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Description of key information

Short description of key information on bioaccumulation potential result:
Turpentine oil, alpha pinene and delta-3-carene are readily absorbed by inhalation.

Only a minor part is exhaled unchanged and even less is excreted unchanged in urine, showing that they are extensively metabolised. Bioaccumulation of these terpene hydrocarbons is not expected, since the substances are efficiently metabolised to yield oxygenated metabolites that are subsequently conjugated with glucuronic acid and excreted mainly in the urine.

Short description of key information on absorption rate:
Results demonstrate rapid penetration of alpha-pinene not only to the first stratum corneum layers but also to viable epidermis and dermis. In an in vitro study, alpha pinene did not permeate across the skin to the acceptor medium due to large cumulation in the skin tissue. However, following immersion of young pigs and one human subject for 30 minutes in baths containing 150 mL of a pine oil mixture, alpha pinene was detected in exhaled air within 20 minutes reaching maximum levels 50-75 minutes after start of the bath and remained detectable after 1 day.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic data on turpentine oil are described for delta-3-carene toxicokinetics because Turpentine oil contains the registered substance and the structurally-related substance alpha-pinene and that toxicokinetic parameters on delta-3-carene were determined after Turpentine oil exposure.

ABSORPTION AND EXCRETION:

Pulmonary uptake of delta-3-carene increased linearly with exposure, approaching 70% for 225 and 450 mg/m3 exposure levels during 2-h exposures. delta-3-Carene persists in the blood with an extended half-life, suggesting affinity for adipose tissues (Falk et al., 1991).

Eight male volunteers were exposed to 450 mg/m3 turpentine oil by inhalation (2 h, 50 W) in an exposure chamber. The mean relative uptakes of alpha pinene, beta pinene, and delta-3-carene were 62%, 66%, and 68% respectively, of the amount inhaled. Between 2% and 5% of the net uptake was excreted unchanged in the expired air after the end of exposure. The mean blood clearance 21 h after exposure (CL21h) of alpha pinene, beta pinene and delta-3-carene, were 0.8, 0.5, and 0.4 L/kg/h, respectively. The mean half lives (t1/2) of the last phase of alpha pinene, beta pinene and delta-3-carene averaged 32, 25, and 42 h, respectively. (Filipsson et al., 1996)

Elimination of turpentine oil and its metabolites is primarily through the urinary tract (Lewander and Aleguas, 1998, cited in HSDB 2003). A portion of the turpentine oil absorbed in industrial exposures is exhaled unchanged in expired air. The remainder is excreted in the urine as glucuronic acid conjugates (Bingham, 2001, cited in HSDB 2003).

The structure-related alpha pinene is readily absorbed through the pulmonary system, the skin, and the intestines (Clayton and Clayton,1981-1982; Budavari et al., 1996; cited in HSDB, 2009a and 2009b). The toxicokinetics of alpha pinene was studied in humans. Eight healthy males were exposed to 10, 225, or 450 mg/m3 (+)-alpha pinene or 450 mg/m3 (-)-alpha pinene for 2 h in an inhalation chamber while performing light work (50 watts). Average pulmonary uptake of (+)-alpha pinene and (-)-alpha pinene amounted to 59% of the exposure concentration. Absolute uptake increased linearly with concentration. Mean blood concentration at the end of exposure were linearly related to inhaled concentration. The terminal t1/2 of alpha pinene from the blood was 695 min for (+)-alpha pinene and 555 min for (-)-alpha pinene. Cumulative urinary excretion of unchanged alpha pinene amounted to less than 0.001% of each dose. Respiratory elimination of (+)-alpha pinene and (-)-alpha pinene was 7.7 and 7.5% of total uptake, respectively (Falk et al., 1990; cited in HSDB 2003 and 2009a).

Similarly, the renal elimination of verbenols after experimental exposure to (+)-alpha pinene and (-)-alpha pinene was studied in humans following exposure to 10, 225 and 450 mg/m3 terpene in an exposure chamber. The pulmonary uptake was about 60%. About 8% was eliminated unchanged in exhaled air. Depending on the exposure level, about 1%-4% of the total uptake was eliminated as cis- and trans-verbenol. Most of the verbenols were eliminated within 20 h after a 2-h exposure. The renal excretion of unchanged alpha pinene was less than 0.001%. (Levin et al., 1992, cited in HSDB 2009a)

The blood and urine monoterpene concentrations were continuously monitored from a patient attempting suicide by ingestion of 400-500 mL pine oil. The blood and urine monoterpene concentrations were continuously monitored. The data suggest that monoterpenes are poorly resorbed in the gastrointestinal tract. The resorbed portion of the hydrocarbons cumulates in the lipophilic body compartments and is slowly metabolized and then excreted by the kidneys. The main metabolic pathways are hydratation, hydroxylation, rearrangement, and acetylation (Koppel, 1981).

METABOLISM:

In a metabolism study, four healthy human volunteers were orally exposed to a single dose of 10 mg delta-3-carene (CRN) via spiked gelatin capsules. CRN-10-COOH was detected in each urine sample with maximum concentration 2-3 h after administration, whereas CRN-10-OH and CRN-3,4-OH were not detected in any of the samples. The renal excretion kinetics of CRN-10-COOH showed an elimination half-life of about 3 h. The cumulative excretion of CRN-10-COOH within 24 h after exposure correlated with about 2 % of the applied dose. The GC-PCI-MS Q1 scan analysis indicated several additional human CRN metabolites: 3% (CRN-M1), 1% (CRN-M2), 5% (CRNM3), 4% (CRN-M4), 11% (CRN-M5), and 2% (CRNM6), respectively. The results of the study indicate that CRN-10-COOH is a relevant product of the human in vivo metabolism of delta-3-carene. (Schmidt,2015)

The biotransformation of (+)-, (-)-, and (+/-)-alpha pinenes and (+)-delta-3-carene in rabbits was investigated. The major metabolites were as follows: (-)-trans-verbenol from (+)-, (-)-, and (+/-)-alpha pinenes; (-)-m-mentha-4,6-dien-8-ol, 3-caren-9-ol, (-)-delta-3-carene-9-carboxylic acid and delta-3-carene-9,10-dicarboxylic acid from (+)-delta-3-carene. (Ishida, 1981)

Similarly, the renal elimination of verbenols after experimental exposure to (+)-alpha pinene and (-)-alpha pinene was studied in humans following exposure to 10, 225 and 450 mg/m3 terpene in an exposure chamber. Depending on the exposure level, about 1%-4% of the total uptake was eliminated as cis- and trans-verbenol. Most of the verbenols were eliminated within 20 h after a 2-h exposure. The renal excretion of unchanged alpha pinene was less than 0.001%. (Levin et al., 1992, cited in HSDB 2009a)

In conclusion, bioaccumulation of these terpene hydrocarbons does not occur, since the substances are efficiently metabolised to yield oxygenated metabolites (verbenol, myrtenol and myrtenic acid) that are subsequently conjugated with glucuronic acid and excreted mainly in the urine.

HSDB (Hazardous Substances Data Bank). 2003. Turpentine. HSDB No. 204. Produced by the National Library of Medicine (NLM), Bethesda, M.D. Last updated 15 October 2003.

HSDB (Hazardous Substances Data Bank). 2009a. Alpha pinene. HSDB No. 720. Produced by the National Library of Medicine (NLM), Bethesda, M.D. Last Revision Date: 26 June 2009

HSDB (Hazardous Substances Data Bank). 2009b. beta pinene. HSDB No. 5615. Produced by the National Library of Medicine (NLM), Bethesda, M.D. Last Revision Date: 26 June 2009

DERMAL ABSORPTION RATE:

Skin absorption of alpha-pinene was studied using human skin mounted on flow-through diffusion cells. Similarly, the elimination kinetics in the skin were analysed during 4 h following 1-h exposure. The results demonstrate rapid penetration of alpha-pinene not only to the first stratum corneum layers but also to viable epidermis and dermis (steady-state concentrations assumed to be obtained at 1-h exposure). However, alpha-pinene did not permeate across the skin to the acceptor medium due to large cumulation in the skin tissue. Two mechanisms of elimination process of terpenes from the SC are suggested: evaporation and slightly progressive penetration from inner layer into dermis. (Cal et al., 2006)

Following immersion of young pigs and one human subject for 30 minutes in baths containing 150 mL of a pine oil mixture (Fichtennadel-Latschenkieferol Kneipp) in 450 L of water, alpha pinene, beta pinene and limonene (components of Latschenkieferol) were detected in exhaled air within 20 minutes reaching maximum levels 50-75 minutes after start of the bath and remained detectable after 1 day. (Opdyke, 1979, cited in HSDB 2009)

HSDB (Hazardous Substances Data Bank). 2009. Alpha pinene. HSDB No. 720. Produced by the National Library of Medicine (NLM), Bethesda, M.D. Last Revision Date: 26 June 2009