. "13 Limonene." Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press, 2008.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 5
Limonene, chemically belonging to the terpene family and bearing an asymmetric carbon atom, exists in two enantiomers, l-limonene [also referred to as (−)-limonene or S-(−)-limonene] and d-limonene [also referred to as (+)-limonene or R-(+)-limonene]. l-Limonene has a piney and turpentine smell, whereas d-limonene has a pleasant lemon-like fragrance and a fresh citrus taste. The former monoterpene is present in pine oils and some trees; the latter is pre-
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13
Limonene
Chiu-wing Lam, Ph.D., D.A.B.T.
Toxicology Group
Habitability and Environmental Factors Division
Johnson Space Center
National Aeronautics and Space Administration
Houston, Texas
PHYSICAL AND CHEMICAL PROPERTIES
Synonym:
1-Methyl-4-(1-methylethenyl) cyclohexene; p-mentha-1,8-diene; enthadiene; carvene; cinene; citrus terpenes; and orange oil terpenes (NICNAS 2002)
CAS number:
5989-27-5
Molecular weight:
136.24
Boiling point:
176°C
Density:
0.84
Vapor pressure:
<3 mm Hg at 14°C
Solubility in water:
Sparingly soluble (13.8 mg/L at 25°C)
Concentration conversion:
1 ppm = 5.6 mg/m3, 1 mg/m3 = 0.18 ppm
OCCURRENCE AND USE
Natural Occurrence and Commercial Uses
Limonene, chemically belonging to the terpene family and bearing an asymmetric carbon atom, exists in two enantiomers, l-limonene [also referred to as (−)-limonene or S-(−)-limonene] and d-limonene [also referred to as (+)-limonene or R-(+)-limonene]. l-Limonene has a piney and turpentine smell, whereas d-limonene has a pleasant lemon-like fragrance and a fresh citrus taste. The former monoterpene is present in pine oils and some trees; the latter is pre-
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sent in lemon, orange, other citrus fruits, and to a lesser extent in vegetables and plants.
d-Limonene is the major constituent of lemon and orange oils; it is also present in other essential oils. Besides being naturally present in fruits, vegetables, and their products (such as orange juice, which contains 100 ppm of d-limonene), it is used as a flavoring agent and is found in common food items, such as ice cream (68 ppm), baked goods (120 ppm), gelatins and puddings (48 to 400 ppm), and nonalcoholic beverages (31 ppm) (NTP 1990, NICNAS 2002). d-Limonene is a food additive on the Food and Drug Administration’s Generally Recognized as Safe List (Opdyke 1978). Consumption of d-limonene has been estimated to be 0.2 to 2 mg/kg body weight per day (or 14 to 140 mg/70 kg/d) (IARC 1999). Because d-limonene can be isolated from a large number of natural sources and has a desirable odor and taste, it is the isomer that is commercially produced and is mainly used in soap, personal hygiene products, medicinal cosmetics, and perfume, in addition to its wide use in foods and beverages. In 1976, 68,000 kg of d-limonene was produced and used in the United States mainly as a fragrance and flavoring agent; by 1984, the consumption increased to 254,000 kg. The use of limonene has continued to increase because consumers prefer natural and organic food additives to synthetic products. d-Limonene seems to have some medicinal properties. It has been shown experimentally to have protective effects against certain types of cancer and was evaluated in phase I clinical trials with advanced cancer patients (Gould 1997).
Because it has good solvent properties, relatively low toxicity, and a pleasant odor, d-limonene is used increasingly as an industrial solvent to replace chlorinated hydrocarbons as a remover/stripper for wax, paints, ink, and adhesives and in degreasing operations and other applications (NICNAS 2002). It has been substituted for xylene in slide preparation in many histopathology laboratories. Because of its widespread presence in botanical and commercial products and its increasing industrial uses, d-limonene is released into the environment from biogenic and anthropogenic sources (NICNAS 2002).
Occurrence and Use in Spacecraft
d-Limonene has been considered for use on the International Space Station (ISS) as a cleansing solvent. On the ISS, low-toxicity water-soluble solvents (especially alcohols such as ethanol and isopropanol) are used in medical applications and for hardware cleansing. These volatile, highly soluble, and low-molecular-weight compounds, which are released into the ISS air after their use, are readily removed together with water vapor by the humidity removal system as water condensate. In the ISS water purification system, the contaminants in the condensate are removed by charcoal filtration and catalytic oxidation. This water recycling system has a limited capacity for removing these water-borne organics. Thus, the ISS program has placed a restriction on the use of water-soluble volatile organic compounds (VOCs).
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d-Limonene, a compound with low solubility in water and relatively low toxicity, has been proposed as a cleansing agent to reduce the use of alcohols and other water-soluble VOCs on the ISS. Replacing these compounds with the water-insoluble terpene would increase d-limonene concentration in the ISS atmosphere. Increased industrial applications of d-limonene would increase its presence in nonmetallic materials as well as increase the potential for off-gassing of limonene into the ISS atmosphere if some of these materials are used for construction of ISS components or flight hardware. Limonene has been commonly and constantly found in the ISS atmosphere. ISS air samples collected in 2003 showed limonene concentrations ranging from 0.036 to 0.13 mg/m3 (JSC 2003); this range is similar to that (0.035 to 0.18 mg/m3) found in the samples collected more recently (JSC 2008). The variation in limonene concentrations in the samples collected at different times during the same ISS mission increment probably reflects the extent the air was circulated through the activated charcoal bed in the ISS trace contaminant removal system.
This document has been drafted to set the airborne exposure limits of d-limonene on the ISS and should also provide the data needed for deciding whether to increase d-limonene uses as a degreaser or cleaner associated with space mission operations.
TOXICOKINETICS AND METABOLISM
Absorption, Distribution, and Excretion
d-Limonene, a small lipophilic compound, has high blood/air, oil/water, and oil/blood partition coefficients (λblood/air = 42, λoil/water = 3,167, λoil/blood = 140) (Falk et al. 1990); it is expected to be taken up readily from the lungs and from the gastrointestinal tract. The toxicokinetics of d-limonene were studied in a group of eight human volunteers engaged in light exercise and exposed for 2 h to the vapor at 10, 225, and 450 mg/m3 (corresponding to ~2, 40, and 80 ppm) (Falk-Filipsson et al. 1993). The average pulmonary uptake of the vapor was 65%, 68%, and 68%, respectively. Measurements obtained in subjects exposed to d-limonene at 450 mg/m3showed that ~1% of the total uptake was eliminated unchanged in expired air after exposure ended, whereas ~0.003% was eliminated unchanged in the urine. The finding that very little of the compound was excreted unchanged in breath and urine indicates that the compound is extensively metabolized or avidly taken up by fat. The half-lives of the triphasic elimination of limonene from blood were 3, 30, and 750 min (Falk-Filipsson et al. 1993). When humans and laboratory animals (rat, guinea pig, hamster, rabbit, and dog) were given oral doses of d-[14C]limonene (which was completely absorbed), 75% to 95% of the radioactivity was recovered in urine within 2 or 3 d after they ingested the compound. Most of the radioactivity was recovered in the first 24 h; less than 10% was found in feces (Kodama et al. 1976). After administration of radiolabeled d-limonene orally to male Wistar rats, Igimi et al. (1974)
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found that radioactivity in the blood reached a maximum 2 h after the treatment. The blood concentrations remained relatively high for 10 h and then declined. A negligible amount of radioactivity was found in the blood 48 h post-treatment. Study of the distribution of radioactivity in the tissues of these rats showed that the liver had the highest concentration, followed by the kidneys and blood (fat was not examined). Autoradiograms also showed that negligible radioactivity remained in the body 48 h after ingestion of d-[14C]limonene. These results show that only small amounts of limonene or its metabolites accumulate in the body. The recovery of radioactivity in urine, feces, and breath (as CO2) was 60%, 5%, and 2%, respectively (Igimi et al. 1974).
Metabolism
The finding that only small amounts of absorbed airborne limonene were eliminated in the urine (0.003%) and breath (~1%) of exposed humans indicates that the compound was extensively metabolized (Falk-Filipsson et al. 1993). As mentioned above, in humans and laboratory animals given d-[14C]limonene, 75% to 95% of the radioactivity was recovered in urine within 2 or 3 d, with most recovered in the first 24 h after dosing (Kodama et al. 1976). Depending on the animal species, the metabolism of limonene could occur by hydroxylation (or epoxidation followed by hydroxylation) of the ethenyl group, hydroxylation of the cyclohexene ring, and/or oxidation of the 1-methyl group. Most of these metabolites are further conjugated by phase II enzymes before they are eliminated in the urine (Igimi et al. 1974, Kodama et al. 1976). Kodama et al. (1976) proposed the metabolic pathway shown in Figure 13-1 based on the information of the metabolites they identified (Table 13-1). In the two human test subjects, about 30% of the administered dose was found in the urine as d-limonene-8,9-diol and its glucuronide; about 10% was identified as perillic acid (M-III; Figure 1). In cancer patients who received oral d-limonene therapy for up to 1 year, the major urinary metabolites were glucuronide conjugates of perillic acid, dihydroperillic acid, limonene-8,9-diol, and monohydroxylimonene (Vigushin et al. 1998). In male rats, some of the d-limonene-1,2-epoxide produced was bound reversibly to 2u-globulin, a protein produced exclusively by the livers of these rodents (Lehman-McKeeman et al. 1989).
TOXICITY SUMMARY
With its pleasant odor and taste, d-limonene dwarfs its levorotary isomer in industrial production and commercial uses. Toxicity studies on limonene have been conducted almost exclusively on the former compound. d-Limonene is ubiquitous in fruits and vegetables; it is a food additive on the Food and Drug Administration’s approved list (Opdyke 1978). This natural flavoring agent has low irritancy and toxicity (Falk-Filipsson et al. 1993). For these reasons, very
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FIGURE 13-1 Major Pathways for d-Limonene Metabolism. Source: Kodama et al. 1976. Reprinted with permission; copyright 1976, Xenobiotica.
few inhalation studies have been conducted to assess the toxicity of this compound. A 2-year carcinogenesis bioassay conducted by the National Toxicology Program (NTP 1990) on rodents gavaged with doses of d-limonene up to 1,000 mg/kg/d showed no histopathology in female rats or both sexes of mice, but kidney lesions and neoplasms were found in male rats (Table 13-2). The lesions were found to be associated with hyaline droplets, which contained α2u-globulin. Because the formation of α2u-globulin in the liver is unique to the male rat and does not occur in humans, and because this protein played a crucial role in the pathogenesis and carcinogenesis of d-limonene, the results for kidney cancer and lesions in these animals are not considered relevant to assessment of the risk to humans of d-limonene exposure (IARC 1999). Table 13-3 summarizes the inhalation toxicity of d-Limonene, while the data on oral toxicity of this compound are summarized in Table 13-4 and 13-5.
Acute and Short-Term Toxicity Studies
Human Exposures
In a study to investigate the pulmonary uptake of inhaled d-limonene in humans (mentioned above), eight test subjects were exposed for 2 h on three occasions at concentrations of approximately 10, 225, and 450 mg/m3 (about 2, 40, or 80 ppm) (Falk-Filipsson et al. 1993). The subjects did not have any irritation or symptoms related to the central nervous system. A slight (~ 2%), but
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TABLE 13-1 Metabolites in Urine
Numbera
Limonene Metabolites
Species in Which Metabolites Have Been Detected
Rat
Guinea Pig
Hamster
Rabbit
Dog
Human
MI
p-Mentha-1,8-dien-10-ol
—
X
X
X
X
X
M-II
p-Mentha-1-ene-8,9-diol
X
X
X
X
X*
X
M-III
Perillic acid
X
X
X
X
X
X
M-IV
Perillic acid-8,9-diol
X*
X
X
X*
X
X
M-V
p-Mentha-1,8-dien-100-yl-β-D-glucopyranosiduronic acid
X
X
X
X
X
X
M-VI
8-Hydroxy-p-menth-1-en-9yl-β-D-glucopyranosiduronic acid
X
X*
X
X
X
X*
M-VII
2-Hydroxy-p-menth-8-en-7-oic acid
X
X
X
X
X
X
M-VIII
Perillylglycine
X
X
X
X
X
X
M-IX
Perillyl-β-D-glucopyranosiduronic acid
X
X
X*
X
X
X
M-X
p-menth-1-ene-6,8,9-triol
X
X
X
X
X
—
M-XI
p-Mentha-1,8-dien-6-ol
X
X
X
X
X
X
aReference to structures shown in Figure 131.
Abbreviations: *, major metabolite; —, metabolite not found; X, metabolite found.
Source: Kodama et al. 1976. Reprinted with permission; copyright 1976, Xenobiotica.
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statistically significant (p < 0.01), decrease in vital capacity measurement was noted after an exposure to d-limonene at the highest concentration, but no clinical symptoms were observed in the test subjects. The exposure duration was very short (total of 6 h) and was unlikely to produce lung lesions that could produce pulmonary restriction reflected clinically as reduction in vital capacity. The assessment that d-limonene is very unlikely to elicit lung lesions after such a short time is supported by the results of other lung function tests, including forced expiratory volumes after 1 second, residual volume, total lung capacity, peak expiratory flow, mean expiratory flow, airway resistance, and airway conductance, which showed no significant changes after the d-limonene exposure. Although it was statistically significant, the authors concluded that the 2% change in vital capacity had no functional significance. The decrease in forced vital capacity was not consistent with the absence of change in total lung capacity and airway conductance, which are two more reliable measures of restriction.
In a study to assess eye irritancy and odor threshold of VOCs, including l-limonene, released by Nordic coniferous trees that produce the characteristic wood odor (when the wood is used for building), 12 volunteers were exposed to four monoterpenes separately (Molhave et al. 2000). With goggle instrumentation, l-limonene was administered to the eyes for 2 min and the threshold of irritation was found to be 3,400 mg/m3 (600 ppm). The odor threshold was found to be 12 mg/m3.
d-Limonene had been tested for toxicity to determine the maximum tolerated doses in cancer patients before it was used as a therapeutic agent to suppress cancer growth on these patients. Thirty-two patients were given d-limonene ranging from 0.5 to 12 g/d/m2 of body surface for 21 d or more; some were dosed for up to 1 year. The maximum tolerated dose was 8 g/d/m2 or about 190 mg/kg/d. The toxicities were limited to gastrointestinal effects (nausea, vomiting, and diarrhea) in a dose-dependent fashion. Vigushin et al. (1998) concluded that d-limonene had low toxicity. In another study, therapeutic administration of 20 g of d-limonene orally to patients with gallstones resulted in diarrhea and painful contractions, but no changes in blood biochemical parameters (Igimi et al. 1976).
TABLE 13-2 Incidence of Kidney Lesions, Including Cancer, in Male Rats Dosed Orally with d-Limonene for 2 Yearsa
Lesions
0 mg/kg/d
75 mg/kg/d
150 mg/kg/d
Papilla mineralization
7/50
43/50
48/50
Papilla epithelial hyperplasia
0/50
35/50
43/50
Tubular cell hyperplasia
0/50
4/50
7/50
Tubular cell adenoma
0/50
4/50
8/50
Tubular cell adenocarcinoma
0/50
4/50
3/50
ad-Limonene in corn oil was administered by gavage 5 days per week.
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TABLE 13-3 Inhalation Toxicity of d-Limonene
Dose, PPM
Exposure Duration
Species
Effects
Reference
Human studies
610a
2 min
Human (n = 12)
Threshold of eye irritation
Molhave et al. 2000
2, 40, or 80
2 h
Human (n = 8)
No irritation
No CNS effects
No changes in pulmonary function
Falk-Filipsson et al. 1993
Animal studies
≤2,421a
30 min
BALB/ca mouse (n = 4)
No pulmonary irritation detected
Larsen et al. 2000
≤1,600
30 min
BALB/ca mouse (n = 4)
No pulmonary irritation detected
Larsen et al. 2000
1,715a
30 min
BALB/ca mouse (n = 4)
RD50b
Larsen et al. 2000
1,163
30 min
BALB/ca mouse (n = 4)
RD50
Larsen et al. 2000
199a
30 min
BALB/ca mouse (n = 4)
RD0c
Larsen et al. 2000
125
30 min
BALB/ca mouse (n = 4)
RD0
Larsen et al. 2000
111
10-30 min
BALB/ca mouse (n = 4)
Respiratory rate depression not detected
Wolkoff et al. 2000
47
1 h
BALB/ca mouse (n = 4)
No effects on respiratory system
Rohr et al. 2002
aStudy conducted on l-limonene.
bRD50, respirable rate depression by 50% due to pulmonary irritation in the exposed animals.
cRD0, no-observed-effect level for respirable irritation in the exposed animals.
TABLE 13-4 Oral Toxicity of d-Limonene in Rodents
Dosage, mg/kg/d
Exposure Durationa
Speciesb
Effects
6,000
16 d
10 rats, 10 mice
10/10 rats died, 10/20 mice died
3,000
16 d
10 rats, 10 mice
2/10 rats died, 1/20 mice died
1,650
16 d
10 rats, 10 mice
No deaths; decrease in body weight gain
825
16 d
10 rats, 10 mice
No observable effects (no histologic exam)
413
16 d
10 rats, 10 mice
No observable effects (no histologic exam)
75-1,200c
21 d
24 rats (12 M, 12 F)
Dose-related granules, contained α2u-globulin in kidneys of male rats
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Dosage, mg/kg/d
Exposure Durationa
Speciesb
Effects
2,400
13 wk
20 rats (10 M, 10 F)
14/20 died; lethargy, excessive lacrimation nephropathy (in male rats only)
2,000
13 wk
20 mice (10 M, 10 F)
3/20 died; lethargy, excessive lacrimation nephropathy (in male rats only)
1,200
13 wk
20 rats (10 M, 10 F)
Rough hair coats, decreased activity, lethargy, excessive lacrimation nephropathy (in male rats only)
1,000
13 wk
20 mice (10 M, 10 F)
Rough hair coats and decreased activity
600
13 wk
20 rats (10 M, 10 F)
Nephropathy (in male rats only)
500
13 wk
20 mice (10 M, 10 F)
None
300
13 wk
20 rats (10 M, 10 F)
Effects (nephropathy) only in male rats
250
13 wk
20 mice (10 M, 10 F)
None
150
13 wk
20 rats (10 M, 10 F)
Effects (nephropathy) only in male rats
125
13 wk
20 mice (10 M, 10 F)
None
1,000
2 y
50 mice (F)
10% less body weight gain, no other effects
500
2 y
50 mice (F)
No effects, decrease in incidence of cytomegaly and multinucleated cells in liver
500
2 y
50 mice (M)
Increase in incidence of cytomegaly and multinucleated cells in liver
250
2 y
50 mice (M)
Decrease in incidence of cytomegaly and multinucleated cells in liver
600
2 y
50 rats (F)
5% less body weight gain, no other effects
300
2 y
50 rats (F)
No effects
150
2 y
50 rats (M)
5% less body weight gain, decrease in survival, renal lesions and tumorsc,d
75
2 y
50 rats (M)
Decrease in survival, renal lesions and tumorsc,d
aDaily doses given by gavage 5 d per week.
bAll these NTP studies used Fischer 344 rats and B6C3F1 mice.
cDoses: 75, 150, 300, 600, and 1200 mg/kg/d.
dSee details in Table 13-2.
Abbreviations: M, male; F, female.
Source: NTP 1990.
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TABLE 13-5 Oral Toxicity of d-Limonene (Non-NTP Studies)
Dose, mg/kg/d
Exposure Duration
Species
Effects
Reference
1,000
6 mo
Dog (5 M, 5 F)
No hyaline droplets or kidney lesions, kidney weight ca. 30% higher than controls
Webb et al. 1990
100
6 mo
Dog (5 M, 5 F)
No hyaline droplets or kidney lesions
Webb et al. 1990
2,363
Gestation days 7-12
15 mice
↓ maternal body weight
↑ fetal skeletal abnormality
Kodama et al. 1977a
591
Gestation days 7-12
15 mice
No effects in dams and fetuses
Kodama et al. 1977a
1,000
Gestation days 6-18
10-18 rabbits
Some fetuses died
↓ maternal body weight
Kodama et al. 1977b
500
Gestation days 6-18
10-18 rabbits
Some fetuses died
↓ maternal body weight
Kodama et al. 1977b
250
Gestation days 6-18
10-18 rabbits
No effects in dams and fetuses
Kodama et al. 1977b
Abbreviations: M, male; F, female.
Animal Exposures
Effects of d-limonene on sensory irritation, pulmonary irritation, and expiratory airflow limitation were investigated in mice; the results showed that an exposure to 47 ppm of limonene for 1 h produced no measurable changes. Wolkoff et al. (2000) reported that, in BALB/c mice exposed to 111 ppm for 30 min, sensory irritation did not occur. Larsen et al. (2000) conducted a study on d-limonene and its enantiomer l-limonene by monitoring respiratory rate, tidal volume, and mid-expiratory flow rate of mice exposed to the compounds for 30 min. Pulmonary irritation and bronchoconstriction were not observed at concentrations ≤ 1,600 ppm for d-limonene and ≤ 2,421 ppm for l- limonene. The concentration that decreased respiratory rate by 50% (RD50) in a 30-min exposure was estimated to be 1,163 ppm for d-limonene and 1,715 ppm for l-limonene; the no-observed-effect levels for sensory irritancy for these two limonene compounds were estimated to be 125 and 199 ppm, respectively.
In a dose-finding study on d-limonene for a subsequent NTP carcinogenesis bioassay, groups of 10 Fisher 344 rats and 10 B6C3F1 mice (5 of each sex) were gavaged with the compound (in corn oil) at 413, 825, 1,650, 3,000, or 6,600 mg/kg/d for 16 d (5d/wk). In the groups that received 3,300 or 6,600 mg/kg/d, 18 rats and 19 mice died. Body weight gain decreased at 1,650 mg/kg/d. No compound-related signs of toxicity were observed in animals administered <1,650 mg/kg/d (NTP 1990).
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Long-Term Toxicity Studies
Long-term human exposures to limonene have not been reported. In an NTP 13-wk (5 d/wk) study, groups of 20 rats (10 males, 10 females) were gavaged with d-limonene at 0, 150, 300, 600, 1,200, or 2,400 mg/kg/d; groups of 20 mice (10 males, 10 females) were dosed at 0, 125, 250, 500, 1,000, or 2,000 mg/kg/d. In the 2,400-mg/kg groups, 14 rats died; in the 2,000-mg/kg groups, 3 mice died. Body weight gain decreased in a dose-related fashion in the male rats starting at 600 mg/kg/d; in male mice, the decrease was observed in the 1,000-and 2,000-mg/kg groups. Male rats administered 1,200 or 2,400 mg/kg/d showed lethargy and excessive lacrimation; lethargy was also observed in male mice treated with the two highest doses (1,000 and 2,000 mg/kg/d). The only compound-related pathologic effect noted was nephropathy in male rats (NTP 1990).
Kanerva et al. (1987) initiated a study to investigate the time and dose relationship of limonene-induced renal lesions, specifically hyaline droplet formation. Groups of five F344 male rats were given (by gavage) d-limonene at 75, 150, or 300 mg/kg/d for up to 4 wk (5 d/wk). The animals were killed at the end of the 1st or 4th week; at these times, an increase in liver weight was noted in the highest dose group. The increase in number of protein droplets in the kidneys of rats was dose dependent. Formation of granular casts and chronic nephrosis were found only in the rats that received 4 wk of limonene treatment. The nephropathy was found to associate with α2u-globulin in the kidney.
In an effort to assess whether nephropathy is unique to male rats, Webb et al. (1990) dosed groups of 10 dogs (5 males, 5 females) with d-limonene at 0, 100, or 1,000 mg/kg/d; the dose was divided and given by gavage twice daily for 6 months. The body weights of the animals were not affected. In the 1,000-mg/kg/d group, the average kidney weight of the female dogs and the absolute kidney weight of male and female dogs were all about 30% higher than that of the controls. The 100-mg/kg/d group showed no effects on kidney weight. Microscopic examination of the kidneys revealed no hyaline droplet nephropathy or other lesions associated with the d-limonene treatment. The authors did not explain or speculate about the reasons for the kidney weight increase in the high-dose group but did point out that this high dose “is more than 10 times higher than that causes frank nephrotoxicity and significant increase in renal cancer in male rats (70 mg/kg body weight, National Toxicology Program, 1990).”
After completing its 13-wk study, NTP (1990) conducted a 2-year carcinogenesis study in which groups of 50 male rats were gavaged daily (5 d/wk) with d-limonene at 0, 75, or 150 mg/kg; female rats were dosed with the compound at 0, 300, or 600 mg/kg. The doses for groups of male mice were 0, 250, and 500 mg and those for female mice were 0, 500, and 1,000 mg/kg. Female mice exposed to the highest dose had 5% to 15% lower mean body weights
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absence or presence of liver microsomes. Chromosomal aberrations were not observed in cultured Chinese hamster ovary cells treated with d-limonene at concentrations up to 162 μL/mL (NTP 1990).
Developmental and Reproductive Toxicity
Two developmental studies were identified, as described below; however, no reproductive toxicity studies were found.
In a developmental toxicity study of d-limonene in ICR mice, groups of 15 pregnant dams were gavaged with the compound at 0, 591, or 2,363 mg/kg/d on gestation days 7 to 12 (Kodama et al. 1977a). The high dose caused a significant decrease in maternal body weight; it also caused a significant increase in the number of fetuses with skeletal abnormalities, including lumbar ribs, fused ribs, and delayed ossification of several bones in the paws. No maternal or fetal effects were observed at the low dose.
Kodama et al. (1977b) also conducted a study on groups of 10 to 18 pregnant Japanese white rabbits gavaged with d-limonene at 0, 250, 500, or 1,000 mg/kg/d on gestation days 6 to 18 (Kodama et al. 1977b). The dams that received the two highest doses had significant reductions in food consumption and body weight; death occurred in the group that received the highest dose. Developmental toxicity in the litters was not observed at any dose.
Allergenicity
To demonstrate that the allergenicity of limonene is due to the oxidative products of limonene, Karlberg et al. (1992) stirred d-limonene (96% pure) in open air for 1 h four times daily for 2 to 4 h and up to 2 to 4 months to induce oxidative products (only 40% d-limonene was left after 2.5 months). Air-unexposed and air-exposed d-limonene together with d-limonene oxide were tested for skin allergenicity on guinea pigs; only d-limonene that had not been exposed to air was shown to be void of allergenicity. A skin sensitization test of d-limonene conducted on 25 volunteers was negative (Grief 1967). Two of 470 patients showed a positive response to a skin patch test carried out in Australia in 1999 (Fewings, personal communication, 2001, as cited in NICNAS 2002). A case report exists on asthma in subjects exposed to perfume containing d-limonene (Jensen and Petersen 1991). These data are insufficient to establish that d-d-limonene, per se, is an allergen and to quantitate a dose response; therefore the data will not be used to calculate an acceptable concentration (AC).
Effects on the Immune System
The effects of d-limonene on the immune system of BALB/c mice were studied by Evans et al. (1987). They prepared the material in buffered saline as an emulsion and made a series of dilutions to attain a dilution as low as 1:16,384
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(no concentrations were given; doses were expressed as dilutions). At a dilution of 1:16,384 and with a daily dose of 0.1 mL per mouse, lipopolysaccharide-induced proliferation of spleen cells in mice was significantly suppressed after 4 wk of treatment, but proliferation increased significantly after 8 wk of treatment. This dilution also produced significant effects on concanavalin A responses, and on phytohemagglutinin-induced proliferation. It could be calculated that mice dosed with d-limonene at this dilution would receive 0.006 mg (or 6 μg) per mouse or a d-limonene concentration of 0.2 mg/kg/d. This dosage of d-limonene would be equivalent to a human drinking half a cup of orange juice daily. It seems unlikely that such a small amount of this low-toxicity compound has such immunologic effects in mice. Before conducting their immunologic study, Evans et al (1987) conducted a dose-finding experiment for the study and reported a 50% lethal dose (LD50) of “0.080 mg d-limonene/kg (corrected for 82% purity).” As stated above, the International Agency for Research on Cancer (IARC 1999) estimated human consumption of d-limonene to be 0.2 to 2 mg/kg/d (or 14 to 140 mg/70 kg/d); these values are greater than the lethal dose in Evans’s study. Vigushin et al. (1998) reported that cancer patients tolerated d-limonene at 189 mg/kg/d and showed no symptoms of toxicity. This human therapeutic dosage is 2,368 times higher than the mouse LD50 reported by Evan et al. In an NTP study involving large numbers of mice, no deaths or other sign of toxicity, other than decreased body weight gain, were observed in B6C3F1 mice exposed to d-limonene at 1,600 mg/kg/d for 16 days (NTP 1990). The dose in this NTP mouse study is 20,000 times higher than the Evans mouse LD50. The data of Evans are not consistent with the findings of others and should not be considered for setting exposure limits.
RATIONALE FOR ACCEPTABLE VALUES
The American Industrial Hygiene Association (AIHA 1993) recommends a Workplace Environmental Exposure Level (WEEL) for d-limonene of 30 ppm. In providing the rationale for reaching this WEEL value, AIHA states that “in the 2-year NTP study, liver effects were noted in male mice at 500 mg/kg, and reduced survival was noted in female rats at 600 mg/kg. The no observable effect levels (NOELs) were 250 and 300 mg/kg, respectively. A WEEL of 30 ppm (165.6 mg/m3) as an 8-h time-weighted average (TWA) is recommended to protect against these effects.” No information is provided about how the WEEL, a recommended airborne concentration for humans, was derived from the rodent oral NOELs.
The Threshold Limit Value (TLV) Committee of the American Conference of Industrial Hygienists Association (ACGIH) has not set an occupational exposure limit on d-limonene. However, for sensory irritants, ACGIH recommends occupational exposure limits of 0.03 × RD50 based on mouse data (Caldwell 2002). This approach was initially proposed by Alarie (1981); he and his colleagues reported an RD50 for limonene in mice of 1,163 ppm, as previously
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discussed (Larsen et al., 2000), and proposed a TLV of 30 to 45 ppm, based on 0.03 × RD50.
Several Nordic countries have occupational exposure limits on limonene of 25 to 75 ppm (see Table 13-6), but no rationales for these values could be found.
RATIONALE FOR SMAC VALUES
As mentioned above, d-limonene has a pleasant odor and dwarfs its levorotary isomer in the amount of industrial production and number of uses. If limonene is found in the spacecraft atmosphere, it is most likely to be the dextrorotary isomer. Because toxicity studies on limonene have been conducted almost exclusively on d-limonene, the exposure limits, based on these data, are also for d-limonene.
As also discussed above, d-limonene is one of the few compounds shown to induce a unique syndrome of nephropathy in male rats after subchronic or chronic exposure. After reviewing the literature on these effects of limonene and other hydrocarbons (EPA 1991), EPA’s Risk Assessment Forum concluded that nephropathy in male rats associated with α2u-globulin accumulation in hyaline droplets is not an appropriate end point to determine potential effects occurring in humans exposed to limonene. Therefore, the results for male rats would not be considered in setting exposure limits. Spacecraft maximum allowable concentrations (SMACs) are derived by using relevant toxicologic data and following the guidelines developed by the Subcommittee on Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants of the Committee on Toxicology (NRC 1992). The irritation study (Falk-Filipsson et al. 1993) conducted in humans exposed to limonene for 2 h was the longest inhalation study on limonene and will be used to set the ACs for all lengths of time under consideration (1 h, 24 h, 7 d, 30 d, 180 d, and 1,000 d). Because there are no long inhalation exposure studies, the data on 13 wk and 2 yr histopathology gavage studies in rodents will be used to set ACs for exposures of 7 d and longer. The SMACs (Table 13-7) are chosen from the lowest AC at each time point summarized in Table 13-8.
ACs Based on Short-Term Studies of Eye and Pulmonary Irritation and Human Test Subjects
When eight human subjects engaged in light activity were exposed to d-limonene at concentrations up to 80 ppm (450 mg/m3) for 2 h, no irritation or symptoms related to the central nervous system were noted. No changes in pulmonary function variables were detected (Falk-Filipsson et al. 1993). If limonene were to cause irritation, it would be the nonreactive type (Alarie, personal communication, 2004). Nonreactive irritation generally causes an effect that is
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TABLE 13-6 Limonene Occupational Exposure Limits Set, Recommended, or Proposed by Other Organizations
Organization/Agency
Limits, ppm
Remarks
Reference
American Industrial Hygiene Association
30 (168 mg/m3)
8-h WEEL TWAa
AIHA 1993
Swedish National Board of Occupational Safety
25 (150 mg/m3)
50 (300 mg/m3)
8 hr TWA STELb
SWEA 2005
Danish Environmental Protection Agency
75
Occupational exposure limit (tentative)
Madsen et al. 2001
Finnish Institute of Occupational Health
25
8-h TWA
NICNAS 2002
Norway
25
8-h TWA
RTECS 2006
aTWA, 8 h/d, 40 h/wk.
bTWA for 15 min.
TABLE 13-7 Spacecraft Maximum Allowable Concentrations for Limonenea
Duration
ppm
mg/m3
Target Toxicity
1 h
80
450
Eye and pulmonary irritation
24 h
80
450
Eye and pulmonary irritation
7 d
20
115
Eye and pulmonary irritation
30 d
20
115
Eye and pulmonary irritation
180 d
20
115
Eye and pulmonary irritation
1,000 d
20
115
Eye and pulmonary irritation
aChosen from the lowest AC at each time point summarized in Table 13-8.
relatively independent of exposure duration. According to Alarie, the maximum response to a nonreactive irritant will occur within the first 10 to 30 min of exposure (Nielson and Alarie 1982). Once this maximum is reached, the degree of irritation response is either maintained at this level or it gradually fades. This observation has been reported for many volatile compounds, including substituted benzenes, alcohols, and pinenes tested by Alarie’s group (Kane et al. 1980, Nielson and Alarie 1982, Kasanen et al. 1998); especially relevant to the assessment of limonene is their study on pinenes. Pinenes, like limonene, are cyclic monoterpenes. Falk-Filipsson showed that a 2-h exposure to 80 ppm of d-limonene did not cause irritation to the eyes and lungs, so it is valid to conclude that this concentration would not cause irritation at any given length of exposure. Therefore, 80 ppm is recommended as the AC for 1 and 24 h. However, the study was conducted in only eight human subjects; it is possible that sensi-
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TABLE 13-8 Acceptable Concentrations and Proposed SMACs for Limonene
Toxicity End Points
Exposure Data
Safety Factor for Exposure Extrapolation
Acceptable Concentration, ppm
Species
Time
Small size sample (n)
1 h
24 h
7 d
30 d
180 d
1,000 d
No irritation in human studya
8 human subjects exposed to 450 mg/m3 or 80 ppm experienced no irritation
1
1
√(100/n)
80
80
20
20
20
20
NOAEL in NTP’s 13-wk toxicity studyb
Rats (10 females) and mice (10 males, 10 females) dosed at 500 and 600 mg/kg/d for 13 wk showed no clinical signs or histopathology. The dose of 500 mg/kg/d is equivalent to an acceptable daily inhalation concentration of ~40 ppm for humans.
10
1 or 2c
--
--
--
40
40
20
--
NOAEL in NTP’s 2-year toxicity and carcino-genesis bioassay.b
Mice (male and female; 50/group) dosed for 2 years with 250 or 300 mg/kg/d showed no clinical signs or organ toxicity. A dose of 250 mg/kg/d is equivalent to an acceptable daily inhalation concentration of ~20 ppm for humans.
10
1
--
--
--
--
--
20
20
SMACsd
80
80
20
20
20
20
aStudy of Falk-Filipsson et al (1993).
bStudy of NTP (1990).
cSee text for details.
dBased on lowest acceptable concentrations.
Abbreviation: NOAEL, no-observed-adverse-effect level; --, not calculated.
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tive individuals could find 80 ppm mildly irritating. Although mild irritation is acceptable for up to 24 h, for longer exposure durations (7, 30, and 180 d), it is necessary to ensure that limonene at the AC will not be irritating to essentially all crewmembers. According to the NRC guidelines (NRC 2000), a NOAEL for a large population could be derived from the NOAEL from a study involving a small number (N) of test subjects by incorporating a factor of √(100/N) (NRC 2000). Therefore, the acceptable limit of 20 ppm for long-term (7, 30, and 180 d) exposure is obtained as shown below.
7-, 30-, and 180-d ACs Based on No-Observed-Adverse-Effect Level of NTP 13-wk Studies
In the 13-wk NTP study (NTP 1990), at a dose of 1,200 mg/kg/d, d-limonene caused a decrease in activity, lethargy, and excessive lacrimation in rats. In mice, rough hair coat and decreased activity were observed at 1,000 mg/kg/d. Doses of 500 and 600 mg/kg/d produced no symptoms, thus, 500 mg/kg/d (the lower of these two doses) is considered a no-observed-adverse-effect-level (NOAEL). In order to extrapolate toxicity data from rodent to human, a species-extrapolating factor of 10 is applied, making the NOAEL for humans 50 mg/kg/d. For a 70-kg person, this dose would be equivalent to 3,500 mg/d.
Thus,
In order to use this 13-wk NTP gavage study data to extrapolate equivalent risk of inhalation exposure, two assumptions are made. The first is that a person would inhale 20 m3 of air per day (NRC 1992) and the second is that limonene uptake in the lung is 76%. This second assumption is based on results of the study by Falk-Filipsson et al. (1993), who reported that when two groups (eight per group) of human subjects were exposed to d-limonene at concentrations of 450 and 225 mg/m3, the pulmonary uptake for each group was 68% ± 4% (Mean + SD). The upper value of 76% (68% + 2 × SD or 68% + 8%), an estimate of the 95th percentile of the pulmonary uptake distribution, was used to calculate the AC. Thus, in order for a person to absorb 3,500 mg of limonene per day (human NOAEL), he or she would have to breathe air containing limonene at 230 mg/m3 for 24 h.
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The AC for 7 and 30 d is set at 230 mg/m3 or 40 ppm; the AC for 180 d is set at 115 mg/m3 or 20 ppm by applying a time factor of 2. The calculation is shown below:
Because the NTP data came from a 13-wk (90-d) study, the AC for 180 d is obtained by applying a time-extrapolating factor of 2.
In the NTP studies, rodents were gavaged with bolus doses. As mentioned above, when humans and laboratory animals (rat, guinea pig, hamster, rabbit, and dog) were given oral doses of d-[14C]limonene, it was completely absorbed (Kodama et al. 1976). In a human inhalation study, the average pulmonary uptake of d-limonene vapor was 68%. Generally, systemic effects produced by a chemical given by bolus dose (in gavage) are more marked than those produced by an equivalent dose absorbed gradually from an inhalation exposure. In other words, an oral dose (x mg/kg) would likely be more toxic than an equivalent dose (x mg/kg) given by inhalation exposure. Therefore, the 3,500 mg/d of limonene absorbed into the body from inhalation exposure will have lower toxicity than that given by gavage, and extrapolation of a gavaged dose to an inhalation dose provides another safety margin.
Similarly, at an equivalent amount of chemical absorbed from an exposure, a short-term exposure to a high concentration generally poses a greater toxicologic risk than a longer exposure to a lower concentration. Haber’s rule (c × t = k) is used to extrapolate data from a shorter exposure to a longer exposure but not the other way around.
AC for 180-d Based on NOAEL of the NTP 2-Year Toxicology and Carcinogenesis Studies
The noncarcinogenic results of the NTP 2-year toxicology and carcinogenesis studies showed that three groups of 50 male mice dosed with d-limonene at 0, 250, and 500 mg/kg/d and female mice dosed with d-limonene at 0, 500, and 1,000 mg/kg all had no compound-related clinical signs of toxicity. After week 28 of the study, the high-dose group of female mice had 5% to 15% lower mean body weights than the control group. In male mice, the incidence of multi-
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nucleated cells in the livers for the control, low-dose, and high-dose groups was 8/49, 4/36, and 32/50, respectively; the incidence of liver cytomegaly in these three groups followed the same pattern, with corresponding rates of 23/49, 11/36, and 38/50. Because the low-dose group showed less effect than the control group, a benchmark dose approach was not used. Therefore, the NOAEL approach is used for AC setting. The mouse dose of 250 mg/kg/d was the NOAEL from the study. Applying a rodent-to-human extrapolation factor of 10 would provide an acceptable human oral exposure dose of 25 mg/kg/d (1,750 mg/70kg/d). Using an approach similar to the one used above for the 13-wk NTP study (pulmonary uptake of 76% and daily inhalation of 20 m3), we can calculate that a person breathing air containing 115 mg/m3 of limonene will absorb 1,750 mg of limonene per day. The equivalent inhalation exposure concentration of 115 mg/m3 or 20 ppm is the AC for 180 d; the calculation is shown below:
AC for 1,000-d Based on NOAEL of the NTP 2-Year Toxicology and Carcinogenesis Studies
As discussed in the section on long-term toxicity studies and the preceding section, when groups of mice were gavaged with d-limonene at daily doses of 0, 250, and 500 mg/kg for 2 years, the incidence of multinucleated cells was 8/49, 4/36, and 32/50, respectively. The incidence of cytomegaly in these three groups followed the same non-dose-dependent pattern, with corresponding rates of 23/49, 11/36, and 38/50. No similar lesions were observed in rats exposed to 300 or 600 mg/kg/d. The chronic treatment dose of 250 mg/kg/d is considered a NOAEL. An acceptable human oral exposure dose of 25 mg/kg/d (1,750 mg/70kg/d) is obtained after applying a rodent-to-human extrapolation factor of 10. As calculated above, 25 mg/kg/d is equivalent to a daily inhalation exposure concentration of 115 mg/m3 or 20 ppm, which is chosen as the AC for 1,000 d. The 2 years (730 days) in the rodent bioassay study is about the lifetime of the mice and rats. For using data from the lifetime bioassay for setting a 1,000-d SMAC, the NRC SMAC committee agrees that no time factor would be needed.
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