(R)-p-Mentha-1,8-dien

Fragrance substance (Limonene) -> IFRA amendment 29

Fragrance Ingredient (d-Limonene) -> IFRA transparency List

Pesticide -> EPA IRIS

Pesticide and(or) Waste-water effluent contaminant

log Kow = 4.57

4.38

4.2

0.8411 at 68 °F (NTP, 1992) - Less dense than water; will float

0.8411 at 20 °C

Relative density (water = 1): 0.84

0.838-0.843

0.84 @ 20°C

Danger

H226: Flammable liquid and vapor [Warning Flammable liquids]

P210, P233, P240, P241, P242, P243, P261, P264, P272, P273, P280, P301+P316, P302+P352, P303+P361+P353, P321, P331, P332+P317, P333+P317, P362+P364, P370+P378, P391, P403+P235, P405, and P501 (click each P-code to see the statement)

Danger

H226 (> 99.9%): Flammable liquid and vapor [Warning Flammable liquids]

P210, P233, P240, P241, P242, P243, P261, P264, P272, P273, P280, P301+P316, P302+P352, P303+P361+P353, P321, P331, P332+P317, P333+P317, P362+P364, P370+P378, P391, P403+P235, P405, and P501 (click each P-code to see the statement)

Chemical: Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)-

Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012)

Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 09-05-2023 https://echa.europa.eu/registration-dossier/-/registered-dossier/15256

Limonene, D-: Does not have an individual approval but may be used under an appropriate group standard

This chemical is combustible. (NTP, 1992)

Flammable. Above 48 °C explosive vapour/air mixtures may be formed.

SYMPTOMS: Symptoms of exposure to this compound may include irritation and sensitization of the skin. It may also cause eye irritation and damage. Ingestion of large doses may lead to albuminuria and hematuria. This type of compound irritates all tissues intensely and may cause circulatory collapse. Ingestion of this type of compound may cause abdominal burning, nausea, vomiting, diarrhea, dysuria, hematuria, unconsciousness, shallow respiration, and convulsions. Inhalation of this type of compound may cause dizziness, rapid and shallow breathing, tachycardia, bronchial irritation, unconsciousness and convulsions. Anuria, pulmonary edema and bronchia pneumonia may complicate recovery after either type of exposure.

d-Limonene is a liquid with a pleasant lemon-like odor. It is used as a solvent to replace chlorinated hydrocarbons and other more volatile and toxic organic solvents. It readily oxidizes when in contact with air. The oxidized form of d-limonene is a known skin sensitizer. [HSDB] A skin and eye irritant that may cause skin sensitization; [ICSC] The racemic mixture of d-limonene and l-limonene is called limonene or dipentene (138-86-3). [Kanerva, p. 1789] Estimated lethal dose orally for humans is 0.5 to 5 g/kg; Healthy men had diarrhea after an oral dose of 20 grams; Liver effects were noted in a chronic high-dose feeding study of mice; [AIHA] See Limonene and l-Limonene.

Synthetic flavoring substances and adjuvants /for human consumption/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Limonene (d-, l-, and dl-) is included on this list.

Synthetic flavoring substances and adjuvants /for animal drugs, feeds, and related products/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Limonene (d-, l-, and dl-) is included on this list.

USEPA/Office of Prevention, Pesticides and Toxic Substances; Reregistration Eligibility Decision Document (RED) - Limonene, EPA 738-R-94-034 (September 1994). The RED summarizes the risk assessment conclusions and outlines any risk reduction measures necessary for the pesticide to continue to be registered in the U.S.[Available from, as of June 3, 2015: http://www.epa.gov/pesticides/reregistration/status.htm]

DHHS/NTP; Toxicology & Carcinogenesis Studies of d-Limonene in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 347 (1990) NIH Publication No. 90-2802

USEPA/OPP; Exposure and Risk Assessment on Lower Risk Pesticide Chemicals - D-Limonene EPA-HQ-OPP-2004-0335-0003 (2004). This document represents the Lower Risk Pesticide Chemical Focus Group's (LRPCFG) Tolerance Reassessment Eligibility Decision (TRED) on d-limonene. This assessment summarizes the available information on the use, physical/chemical properties, toxicological effects, exposure profiles, and environmental fate and ecotoxicity for d-limonene.[Available from, as of July 28, 2015: http://www.regulations.gov/#!home]

Fires involving this material can be controlled with a dry chemical carbon dioxide or Halon extinguisher. (NTP, 1992)

Use water spray, powder, alcohol-resistant foam, carbon dioxide. In case of fire: keep drums, etc., cool by spraying with water.

Fresh air, rest.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth.

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

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

/Use/ powder, alcohol-resistant foam, water spray, carbon dioxide. In case of fire: keep drums, etc., cool by spraying with water.

Fireproof. Separated from strong oxidants. Store in an area without drain or sewer access.

Safe Storage of Pesticides. Always store pesticides in their original containers, complete with labels that list ingredients, directions for use, and first aid steps in case of accidental poisoning. Never store pesticides in cabinets with or near food, animal feed, or medical supplies. Do not store pesticides in places where flooding is possible or in places where they might spill or leak into wells, drains, ground water, or surface water.

Collect leaking and spilled liquid in sealable containers as far as possible. Absorb remaining liquid in sand or inert absorbent and remove to safe place.

If a spill occurs, clean it up promptly. Don't wash it away. Instead, sprinkle the spill with sawdust, vermiculite, or kitty litter. Sweep it into a plastic garbage bag, and dispose of it as directed on the pesticide product label.

After Applying a Pesticide, Indoors or Outdoors. To remove pesticide residues, use a bucket to rinse tools or equipment three times, including any containers or utensils that you used when mixing the pesticide. Then pour the rinsewater into the pesticide sprayer and reuse the solution by applying it according to the pesticide product label directions. After applying any pesticide wash your hands and any other parts of your body that may have come in contact with the pesticide..To prevent tracking pesticides inside, remove or rinse your boots or shoes before entering your home. Wash any clothes that have been exposed to a lot of pesticide separately from your regular wash.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. Then, use absorbent paper to pick up all liquid spill material. Your contaminated clothing and absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Safe Disposal of Pesticides. The best way to dispose of small amounts of excess pesticides is to use them - apply them - according to the directions on the label. If you cannot use them, ask your neighbors whether they have a similar pest control problem and can use them. If all of the remaining pesticide cannot be properly used, check with your local solid waste management authority, environmental agency, or health department to find out whether your community has a household hazardous waste collection program or a similar program for getting rid of unwanted, leftover pesticides. These authorities can also inform you of any local requirements for pesticide waste disposal.

Safe Disposal of Pesticides. An empty pesticide container can be as hazardous as a full one because of residues left inside. Never reuse such a container. When empty, a pesticide container should be rinsed carefully three times and the rinsewater thoroughly drained back onto the sprayer or the container previously used to mix the pesticide. Use the rinsewater as a pesticide, following label directions. Replace the cap or closure securely. Dispose of the container according to label instructions. Do not puncture or burn a pressurized container like an aerosol - it could explode. Do cut or puncture other empty pesticide containers made of metal or plastic to prevent someone from reusing them. Wrap the empty container and put it in the trash after you have rinsed it.

Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Do NOT let this chemical enter the environment. Collect leaking and spilled liquid in sealable containers as far as possible. Absorb remaining liquid in sand or inert absorbent. Then store and dispose of according to local regulations.

/Provide adequate/ ventilation. /Wear/ protective gloves, clothing; and safety glasses.

Do not eat, drink, or smoke during work.

Wear the items of protective clothing the label requires: for example, non-absorbent gloves (not leather or fabric), rubber footwear (not canvas or leather), a hat, goggles, or a dust-mist filter. If no specific clothing is listed, gloves, long-sleeved shirts and long pants, and closed shoes are recommended. You can buy protective clothing and equipment at hardware stores or building supply stores.

Indoor Applications. If the label directions permit, leave all windows open and fans operating after the application is completed. If the pesticide product is only effective in an unventilated (sealed) room or house, do not stay there. Put all pets outdoors, and take yourself any your family away from treated areas for at least the length of time prescribed on the label. Apply most surface sprays only to limited areas such as cracks; don't treat entire floors, walls, or ceilings. Don't let pesticides get on any surfaces that are used for food preparation. Wash any surfaces that may have pesticide residue before placing food on them.

For more Preventive Measures (Complete) data for (D)-LIMONENE (7 total), please visit the HSDB record page.

D-limonene is a naturally occurring monoterpene and has been found to possess numerous therapeutic properties. In this study, we used D-limonene as a protective agent against the nephrotoxic effects of anticancer drug doxorubicin (Dox). Rats were given D-limonene at doses of 5% and 10% mixed with diet for 20 consecutive days. Dox was given at the dose of 20 mg/kg body weight intraperitoneally. The protective effects of D-limonene on Dox-induced oxidative stress and inflammation were investigated by assaying oxidative stress biomarkers, lipid peroxidation, serum toxicity markers, proinflammatory cytokines, and expression of nuclear factor kappa B (NFkB), cyclo-oxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and Nitrite levels. Administration of Dox (20 mg/kg body weight) in rats enhanced renal lipid peroxidation; depleted glutathione content and anti-oxidant enzymes; elevated levels of kidney toxicity markers viz. kidney injury molecule-1 (KIM-1), blood urea nitrogen (BUN), and creatinine; enhanced expression of NFkB, COX-2, and iNOS and nitric oxide. Treatment with D-limonene prevented oxidative stress by restoring the levels of antioxidant enzymes, further both doses of 5% and 10% showed significant decrease in inflammatory response. Both the doses of D-limonene significantly decreased the levels of kidney toxicity markers KIM-1, BUN, and creatinine. D-limonene also effectively decreased the Dox induced overexpression of NF-kB, COX-2, and iNOS and nitric oxide. Data from the present study indicate the protective role of D-limonene against Dox-induced renal damage.

Clinical trials have shown that docetaxel combined with other novel agents can improve the survival of androgen-independent prostate cancer patients. d-Limonene, a non-nutrient dietary component, has been found to inhibit various cancer cell growths without toxicity. We sought to characterize whether a non-toxic dose of d-limonene may enhance tumor response to docetaxel in an in vitro model of metastatic prostate cancer. Human prostate carcinoma DU-145 and normal prostate epithelial PZ-HPV-7 cells were treated with various concentrations of d -limonene, docetaxel or a combination of both, and cell viability was determined by MTT assay. Intracellular reactive oxygen species (ROS), reduced glutathione (GSH) and caspase activity were measured. Apoptosis and apoptosis-related proteins were studied by enzyme-linked immunosorbent assay and Western blotting, respectively. d-Limonene and docetaxel in combination significantly enhanced the cytotoxicity to DU-145 cells than PZ-HPV-7 cells. Exposure of DU-145 cells to a combined d-limonene and docetaxel resulted in higher ROS generation, depletion of GSH, accompanied by increased caspase activity than docetaxel alone. It also triggered a series of effects involving cytochrome c, cleavages of caspase-9, 3 and poly (ADP-ribose) polymerase, and a shift in Bad:Bcl-xL ratio in favor of apoptosis. Apoptotic effect was significantly blocked on pretreatment with N-acetylcysteine, indicating that antitumor effect is initiated by ROS generation, and caspase cascades contribute to the cell death. Our results show ... that d-limonene enhanced the antitumor effect of docetaxel against prostate cancer cells without being toxic to normal prostate epithelial cells. The combined beneficial effect could be through the modulation of proteins involved in mitochondrial pathway of apoptosis. d-Limonene could be used as a potent non-toxic agent to improve the treatment outcome of hormone-refractory prostate cancer with docetaxel.

There are concerns about ozone-initiated chemistry, because the formation of gaseous oxidation products and ultrafine particles may increase complaints, morbidity and mortality. Here we address the question whether the gaseous products or the ultrafine particles from the ozone-initiated chemistry of limonene, a common and abundant indoor pollutant, cause acute airway effects. The effects on the airways by d-limonene, a ca. 16s old ozone/d-limonene mixture, and clean air were evaluated by a mice bioassay, from which sensory irritation of the upper airways, airflow limitation, and pulmonary irritation can be obtained. A denuder was inserted to separate the ultrafine particles from the gaseous products prior to the exposure chamber. Reduction of mean respiratory frequency (>30%) and 230% increase of time of brake were observed without denuder, during 30 min exposure, to the ozonolyzed d-limonene mixture, which are indicative of prominent sensory effects. The initial concentrations (ppm) were 40 d-limonene and 4 ozone. The exposure concentrations (ppm) were about 35 d-limonene and 0.05 ozone. Formaldehyde and residual d-limonene, the salient sensory irritants, accounted for up to three-fourth of the sensory irritation. The upper airway effects reversed to baseline upon cessation of exposure. An effect on the conducting airways was also significant, which did not reverse completely upon cessation. Airway effects were absent with the denuder inserted, which did not alter the size distribution of ultrafine particles (approximately 10 mg/cu m), significantly. The result was statistically indistinguishable from clean dry air. It is concluded that ultrafine particles that are generated from ozone-initiated d-limonene chemistry and denuded are not causative of sensory effects in the airways.

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.

For more Interactions (Complete) data for (D)-LIMONENE (16 total), please visit the HSDB record page.

LC50; Species: Eisenia fetida Savigny (Earthworm) 6.0 ppm for 48 hr /from table/

LC50; Species: Daphnia magna (Water flea); Conditions: flow through; Concentration: 0.577 mg/L for 48 hr /from table/

EC50; Species: Daphnia magna (Water Flea) age 24 hr, neonate; Conditions: freshwater, static, 20 °C; Concentration: 7850 ug/L for 48 hr (95% confidence interval: 6860-8960 ug/L); Effect: intoxication, immobilization /97% purity/

EC50; Species: Daphnia pulex (Water Flea) age <24 hr, neonate; Conditions: freshwater, static, 17 °C; Concentration: 69600 ug/L for 48 hr; Effect: intoxication, immobilization /> or =96% purity/

LC50; Species: Pimephales promelas (Fathead minnow) age 32-34 days, length 21.8 mm, weight 0.177 g; Conditions: freshwater, flow through, 24.4 °C, pH 7.6, hardness 46.3 mg/L CaCO3, alkalinity 39.5 mg/L CaCO3, dissolved oxygen 5.9 mg/L; Concentration: 702 ug/L for 96 hr (95% confidence interval: 619-796 ug/L) /97% purity/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1120(SRC), determined from a structure estimation method(2), indicates that d-limonene is expected to have very low mobility in soil(SRC). Volatilization of d-limonene from moist soil surfaces is expected(SRC) given a Henry's Law constant of 0.0281 atm-cu m/mole(3). However, adsorption to soil is expected to attenuate volatilization(SRC). d-Limonene is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 1.98 mm Hg at 25 °C(4). A 73% of theoretical BOD using activated sludge in the Japanese MITI test(5) suggests that biodegradation is an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1120(SRC), determined from a structure estimation method(2), indicates that d-limonene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 0.0281 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3.5 hours and 4.6 days, respectively(SRC). d-Limonene is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). According to a classification scheme(5), an estimated BCF of 480(SRC), from its log Kow of 4.57(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). A 73% of theoretical BOD using activated sludge in the Japanese MITI test(7) suggests that biodegradation is an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), d-limonene, which has a vapor pressure of 1.98 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase d-limonene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC). The half-life for the reaction with hydroxyl radicals is estimated to be 2.6 hours(SRC), calculated from its rate constant of 1.71X10-10 cu cm/molecule-sec at 25 °C(3). The rate constant for the vapor-phase reaction of d-limonene with ozone has been reported as 4.42X10-16 cu cm/molecule-sec at 25 °C(4); this corresponds to an atmospheric half-life of about 37 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(5). The calculated nighttime lifetime for the reaction of d-limonene with nitrate radicals is 9 minutes(6). d-Limonene does not contain chromophores that absorb at wavelengths >290 nm(7) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

d-Limonene detections in 40 foods(1).[Table#4852]

d-Limonene has been reported in alcoholic and non-alcoholic beverages, baked goods, chewing gum, relish, frozen dairy, pudding, gelatin, gravies, hard and soft candy, and meat products(1). d-Limonene has been detected in beer, wine and spirits(2).

IDENTIFICATION AND USE: D-Limonene is a colorless liquid or oil with citrus odor. D-Limonene, a major constituent of citrus oils, is a monoterpene widely used as a flavor/fragrance additive in cosmetics, foods, and industrial solvents as it possesses a pleasant lemon-like odor. It is registered for pesticide use in the USA but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. D-Limonene is also used as gallstone solubilizer in animals and humans. HUMAN EXPOSURE AND TOXICITY: Skin irritation or sensitizing potential was reported following widespread use of this agent in various consumer products. In humans, oxidation products or metabolites of d-limonene were shown to act as skin irritants. The potential occurrence of skin irritation necessitates regulation of this chemical as an ingredient in cosmetics. In humans, d-limonene has demonstrated low toxicity after single and repeated dosing for up to one year. D-Limonene was reported to significantly damage and increase permeability of membranes of human lung fibroblasts. ANIMAL STUDIES: In experimental animals oxidation products or metabolites of d-limonene were shown to act as skin irritants. D-Limonene has been designated as a chemical with low toxicity based upon lethal dose (LD50) and repeated-dose toxicity studies when administered orally to animals. Carcinogenic effects have also been observed in male rats, but the mode of action (MOA) is considered irrelevant for humans as the protein alpha(2u)-globulin responsible for this effect in rodents is absent in humans. d-Limonene induced hyaline droplet nephropathy in male rats. The liver was identified as a critical target organ following oral administration of d-limonene. D-Limonene (2363 mg/kg, orally) given to mice for 6 days from day 7-12 of gestation decreased body weight gain and increased incidence of abnormal bone formation in fetuses. D-Limonene also decreased body weight gain in male offspring; however, the toxicity of d-limonene was not severe. D-Limonene was not mutagenic in four strains of Salmonella typhimurium (TA 98, TA 100, TA 1535, or TA 1537), 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 CHO cells. All assays were conducted in the presence and absence of exogenous metabolic activation.

As described in multiple studies/evaluations conducted during the last several decades, d-limonene does not pose any carcinogenic or nephrotoxic risk to humans. For example, the renal tumors induced in male rats are not relevant to human carcinogenicity.

The intake of d-limonene in food varies due to differing diet patterns. Based on daily US consumption of d-limonene per capita, the intake of d-limonene from food for the general population was estimated to be 0.27 mg/kg body weight per day(1).

d-Limonene was detected in the volatile emissions of red maple (Acer rubrum), silver maple (Acer saccharinum), paper birch (Betula papyrifera), tulip poplar (Liriodendron tulipifera), narrow leaf cottonwood (Populus angustifolia), big tooth aspen (Populus grandidentata), trembling aspen (Populus tremuloides), blue spruce (Picea pungens), short-leaf pine (Pinus echinata), Ponderosa pine (Pinus ponderosa), red pine (Pinus resinosa), gray "Digger" pine (Pinus sabiniana), white pine (Pinus strobus), beach pine (Pinus sylvestris), Scots pine (Pinus sylvestris L.), loblolly pine (Pinus teada), Douglas fir (Pseudotsuga menziesii), sumac (Rhus glabra), juniper bush (Juniperus sp.), fennel (Ferula communis), sunflower (Helianthus annuus) and tomato (Lycopersicon esculetum)(1). Samples were collected during the growing season from 2004 to 2006 in forests in Michigan, North Carolina, Colorado and California(1).

d-Limonene concentrations in plants(1).[Table#4855]

d-Limonene detections in plants(1).[Table#4856]

Redness. Pain.

Redness.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=5989-27-5]

d-Limonene was detected in air samples at all stages in a municipal solid waste treatment plant located in China, samples were collected Dec 2011(1). d-Limonene was not detected (detection limit 0.5 ug/L) in effluent samples from 10 waste water treatment plants located around the country (Arizona, Colorado, Georgia, Iowa, Kansas, Minnesota, Nevada, New Jersey, New York, South Dakota)(2).

Synthetic flavoring substances and adjuvants /for human consumption/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Limonene (d-, l-, and dl-) is included on this list.

Synthetic flavoring substances and adjuvants /for animal drugs, feeds, and related products/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Limonene (d-, l-, and dl-) is included on this list.

d-Limonene; tolerances for residues. (a) General. (1) The insecticide d-limonene may be safely used in insect-repellent tablecloths and in insect-repellent strips used in food- or feed-handling establishments. (2) To assure safe use of the insect repellent, its label and labeling shall conform to that registered by the U.S. Environmental Protection Agency, and it shall be used in accordance with such label and labeling.

Residues of d-limonene are exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. Use: solvent, fragrance.

Residues of d-limonene are exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. Use: solvent, fragrance.

Based on the reviews of the generic data for the active ingredients Limonene, the Agency has sufficient information on the health effects of Limonene and on its potential for causing adverse effects in fish and wildlife and the environment. Therefore, the Agency concludes that products containing Limonene for all uses are eligible for reregistration. The Agency has determined that limonene products, labeled and used as specified in this Reregistration Eligibility Decision, will not pose unreasonable risks or adverse effects to humans or the environment. /Limonene/

The sequence of events /in the spontaneously occurring nephropathy in mature male rats/ appears to be that: (1) protein accumulates in the lysosomes in the cytoplasm of epithelial cells of the P2 segment of the proximal convoluted tubules in the kidney cortex; (2) the accumulated material becomes so abundant that it crystallizes, forming the microscopically visible hyaline droplets; (3) the continued build-up of material eventually leads to the death of epithelial cells with a concomitant thinning of the epithelial layer (although some regeneration is usually seen); and (4) the dead cell debris becomes lodged in the outer strip of the outer medulla where the tubules narrow, forming granular casts and causing tubule dilation with pressure necrosis of the cells of the tubule walls. There is also an increase in the relative weight of the kidneys accompanying this phenomenon. ...Agents ...that appear to exacerbate this hyaline droplet formation and its consequences in mature male rats /include/ ...d-limonene.

The mechanism by which d-limonene causes alpha2u-globulin accumulation in the male rat kidney has been elucidated. The prerequisite step in the development of the nephropathy is the binding to alpha2u-globulin of an agent, which in the case of d-limonene is the 1,2-epoxide. This binding is specific for alpha2u-globulin and reversible, with a binding affinity (Kd) of approximately 5.6X10-7 mol/L. Binding of this ligand to alpha2u-globulin reduces the rate of its lysosomal degradation relative to that of native protein, thereby causing it to accumulate. Lysosomal cathepsin activity towards other protein substrates is not altered. Whereas accumulation of alpha2u-globulin can be observed after a single oral dose of d-limonene, continued treatment results in additional histological changes in the kidney. Phagolysosomes become enlarged, engorged with protein and show polyangular crystalloid inclusions. After 3-4 weeks of dosing, progressive renal injury, characterized by single-cell degeneration and necrosis in the P2 segment of the renal proximal tubule, is noted. Dead cells are sloughed into the lumen of the nephron, contributing to the development of granular casts at the cortico-medullary junction. Renal functional perturbations, including reduced uptake of organic anions, cations and amino acids and mild proteinuria resulting from a large increase in the amount of alpha2u-globulin excreted in urine, are observed. These functional changes occur only in male rats and only at doses that exacerbate the protein droplet formation. In response to the cell death and functional changes, there is a compensatory increase in cell proliferation in the kidney, most notably in the P2 segment of the proximal tubules, the site of protein accumulation. With continued treatment, the cell proliferation persists, but it does not restore renal function. The increase in cell proliferation is linked to the development of renal tubular tumors. alpha2u-Globulin nephropathy and renal-cell proliferation occur at doses consistent with those that produce renal tubular tumors.

In the male rat, the production of renal tumors by chemicals inducing alpha2u-globulin accumulation (CIGA) is preceded by the renal lesions ascribed to alpha2u-globulin-associated nephropathy. The involvement of hyaline droplet accumulation in the early nephrotoxicity associated with CIGA is a major difference from the sequence seen for classical carcinogens. The pathologic changes that precede the proliferative sequence for classical renal carcinogens also include a form of early nephrotoxicity, but no apparent hyaline droplet accumulation. Investigations performed in multiple laboratories ... have demonstrated a consistent association between hyaline droplets containing alpha2u-globulin and production of certain lesions in the male rat kidney. These renal lesions are not found in mice, female rats, or other laboratory species tested. The histopathological sequence in the male rat consists of the following: (1) an excessive accumulation of hyaline droplets containing alpha2u-globulin in renal proximal tubules; (2) subsequent cytotoxicity and single-cell necrosis of the tubule epithelium; (3) sustained regenerative tubule cell proliferation, providing exposure continues; (4) development of intralumenal granular casts from sloughed cell debris associated with tubule dilation, and papillary mineralization; (5) foci of tubule hyperplasia in the convoluted proximal tubules; and finally, (6) renal tubule tumors. Biochemical studies with model compounds show that CIGA or their metabolites bind specifically. but reversibly, to male rat alpha2u-globulin. The resulting alpha2u-globulin-CIGA complex appears to be more resistant to hydrolytic degradation by lysosomal enzyemes than native, unbound alpha2u-globulin. Inhibition of the catabolism of alpha2u-globulin, a protein only slowly hydrolyzed by renal lysosomal enzymes under normal physiological conditions, provides a plausible basis for the initial stage of protein overload in the nephropathy sequence.

75-95% excreted within 2-3 days; [AIHA]

Following the inhalation exposure of volunteers to d-limonene at 450 mg/cu m for 2 hours, three phases of elimination were observed in the blood, with half-lives of about 3, 33, and 750 minutes, respectively. ...

Incubation of d-limonene with rat liver microsomes produced d-limonene-1,2-diol and d-limonene-8,9-diol as metabolites and d-limonene-1,2-epoxide and d-limonene-8,9-epoxide were identified as intermediates.

After oral administration of (14)C-labeled d-limonene, 5 new metabolites were isolated from dog and rat urine: 2-hydroxy-p-menth-8-en-7-oic acid, perillylglycine, perillyl-beta-d-glucopyranosiduronic acid, p-mentha-1,8-dien-6-ol, and probably p-menth-1-ene-6,8,9-triol.

The major metabolite of d-limonene in urine was perillic acid 8,9-diol in rats and rabbits, perillyl-beta-d-glucopyranosiduronic acid in hamsters, p-menth-1-ene-8,9-diol in dogs, and 8-hydroxy-p-menth-1-ene-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.

For more Metabolism/Metabolites (Complete) data for (D)-LIMONENE (8 total), please visit the HSDB record page.

(+)-limonene has known human metabolites that include Limonen-10-ol and Carveol.

The fate of dermally applied [(14)C]d-limonene was evaluated in humans and Long-Evans rats. In rats, 5 mg/kg body weight of [(14)C]d-limonene applied dermally to the shaved back under occlusion, resulted in the absorption of approximately 12% of the dose. The absorbed d-limonene was completely metabolized and excreted rapidly, primarily from the urine (80%) with a small fraction (20%) excreted in the feces. There was no long-term retention of the test material in body tissues. In humans, following dermal application of 12 mg of [(14)C]d-limonene in ethanol (1 mL) to the back under nonocclusive conditions (for 1 h after application to allow the material to dry, thereafter under occlusion), only 0.16% of the dose was absorbed and the radioactivity was recovered from the urine. Radioactivity in human feces was below the limit of detection. These results indicate that under conditions of simulated use of fragrances and cosmetics, d-limonene has a low potential for dermal absorption and tissue accumulation, and the d-limonene that is absorbed is rapidly excreted in the urine. Based upon these findings and the knowledge that d-limonene possesses a low-systemic toxicity profile, it is reasonable to conclude that dermal exposure to d-limonene from fragrance and cosmetic applications is highly unlikely to result in any clinically significant human toxicity.

After oral administration of (14)C-labeled d-limonene to animals and humans, 75-95 and <10% of the radioactivity was excreted in the urine and feces respectively within 2-3 days.

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 concentrations 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.

Orally administered d-limonene is rapidly and almost completely taken up from the gastrointestinal tract in humans as well as in animals. Infusion of labelled d-limonene into the common bile duct of volunteers revealed that the chemical was very poorly absorbed from the biliary system.

For more Absorption, Distribution and Excretion (Complete) data for (D)-LIMONENE (10 total), please visit the HSDB record page.

Used in flavorings, fragrances, and cosmetics and as a solvent and wetting agent; Also used to make resins, insecticides, insect repellants, and animal repellants; [HSDB]

Metal Degreasing [Category: Clean]

Smoking cigarettes [Category: Food & Drugs]

For (d)-limonene (USEPA/OPP Pesticide Code: 179701) ACTIVE products with label matches. /SRP: Registered for use in the USA but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Flavoring, fragrance and perfume materials, solvent, wetting agent, resin manufacture. /Limonene/

Insecticide, repellant. /Limonene/

2023: 10,000,000 - <25,000,000 lb

(1979) MORE THAN 4.5X10+5 G /UNSPECIFIED ISOMER/

Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)- is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438).

Production volume for non-confidential chemicals reported under the 2006 Inventory Update Rule. Chemical: Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)-. Aggregated National Production Volume: < 500,000 pounds.

Non-confidential 2012 Chemical Data Reporting (CDR) information on the production and use of chemicals manufactured or imported into the United States. Chemical: Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)-. National Production Volume: 2,466,806 lb/yr.

Limonene

p-Mentha-1,8-diene; 1-methyl-4-prop-1-en-2-ylcyclohexene; 1-Methyl-4-(1-methylethenyl)cyclohexene; 1-Methyl-4-isopropenyl-1-cyclohexene; 4-Isopropenyl-1-methylcyclohexene; Cyclohexene, 1-methyl-4-(1-methylethenyl)-; Dipentene

IFRA_STD_186.pdf

29

IFRA 51st Amendment - Guidance for the use of IFRA Standards

Specification: This material should be used only if it meets the criteria stated in the Standard

d-Limonene may be obtained by steam distillation of citrus peels and pulp resulting from the production of juice and cold-pressed oils, or from deterpenation of citrus oils; it is sometimes redistilled.

Isolation of d-limonene from mandarin peel oil (Citrus reticulata Blanco, Rutaceae).

Pressurized liquid, ready-to-use liquid, and emulsifiable and soluble concentrate formulations.

Emulsifiable concentrate, granular, impregnated material, pressurized liquid, liquid - ready to use. /Limonene/

The purity of commercial d-limonene is about 90-98%.

Whitmire Micro-Gen TC 232 (BASF Corporation): Active ingredient: d-limonene 10.0%.

For more Formulations/Preparations (Complete) data for (D)-LIMONENE (26 total), please visit the HSDB record page.

Cosmetics product ingredient: Limonene (1-methyl-4-prop-1-en-2-yl-cyclohexene; dl-limonene (racemic); Dipentene; (R)-p-mentha-1,8-diene; (d-limonene); (S)-p-mentha-1,8-diene; (l-limonene))

Information on 1542 consumer products that contain d-Limonene in the following categories is provided:

EPA Safer Chemical Functional Use Classes -> Solvents

Safer Chemical Classes -> Yellow triangle - The chemical has met Safer Choice Criteria for its functional ingredient-class, but has some hazard profile issues

Fragrance Ingredients

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavoring Agents -> JECFA Flavorings Index

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

All Other Basic Organic Chemical Manufacturing

Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)-: ACTIVE

The (+)-isomer is present in citrus peel oils at a concentration of over 90%.