Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Alchisor TAL 123 can be characterised according to three constituents: Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), undecan-1-ol and dodecan-1-ol. Study data for each constituent has been evaluated.

 

Toxicokinetic study information is available for Alchisor TAL 123 alcohol constituents and the Hydrocarbons C11 -C14, n-alkanes, isoalkanes, cyclics, aromatics (2 -25%), from the category C9-C14 aliphatics (2-25% aromatics). In the case of C9-C14 aliphatics (2-25% aromatics) this is principally presented as read across data from the additional substance categories (C9-C14 aliphatics (<2% aromatics) and C9 aromatics).

 

 

C9-C14 Aliphatics (2-25% aromatics)

 

Absorption

 

On the basis of constituent toxicokinetic data available, the C9-C14 aliphatic (2-25% aromatic) constituent category is expected to be readily absorbed when inhaled or ingested. In addition there is evidence from the C9 aromatic hydrocarbon group to suggest that dermal absorption is likely to occur resembling the pattern occurring with inhalation exposure.

 

Distribution

 

Distribution evidence for the C9-C14 Aliphatics (2-25% aromatics) constituent category of Alchisor TAL 123 has been derived from read across data.

 

Read Across From C9-C14 Aliphatics (<2% aromatics):C9-C14 isoalkanes are taken up into the blood and distributed to the internal organs including brain, liver, kidney and fat.  Twelve hours after the exposure, levels in blood, brain, liver and kidney were below detection levels; levels in fat were about half those found at the end of the exposure period.  These data demonstrate that isoalkanes are rapidly eliminated and do not accumulate. The concentration of isoalkanes in blood, brain, liver and fat increased with increasing number of carbon atoms. The C9 and C10 isoalkanes showed increasing concentrations in fat during the exposure period and high concentrations 12 hours after cessation of exposure.

 

Inhaled alkanes, C9-C13, are taken up into the blood and distributed to the internal organs including the brain. There is also a corresponding reduction in the blood/air and brain/air ratios with increasing carbon numbers up to C10.  At high carbon numbers the ratios decrease suggesting blood/brain barrier effects for high molecular weight hydrocarbons (Nilsen1988). Thus the efficiency of uptake into both blood and brain also decreases with increasing carbon number. A brain/blood ratio of 11.4 and a fat/blood ratio of 113 was determined for nonane. Decane was found to have a half-life of 2 hours. The percentage retention of alkanes showed an inverse linear relationship to chain length that was describable by the regression line: (percentage retained) = 115.9-3.94 * (number of carbon atoms). This line had a correlation coefficient of -0.995, standard error of estimate Sy * x= 3.30, t = 30.85 and P < 0.001. The absorption of paraffins with 9-13 carbons, ranges from 65-80%.  

 

Based on a study of jet propellant 8 (JP-8) jet fuel components, the in vitro (rat liver microsomal oxidation) nonlinear kinetic constants for nonane and decane were V(max) (nmol/mg protein/min) = 7.26 +/- 0.20 and 2.80 +/- 0.35, respectively, and K(M) (micro M) = 294.83 +/- 68.67 and 398.70 +/- 42.70, respectively. Metabolic capacity as assessed by intrinsic clearance, V(max)/K(M), was approximately four-fold higher for nonane (0.03 +/- 0.005) than for decane (0.007 +/- 0.001) (Anand Sathanandam 2007).

 

The blood/brain ratio and the fat/blood ratios for trimethylcyclohexane were determined to be 11.4 and 135, respectively. A marked decrease in biological concentrations of trimethylcyclohexane during the initial phase of exposure indicates that this hydrocarbon is capable of inducing its own metabolic conversion resulting in lower steady state levels.

 

 

Read Across From C9 Aromatics:

 

Human data for the C9 aromatics was available.1,3,5-trimethylbenzene has a very large volume of distribution (30-30 L/kg), implying wide tissue distribution and substantial partitioning in the tissues (Jarnberg 1996).  One hour post exposure blood levels of 1,3,5-trimethylbenzene in human volunteers exposed to 25 ppm for 4 hours were similar to the steady-state level that occurred during the exposure period (Jarnberg 1996, Jones 2006).  These data, combined with the very high oil:air partition coefficients of trimethylbenzenes (9620-11300) imply substantial redistribution of inhaled trimethylbenzenes to fatty tissues (Jarnberg 1996, Jones 2006, Jarnberg 1995).

 

In an inhalation study in rats, tissue levels of 1,2,4-trimethylbenzene following exposure to 100 ppm for 12 hours per day for 3 days are summarized in Table 1.

 

Table 1.  Distribution of 1,2,4-trimethylbenzene in rat tissues (mean value from four animals)following exposure to 100 ppm of the substances 12 h daily for 3 days. Values in parentheses are from animals that had a 12-h recovery period after the last exposure (Zahlsen 1990).           

                                                                                  

 

Tissue

Concentration (µmol/kg)

Blood  

17.1

Brain

36.5

Liver

35.4

Kidney

103.6

Fat

1070 (120)

 

 

 

 

 

 

Following inhalation exposure in rats, the fat:blood partition coefficient of trimethylbenzenes is around 63 (Zahlsen 1990,Eide 1990). The data in Table 1 is consistent with this partition coefficient given the selective redistribution of 1,2,4-trimethylbenzene to adipose tissue.  Twelve hours following the cessation of exposure, adipose tissue levels of 1,2,4-trimethylbenzene were decreased by a factor of approximately 9, demonstrating rapid mobilization of this substance from body adipose tissue.  Thus normally, long-term accumulation of this material in fat does not occur. Trimethylbenzene does not selectively redistribute to other body tissues other than adipose tissues.

 

Oral dosing of rats with 14C-1,2,4-trimethylbenzene was associated with a rapid and wide tissue distribution of radioactivity throughout the body, with selective and preferential re-distribution to adipose tissue (Huo 1989). There was no preferential uptake of radioactivity into any other organ or tissue (Huo 1989).

 

Collectively, these data demonstrate that during inhalation exposure, C9 aromatics undergo substantial partitioning into adipose tissues.  Following cessation of exposure, the level of C9 aromatics in body fats rapidly declines.  Thus, the C9 aromatics are unlikely to bioaccumulate in the body.  Selective partitioning of the C9 aromatics into the non-adipose tissues is unlikely. No data is available regarding distribution following dermal absorption.  However, distribution following this route of exposure is likely to resemble the pattern occurring with inhalation exposure.

 

Metabolism

 

Read Across From C9 Aromatics:

 

In humans, the major metabolites of trimethylbenzenes most commonly identified in urine are the dimethylbenzoic acid and dimethylhippuric acid derivatives of the parent molecule (Kostrzewski 1997, Jarnberg 1996, Jones 2006, Jarnberg 1999, Fukaya 1994, Jarnberg 1998, Kostrzewski 1995, Jarnberg 1997, Stahlbon 1997, Ichiba 1992).  Both the dimethylbenzoic and hippuric acid metabolites of the trimethylbenzenes are commonly used for biomonitoring of human exposures.

 

In rats, urinary metabolites of 1,2,4-trimethylbenzene consist of a complex mixture of isomeric triphenols, the sulphate, glucuronide and mercapturic conjugates of dimethylbenzyl alcohols, dimethylbenzoic acids and dimethylhippuric acids (Huo 1989).  The major metabolites are 3,4-dimethylhippuric acid (30.2% of the dose), sulphate and glucuronide conjugates of 2,4-dimethylbenzyl alcohol (12.7% of the dose), and sulphate and glucuronide conjugates of 2,5-dimethylbenzyl alcohol (11.7% of the dose) (Huo 1989).

 

In rats, approximately 78% of an oral dose of 1,3,5-trimethylbenzene is excreted as 3,5-dimethylhippuric acid; an additional 7.6 and 8.2% were excreted as glucuronic and sulphuric acid conjugates (Mikulski 1975). The corresponding values for the glycine, glucuronic and sulphuric acid conjugates of 1,2,4-trimethylbenzene and 1,2,3-trimethylbenzene were 43.2, 6.6, and 12.9% and 17.3, 19.4, and 19.9%, respectively (Mikulski 1975). In rabbits, the major urinary metabolites of 1,2,4-trimethylbenzene following oral dosing are 2,4-dimethylbenzoic acid and 3,4-dimethylhippuric acid (Cerf 1980).

 

Biotransformation of 1,2,4-trimethylbenzene to dimethylbenzoic acids in the rat follows the Lineweaver-Burk equation with Km ranging from 7-28 mg/l and Vmax ranging from 23-96 mg/h/kg depending on the particular species of dimethylbenzoic acid formed (Swiercz 2002). Biotransformation to 3,4-dimethylbenzoic acid is favoured, given its Km of 28 mg/l and Vmax of 96 mg/h/kg.  Notably, in rats, the biotransformation of trimethylbenzenes is inhibited by pre-treatment with ethanol and enhanced by ethyl acetate (Romer 1986, Freundt 1989). In rats, 1,3,5-trimethylbenzene is an inducer of cytochrome p450, cytochrome b5, aminopyrine N-demethylase, aryl hydrocarbon hydroxylase, aniline hydroxylase,and NADPH-cytochrome c reductase in the rodent liver (Pyykko 1980).  In the kidney, 1,3,5-trimethylbenzene induces cytochrome P-450 and cytochrome b5 (Pyykko 1980).  Thus, trimethylbenzenes are inducers of their own metabolism in the rat.  These data are consistent with the low propensity for bioaccumulation of trimethylbenzenes in mammals.

 

Collectively these data demonstrate that C9 aromatics may undergo several different Phase I dealkylation, hydroxylation and oxidation reactions which may or may not be followed by Phase II conjugation to glycine, sulphation or glucuronidation.  However, the major predominant biotransformation pathway is typical of that of the alkylbenzenes and consists of: (1) oxidation of one of the alkyl groups to an alcohol moiety; (2)oxidation of the hydroxyl group to a carboxylic acid; (3) the carboxylic acid is then conjugated with glycine to form a hippuric acid. The minor metabolites can be expected to consist of a complex mixture of isomeric triphenols, the sulphate and glucuronide conjugates of dimethylbenzyl alcohols, dimethylbenzoic acids and dimethylhippuric acids.  Consistent with the low propensity for bioaccumulation of the C9 aromatics, these substances are likely to be significant inducers of their own metabolism. 

 

Elimination and Excretion

 

Read Across From C9-C14 Aliphatics (<2% aromatics):

The tissue disposition after 3 weeks of exposure to dearomatised white spirit, mixed aliphatic, and cycloaliphatic constituents was determined. After 3 weeks of exposure the concentration of total white spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 ppm, respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure. Two hours after the end of exposure the n-decane concentration decreased to about 25% in blood and 50% in brain. A similar pattern of elimination was also observed for n-nonane, n-undecane and total white spirit in blood and brain. In fat tissue the concentrations of n-nonane, n-decane, n-undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady-state concentrations is longer than 3 weeks. Post-exposure decay in blood could be separated into two phases with half-lives of approximately 1 and 8 hr for n-nonane, n-decane, and n-undecane. In brain tissue two slopes with half-lives of 2 and 15 hr were identified. In fat tissue, only one slope with half-life of about 30 hr was identified. In conclusion, after 3 weeks of exposure the fat:brain:blood concentration coefficients for total white spirit were approximately 250:3:1.

 

 

Read Across From C9 Aromatics:

 

Human Data: The identified routes of excretion of the trimethylbenzenes following inhalation exposure in humans include: (1) exhalation of the unchanged volatile parent substance (Jones 2006); (2) urinary excretion of the unchanged volatile parent substance(Janasik 2008); and (3) urinary excretion of metabolites (1-3, 5, 15-20).  Post-exposure exhalation of unmetabolized trimethylbenzenes accounts for 20-37% of the absorbed amount (2).  Urinary excretion of unmetabolized trimethylbenzenes is low (< 0.002%) (2).  Overall urinary excretion of metabolites (predominantly 3,4-dimethylhippuric acid) of 1,2,4-trimethylbenzene in the first 24 hours post-exposure accounts for 22% of the inhaled dose (18). Urinary excretion of unconjugated dimethylbenzoic acid metabolites accounts for only small percent of the inhaled dose of trimethylbenzenes (18). The bulk of the absorbed dose of trimethylbenzenes is metabolized and excreted in urine, predominantly as their dimethylhippuric acids or conjugated (sulphated or glucuronidated) dimethylbenzoic acid derivatives (Kostrzewski 1997, Jarnberg 1996, Jones 2006, Jarnberg 1999, Fukaya 1994, Jarnberg 1998, Kostrzewski 1995, Jarnberg 1997, Stahlbon 1997, Ichiba 1992).  The urinary excretion of dimethylhippuric acids is well-correlated with exposure to trimethylbenzenes and has been commonly used for biomonitoring purposes. 

The initial blood clearance of trimethybenzenes in man is 0.6-1 l/hr/kg (Jarnberg 1996). However, trimethylbenzenes have longer terminal half-lives in blood (T-1/2 78 -120 hr) due to their extensive partitioning into adipose tissues (Jarnberg 1996).  The kinetics of urinary elimination of unmetabolized 1,3,5-trimethylbenzene follows a biphasic pattern with a T-1/2 for Phase I of 0.45-0.88 hr and a T-1/2 for Phase II of 6.7-19.2 hr.25  Elimination of unmetabolized 1,3,5-trimethylbenzene in exhaled air is biphasic with an initial T-1/2 of 1 hr (Jones 2006).  Urinary elimination of dimethylbenzoic acids following inhalation exposure to 1,3,5-trimethylbenzene is biphasic with a T-1/2 for Phase I of 13 hr and a T-1/2 for Phase II of 60 hr (Jones 2006).  Notably, co-exposure to white spirits interferes with the metabolic elimination of 1,2,4-trimethylbenzene (Jarnberg 1997, Jarnberg 1998).

 Animal Data: Following oral administration of 14C-1,2,4-trimethylbenzene, > 99% of the administered radioactivity was excreted in urine within 24 hours (Huo 1989).  The predominant urinary species being the 3,4-dimethylhippuric acid metabolite (Huo 1989).  Likewise, urine is the major route of excretion of trimethylbenzene metabolites in rats following inhalation exposure. As in humans, there is a strong correlation between the level of trimethylbenzene inhalation exposure and the concentration of metabolites in urine.

Summary: Collectively these data demonstrate that the predominant route of excretion of C9 aromatics following inhalation exposure involves either exhalation of the unmetabolized parent compound, or urinary excretion of its metabolites.  When oral administration occurs, there is little exhalation of unmetabolized C9 aromatics, presumably due to the first pass effect in the liver.  Under these circumstances, urinary excretion of metabolites is the dominant route of excretion.

 

Undecan-1-ol and Dodecan-1-ol

 

Absorption

 

Alcohol components of Alchisor TAL 123 are represented in this dossier by the medium-chain length aliphatic alcohols; undecan-1-ol and dodecan-1-ol. Absorption of both undecan-1-ol and dodecan-1-ol is likely to occur following exposure by all the common physiological routes (oral, dermal and inhalation).

 

The extent of absorption of aliphatic alcohols depends upon chain length. For example, in rats, the extent of dermal penetration increases up to C7 (1-heptanol) and thereafter decreases with longer chain lengths (Valette and Cavier, 1954). Dermal absorption studies in hairless mice, and comparative in vitro skin permeation data, show that for aliphatic alcohols with chain lengths varying from 8 to 16 carbon atoms, there is an inverse relationship between absorption and chain length. Significant dermal absorption may occur for the short to intermediate chain alcohols (up to C12). When applied to the skin of hairless mice, 2.84% of a dose of radiolabelled n-[1-14C] dodecanol was absorbed over 24 hours (compared with approximately 7% of a dose of14C-labelled 1-decanol) (Iwata et al. 1987). Furthermore lipophilic substances that come into contact with the skin can readily penetrate the lipid-rich stratum corneum by passive diffusion at a rate proportional to their lipid solubility and inversely to their molecular weight (Marzulli et al. 1965).

 

The extent of absorption of aliphatic alcohols from the gastrointestinal tract also depends upon chain length. Although no data was identified for both undecan-1-ol and dodecan-1-ol, short-chain aliphatic alcohols are known to be rapidly and extensively absorbed from the gastrointestinal tract (Aaes-Jorgensen et al. 1959; Bandi et al. 1971a, 1971b), whereas the long-chain saturated alcohols (e.g. C18) are said to be poorly absorbed (CIR, 1985).

 

Distribution

 

Absorbed undecan-1-ol and dodecan-1-ol could potentially be widely distributed within the body (OECD 2006). The rapid and efficient metabolism and excretion of both of these compounds from the body means that they are unlikely to be retained or to accumulate (Bevan 2001; OECD, 2006). Short-chain aliphatic alcohols readily penetrate the blood-brain barrier, whereas longer chain alcohols (C16-C18) cross this barrier in only trace amounts (Gelman and Gilbertson, 1975).

 

Metabolism

 

As primary alcohols, absorbed undecan-1-ol and dodecan-1-ol will initially be metabolised (oxidised), primarily by alcohol dehydrogenase, to the corresponding aldehyde (e.g. undecan-1-ol to undecanal and dodecan-1-ol to dodecanal). Aldehydes are a transient intermediate that are rapidly converted by further oxidation to the acid (undecanoic or dodecanoic acid) by aldehyde dehydrogenase. These acids are susceptible to degradation via acyl-CoA intermediates of the mitochondrial b-oxidation process. This mechanism removes C2 units in a stepwise process. The rate of b-oxidation tends to increase with increasing chain length (JECFA, 1999). Mice excreted more than 90% of the absorbed dose of dodecan-1 -ol (radiolabelled with 14C on the 1 -carbon atom) in expired air (evidently as carbon dioxide) following skin application. This also suggests that metabolism of absorbed undecan-1-ol would also be extensive (Iwata et al. 1987).

An alternative metabolic pathway exists through microsomal or peroxisomal degradation of the carboxylic acid metabolite (undecanoic or dodecanoic acid) via w- orw-1 oxidation followed by ß-oxidation (Verhoeven et al. 1998). [This pathway provides an efficient route for the degradation of branched-chain alcohols.] The acids formed from the longer-chain aliphatic alcohols can also enter lipid biosynthesis and may be incorporated in phospholipids and neutral lipids (Bandi et al. 1971a, 1971b; Mukherjee et al. 1980). The hydroxyl function of the parent primary alcohols (e.g. undecan-1-ol or dodecan-1-ol) and the carboxy function of the acid metabolite may also undergo conjugation reactions to form sulphates and/or glucuronides (Kamil et al. 1953; McIsaac and Williams, 1958). For linear aliphatic alcohols, this pathway generally accounts for less than 10% of the metabolism (Kamil et al. 1953; McIsaac and Williams, 1958).

 

 

Excretion

 

Following the 24-hour application of dodecan-1-ol (radiolabelled with14C on the 1-carbon atom) to the skin of hairless mice, more than 90% of the absorbed dose was excreted in expired air and 3.5% was eliminated in the faeces and urine by 24 hours; only 4.6% of absorbed dose [representing 0.13% of applied dose] remained in the body (Iwata et al. 1987). A similar general pattern of extensive and rapid excretion would be expected for 1-undecanol.

 

When rats were given an oral dose of the shorter-chain 1-octanol, only trace amounts (<0.5%) were detected unchanged in the faeces (, 1955), whereas for higher alcohols such as 1-hexadecanol and 1-octadecanol, faecal recoveries were 20 and 50%, respectively (McIsaac and Williams, 1958; Miyazaki, 1955). No data were found for 1-undecanol but an intermediate value between the C8 and C16-C18 values would be expected.

 

The glucuronic acid conjugates formed during the metabolism of most aliphatic alcohols are excreted in the urine (Wasti, 1978; Williams, 1959).For the close analogue 1-decanol, 3.5% of an oral dose was excreted by rabbits in urine as glucuronide (Kamil et al. 1953).

 

Although lipophilic alcohols such as 1-undecanol have the physiochemical potential to accumulate in breast milk, rapid metabolism to the corresponding carboxylic acid followed by further degradation suggests that breast milk can only be, at most, a minor route of elimination from the body (OECD, 2006).

 

 

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