Pentadecane, 7-methylene-, mixed with 1-tetradecene, dimers and trimers, hydrogenated

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
No substance specific data available
Short description of key information on absorption rate: 
A QSAR estimates the permeation rate for the substance to be 5.9 pg/cm2/hr.

Additional information

There is no available data on the toxicokinetics of the substance Pentadecane, 7-methylene, mixed with 1-tetradecene, dimers and trimers hydrogenated (CAS 1000172-11-1), which is a C_28-80H_58-162hydrogenated polyalphaolefin with a typical M_n=440Da and an M_w=450Da.  The toxicokinetic assessment is therefore built on read across from similar saturated higher molecular weight alkanes.

Absorption, distribution and excretion (ADE)

The ADE of a very similar substance hydrogenated polyalphaolefin (1-decene, hydrogenated homopolymer, hydrogenated, CAS 68037-01-4, EC 500-183-1, C_30-60H_62-122) was reviewed by the EU Scientific Committee on Food.  Their review is quoted below:

The adsorption , distribution and excretion has been investigated in the rat.  The test compound was prepared by catalytic reduction, using a mixture of tritium and hydrogen, of a mixture of poly-1-decenes identical to that used in the manufacture of regular hydrogenated poly-1-decene. The radiochemical purity of 3H labelled hydrogenated poly-1- decene used in the studies was >97%. Rats were given single oral doses (30, 120 or 1500 mg/rat) or an intravenous dose (30 mg/rat) of radiolabelled test compound to investigate absorption, toxicokinetics, tissue distribution and excretion. Other rats were given repeated daily oral doses of unlabelled compound (210 mg/rat) over 14 days followed by a single oral dose of labelled compound on day 15 to investigate the influence of repeated dosing. A fourth group of rats with cannulated bile ducts were given a single oral dose of radiolabelled compound (210 mg/rat) to investigate biliary, urinary and faecal excretion.

Very low ³H concentrations were found in plasma after oral or intravenous dosing. The data were fitted to a kinetic model which gave a long half-life consistent with ³H2O in the body water of rats. As expected from tritium exchange, ³H2O accounted for most of plasma radioactivity, especially at 24 hours or more after dosing. At plasma C_max values for oral dosing, tritium exchange represented about 0.1-0.5% of the dose. Non-volatile radioactivity (³H-hydrogenated poly-1-decene or its metabolites) accounted for only 14-31% of plasma radioactivity. At tissue T_max values, most of the radioactivity within the carcass was associated with the gastrointestinal tract. The proportion of the dose in, or estimated to be in fat, kidneys, lymph nodes and spleen was 0.1% of the dose. Only the liver (at 8 and 24 hrs after the 30 mg dose) contained >0.1% dose, with the proportion decreasing with increasing dose level, as expected for a poorly-absorbed compound. The amounts of radioactivity excreted in the urine (mean 0.16% of dose) and bile (mean 0.01% of dose) were very small. Faeces were the major route of elimination after oral dosing and represented an average of 102.0%, 94.9% and 91.7% of the dose at 30, 210 and 1,500 mg/rat respectively. Absorption of the dose can be estimated by summation of radioactivity present in urine, cage wash and residual carcass (excluding the gastrointestinal tract): the averages were 0.31%, 0.07% and 0.95% for doses of 30, 210 and 1,500 mg/rat respectively. These estimates are 1% in total and represent a value lower than the level of impurities (3%).

The data indicates that following oral ingestion, absorption is very low.  This conclusion is supported by the review of Gobas (2000) who summarized the physicochemical characteristics of substances that influence their biological uptake in animals.  This review concluded that molecules of internal cross-section >0.95nM are too large to cross biological membranes and are therefore not bioavailable.  Such substances as these, with a very high logKow will, if ingested, be predominantly eliminated in the faeces and any absorption that does occur will be very slow and reach steady state very slowly.  These predictions are borne out by the experimental data available described above.

The very low volatility precludes significant absorption by the inhalation route and a QSAR model SkinPerm predicts that dermal absorption is negligible.

Metabolism

Metabolism of decane and higher alkanes occurs mainly via ω -hydroxylation to yield the corresponding primary alcohols.  Using mouse liver microsomes, the corresponding alcohol, acid and α,ω-diglycol were observed as major metabolic products of decane.  Further work has shown that metabolism is not just limited to the liver, but can similarly occur in the kidney and lung.  Decane, dodecane and tetradecane have all been demonstrated to metabolise similarly.  It would be expected that he same metabolic paths would exist for polyalphaolefins that reach the systemic circulation.

Metabolism studies have also been carried out on the C10 alkane 2,2,4-trimethylpentane (TMP). Hydrocarbons in general are oxidised to alcohols by the Cytochrome P450 monooxygenase system.  These intermediate alcohols are further oxidised to aldehydes by aldehyde dehydrogenase and eventually to acids.  TMP, and by inference substance 1000172-11-1, are not exception to this rule.  Based on the quantitative work by Charbonneau, around 72% of TMP is excreted from male rats within 24 hrs whilst 81% is excreted from females.

The data available on metabolism for lower molecular weight alkanes strongly suggests that any hydrogenated polyalphaolefin that reached the systemic circulation would be metabolised relatively easily.

Discussion on bioaccumulation potential result:

Toxicokinetic assessment

There is no available data on the toxicokinetics of the substance Pentadecane, 7-methylene, mixed with 1-tetradecene, dimers and trimers hydrogenated (CAS 1000172-11-1), which is a C_28-80H_58-162hydrogenated polyalphaolefin with a typical M_n=440Da and an M_w=450Da.  The toxicokinetic assessment is therefore built on read across from similar saturated higher molecular weight alkanes.

Absorption, distribution and excretion (ADE)

The ADE of a very similar substance hydrogenated polyalphaolefin (1-decene, hydrogenated homopolymer, hydrogenated, CAS 68037-01-4, EC 500-183-1, C_30-60H_62-122) was reviewed by the EU Scientific Committee on Food (2001).  Their review is quoted below:

The adsorption , distribution and excretion has been investigated in the rat.  The test compound was prepared by catalytic reduction, using a mixture of tritium and hydrogen, of a mixture of poly-1-decenes identical to that used in the manufacture of regular hydrogenated poly-1-decene. The radiochemical purity of 3H labelled hydrogenated poly-1- decene used in the studies was >97%. Rats were given single oral doses (30, 120 or 1500 mg/rat) or an intravenous dose (30 mg/rat) of radiolabelled test compound to investigate absorption, toxicokinetics, tissue distribution and excretion. Other rats were given repeated daily oral doses of unlabelled compound (210 mg/rat) over 14 days followed by a single oral dose of labelled compound on day 15 to investigate the influence of repeated dosing. A fourth group of rats with cannulated bile ducts were given a single oral dose of radiolabelled compound (210 mg/rat) to investigate biliary, urinary and faecal excretion.

Very low ³H concentrations were found in plasma after oral or intravenous dosing. The data were fitted to a kinetic model which gave a long half-life consistent with ³H2O in the body water of rats. As expected from tritium exchange, ³H2O accounted for most of plasma radioactivity, especially at 24 hours or more after dosing. At plasma C_max values for oral dosing, tritium exchange represented about 0.1-0.5% of the dose. Non-volatile radioactivity (³H-hydrogenated poly-1-decene or its metabolites) accounted for only 14-31% of plasma radioactivity. At tissue T_max values, most of the radioactivity within the carcass was associated with the gastrointestinal tract. The proportion of the dose in, or estimated to be in fat, kidneys, lymph nodes and spleen was 0.1% of the dose. Only the liver (at 8 and 24 hrs after the 30 mg dose) contained >0.1% dose, with the proportion decreasing with increasing dose level, as expected for a poorly-absorbed compound. The amounts of radioactivity excreted in the urine (mean 0.16% of dose) and bile (mean 0.01% of dose) were very small. Faeces were the major route of elimination after oral dosing and represented an average of 102.0%, 94.9% and 91.7% of the dose at 30, 210 and 1,500 mg/rat respectively. Absorption of the dose can be estimated by summation of radioactivity present in urine, cage wash and residual carcass (excluding the gastrointestinal tract): the averages were 0.31%, 0.07% and 0.95% for doses of 30, 210 and 1,500 mg/rat respectively. These estimates are 1% in total and represent a value lower than the level of impurities (3%).

The data indicates that following oral ingestion, absorption is very low.  This conclusion is supported by the review of Gobas (2000) who summarized the physicochemical characteristics of substances that influence their biological uptake in animals.  This review concluded that molecules of internal cross-section >0.95nM are too large to cross biological membranes and are therefore not bioavailable.  Such substances as these, with a very high logKow will, if ingested, be predominantly eliminated in the faeces and any absorption that does occur will be very slow and reach steady state very slowly.  These predictions are borne out by the experimental data available described above.

The very low volatility precludes significant absorption by the inhalation route.

Metabolism

Metabolism of decane and higher alkanes occurs mainly via ω -hydroxylation to yield the corresponding primary alcohols (Ichihara 1969, Lu 1970).  Using mouse liver microsomes, the corresponding alcohol, acid and α,ω-diglycol were observed as major metabolic products of decane.  Further work elucidated that metabolism is not just limited to the liver, but can similarly occur in the kidney and lung.  Decane, dodecane and tetradecane have all been demonstrated to metabolise similarly.  It would be expected that he same metabolic paths would exist for polyalphaolefins that reach the systemic circulation.

Metabolism studies have also been carried out on the C10 alkane 2,2,4-trimethylpentane (TMP) (Charbonneau, 1987; Olson, 1985)  Hydrocarbons in general are oxidised to alcohols by the Cytochrome P450 monooxygenase system.  These intermediate alcohols are further oxidised to aldehydes by aldehyde dehydrogenase and eventually to acids.  TMP, and by inference substance 1000172-11-1, are not exception to this rule.  Based on the quantitative work by Charbonneau, around 72% of TMP is excreted from male rats within 24 hrs whilst 81% is excreted from females.

The data available on metabolism for lower molecular weight alkanes strongly suggests that any hydrogenated polyalphaolefin that reached the systemic circulation would be metabolised relatively easily.

References

-       Charbonneau M, Lock EA, Strasser J et al (1987) “2,2,4-trimethylpentane induced nephrotoxicity: I. Metabolic disposition of TMP in male and female Fischer 344 rats” Tox App Pharmacol, 91, 171-81

-       EU Scientific Committee on Food.  Opinion of the Scientific Committee on Food onhydrogenated poly-1-decene.  SCF/CS/ADD/MsAd/199 Final 12 July 2001

-       Gobas (2000) Bioconcentration and Biomagnification in the Aquatic Environment, in Chapter 9, Handbook of Property Estimation methods for Chemical. Environmental Health Sciences, ed Boethling RS, Mackay D, Lewis publishers.

-       Ichihara K, Kusunose E, Kusunose M (1969) Microsomal hydroxylation of decane, Biochim Biophys Acta, 176, 713-9

-       Lu AYH, Strobel HW, Coon MJ (1970) Properties of a solubilized form of cytochrome P-450 containing mixed function oxidase of liver microsomes Mol Pharmacol, 6, 213-20

-       Olson CT, Yu KO, Hobson DW et al (1985) “Identification of urinary metabolites of the nephrotoxic hydrocarbon 2,2,4-trimethylpentane in male rats.” Biochem Biophys Res Comm, 130, 313-6

-       Tsurata H (1982) Percutaneous absorption of organic solvents III.  ON the penetration rates of hydrophobic solvents through excised rat  skin.  Hlth, 20, 335-45

Discussion on absorption rate:

A QSAR model SkinPerm predicts that dermal absorption is negligible.  This is confirmed by Tsurata (1982) who found that penetration of excised rat skin by hydrocarbons of greater than C8 is very slow.

Reference

-       Tsurata H (1982) Percutaneous absorption of organic solvents III.  ON the penetration rates of hydrophobic solvents through excised rat  skin.  Hlth, 20, 335-45