed by
rapid heating to 230 deg C, gave reasonable results for some significant constituents of
teatree oil. Nevertheless, 3% (MBT)2 on Graphpac was preferable for assaying this and
sweet fennel oil by providing a more reliable melted liq crystal stationary phase, with
low temp versatility.
Volatile org determination of indoor air tobacco smoke by multisorbent thermal
desorption/GC/mass selective detection in relation to tracers ethenylpyridine, as
indicator of environmental tobacco smoke.
Sampling Procedures:
Air analysis Volatile org cmpd detn in indoor air from tobacco smoke by using
multisorbent thermal desorption/GC/mass selective detection.
Special References:
Synonyms and Identifiers:
Synonyms:
ACINTENE DP DIPENTENE
**PEER REVIEWED**
CAJEPUTEN
**PEER REVIEWED**
CAJEPUTENE
**PEER REVIEWED**
CINEN
**PEER REVIEWED**
CINENE
**PEER REVIEWED**
CYCLOHEXENE, 1-METHYL-4-(1-METHYLETHENYL)-
**PEER REVIEWED**
DIPENTEN
**PEER REVIEWED**
DIPENTENE
**PEER REVIEWED**
DIPENTENE 200
**PEER REVIEWED**
EULIMEN
**PEER REVIEWED**
INACTIVE LIMONENE
**PEER REVIEWED**
4-ISOPROPENYL-1-METHYL-1-CYCLOHEXENE
**PEER REVIEWED**
KAUTSCHIN
**PEER REVIEWED**
LIMONEN
**PEER REVIEWED**
ALPHA-LIMONENE
**PEER REVIEWED**
P-MENTHA-1,8-DIENE, DL-
**PEER REVIEWED**
P-MENTHA-1,8-DIENE
**PEER REVIEWED**
1,8(9)-P-MENTHADIENE
**PEER REVIEWED**
1-METHYL-4-ISOPROPENYL-1-CYCLOHEXENE
**PEER REVIEWED**
1-METHYL-4-(1-METHYLETHENYL)CYCLOHEXENE
**PEER REVIEWED**
NESOL
**PEER REVIEWED**
DELTA-1,8-TERPODIENE
**PEER REVIEWED**
Associated Chemicals:
(DL)-Limonene;7705-14-8
(L)-Limonene;5989-54-8
Formulations/Preparations:
GRADES: STEAM-DISTILLED; DESTRUCTIVELY DISTILLED.
Shipping Name/ Number DOT/UN/NA/IMO:
UN 2052; Dipentene
IMO 3.3; Dipentene
RTECS Number:
NIOSH/OS8100000
Administrative Information:
Hazardous Substances Databank Number: 1809
Last Revision Date: 20010809
Last Review Date: Reviewed by SRP on 3/2/1994
Update History:
Complete Update on 08/09/2001, 1 field added/edited/deleted.
Complete Update on 02/02/2000, 1 field added/edited/deleted.
Complete Update on 09/21/1999, 1 field added/edited/deleted.
Complete Update on 08/26/1999, 1 field added/edited/deleted.
Complete Update on 05/11/1999, 1 field added/edited/deleted.
Complete Update on 06/02/1998, 1 field added/edited/deleted.
Complete Update on 04/08/1998, 2 fields added/edited/deleted.
Complete Update on 02/27/1998, 1 field added/edited/deleted.
Complete Update on 10/23/1997, 1 field added/edited/deleted.
Complete Update on 05/08/1997, 1 field added/edited/deleted.
Complete Update on 04/23/1997, 2 fields added/edited/deleted.
Complete Update on 01/21/1996, 1 field added/edited/deleted.
Complete Update on 12/28/1994, 1 field added/edited/deleted.
Complete Update on 05/18/1994, 69 fields added/edited/deleted.
Field Update on 03/21/1994, 1 field added/edited/deleted.
Field update on 12/22/1992, 1 field added/edited/deleted.
Complete Update on 10/05/1990, 4 fields added/edited/deleted.
Field Update on 11/27/1989, 1 field added/edited/deleted.
Field Update on 11/27/1989, 1 field added/edited/deleted.
Complete Update on 04/13/1989, 1 field added/edited/deleted.
Complete Update on 10/14/1986
Record Length: 100584