1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters

Endpoint summary

Description of key information

Accumulation in man of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters is unlikely. Reasons (including data on structurally related phthalates and the trimellitate tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate): 
-low bioaccumulation factor of the substance 
-likely that mainly the hydrolysis products will be absorbed, likely that hydrolysis is slow, therefore also oral absorption is low 
-dermal and inhalative absorption are lower than oral absorption (dermal < < inhalative < oral) 
- rats are far more efficient at hydrolysing the esters and, subsequently, absorbing the monoester than primates (and presumably humans) 
- rapidly metabolised and excreted in the urine and faeces 
- accumulation is negligible (based on an oral rat study) 
- minimal or no evidence of accumulation in rodent tissues. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The substance is a trimellitate ester with linear C8 and C10 alkyl chains. Experimental data are not available for the assessment of the toxicokinetic properties of the C8 -C10 trimellitate and read-across for toxicokinetic property assessment is therefore a possible approach to characterise toxicokinetic endpoints for the substance. Based on structurally similarity to phthalate esters (with two instead of three carboxylic functions) a similar toxicokinetic behaviour can be expected.

Accumulation in man of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters is unlikely. Reasons (including data on structurally related phthalates and the trimellitate tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate):

-low bioaccumulation factor of the substance

-likely that mainly the hydrolysis products will be absorbed, likely that hydrolysis is slow, therefore also oral absorption is low

-dermal and inhalative absorption are lower than oral absorption (dermal < inhalative < oral)

- rats are far more efficient at hydrolysing the esters and, subsequently, absorbing the monoester than primates (and presumably humans)

- rapidly metabolised and excreted in the urine and faeces

- accumulation is negligible (based on an oral rat study)

- minimal or no evidence of accumulation in rodent tissues.

Experimental data are not available for the assessment of the toxicokinetic properties of the C8 -C10 trimellitate and read-across for toxicokinetic property assessment is therefore a possible approach to characterise toxicokinetic endpoints for the substance. A structural related trimellitate, the Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate (TOTM) was investigated in an oral rat study. Both substances contain the same acid function, but are esterified with different alcohols (linear C8 and C10 vs. branched C8). Additionally helpful information on phthalates is available. Based on structurally similarity to phthalate esters (with two instead of three carboxylic functions) a similar toxicokinetic behaviour can be expected for that substance class. Absorption and metabolism were studied for Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate (TOTM) (14C-labeled on the 2-carbon atom of 2-ethylhexyl group) mixed with corn oil and administered by gavage in a single dose of 100 mg/kg of body weight in four male Sprague Dawley rats. Rats were placed in glass metabolism cages and urine, feces and expired air were collected for 144 hrs. About 75% of the dose was excreted unchanged in the feces, 16% in the urine as metabolites and 1.9% was expired as 14CO2. Radioactivity was excreted in the feces as unchanged TOTM (85% of the fecal radioactivity), mono- and di(2-ethylhexyl) trimellitate (MOTM and DOTM, respectively,) and unidentified polar metabolites. Metabolites in the urine were identified as MOTM and metabolites of 2-ethylhexanol. Less than 0.6% of the dose remained in whole tissues. Elimination of 14CO2 was biphasic with half-lives of 4.3 and 31 hours, and excretion of radioactivity in the urine was biphasic with half-lives of 3.4 hours and 42 hours. Based on remaining labeled ratio (less than 0.6% of dose) in whole tissues at 144 hours, it is considered that the accumulation of this chemical is negligible (SIDS, Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate, 2002). The same is likely for 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters. Hydrolysis of the phthalate diester to a monoester enhances absorption. Studies have shown that for high-MW esters, breakdown (metabolism; hydrolysis) of the ester bond to liberate one alcohol and a remaining monoester greatly increases the absorption, since the monoester and alcohol are absorbed more rapidly than the diester. The more hydrolysis occurs, the more monoester is available for absorption. Once absorbed, the monoester continues to be metabolised into subsatnces that are excreted in the urine. If exposure is through skin from contact with polyvinylchloride (PVC) articles containing phthalate esters, the absorption is very slow because the ester is not hydrolysed and must be absorbed intact. Experiments with laboratory animals and human skin have demonstrated that the absorption rate of high levels of exposure of the skin to neat chemical might not result in adverse health effects because the absorption is so slow and the metabolism of the ester is minimal. For inhalation exposure, absorption is likely to be slow but faster than absorption through the skin and slower than absorption from ingestion. The route of exposure that results in the most efficient absorption of phthalate esters is ingestion. Laboratory studies have demonstrated, however, that rats are far more efficient at hydrolysing the esters and, subsequently, absorbing the monoester than primates (and presumably humans). This means that when studies of phthalate esters are conducted in laboratory animals where health effects are observed following very high doses of an ester, it is very difficult to reproduce such effects in primates (and presumably humans) because primates do not absorb phthalate esters as efficiently as other laboratory animals. Primates and humans absorb about seven times less phthalate than do rats (especially for high MW-esters). At low doses, the absorption may be more comparable (Staples, 2003). It is likely that the hydrolysis of trimellitates to the corresponding monoesters is worse simply because of the existence of three instead of two ester groups and additionally because of possible steric hinderance of hydrolysis. Hence it is likely that the absorption is also worse compared to phthalates.

Various reviews of different phthalate esters by the Australian National Industrial Chemicals Notification and Assessment Scheme (NICNAS) are available. There are at least some toxicokinetic data available for many of the 24 phthalates, with the majority of testing conducted via the oral and dermal route. Limited data on absorption are available. Data, mostly from rats and with one human study on DEHP, suggest phthalates are readily absorbed via the oral route. A clear trend was noted in dermal absorption with data collected from five phthalates, DEP, BBP, DEHP, DINP and DIDP. Studies indicated a decrease in dermal absorption with increasing side chain length. The only information available on inhalation is on DIDP, which was readily absorbed from the lung. There is minimal or no evidence of accumulation in rodent tissues (NICNAS, Phthalates Hazard Compendium, 2008). Studies on several phthalates indicate that they are rapidly metabolised and excreted in the urine and faeces. They undergo phase I biotransformation, that is, primary metabolism into their hydrolytic monoesters by hydrolysis of one of their ester bonds. Further enzymatic oxidation of the alkyl chain occurs in some of the phthalates, resulting in more hydrophilic oxidative metabolites. Monoesters and the oxidative metabolites of phthalates may continue to undergo phase II biotransformation to produce glucuronide conjugates with increased water solubility. The data on the toxicokinetics indicate that phthalates in general are likely to be rapidly absorbed as the monoester from the gut and excreted via the urine ((NICNAS, Phthalates Hazard Compendium, 2008). For example following ingestion, di-n-octyl phthalate (DnOP) is rapidly metabolised and absorbed from the gastrointestinal tract as the monoester mono-n-octylphthalate (MnOP). Half-life of the monoester in the blood is approximately 3 hours. The liver is capable of metabolising DnOP. Elimination occurs via the urine with levels of MnOP exceeded after 24 hours by the other oxidative metabolite mono-(3-carboxypropyl) phthalate (MCPP) (NICNAS, 2008).

Literature

NICNAS, 2008; Existing Chemical Hazard Assessment Report, di-n-octyl phthalate, Australian Government of Health and Ageing NICNAS

NICNAS, 2008; Phthalate Hazard Compendium, A summary of physicochemical and human health hazard data for 24 ortho-phthalate chemicals, Australian Government of Health and Ageing NICNAS, June 2008

SIDS, 2002, SIDS Initial Assessment Report For SIAM 14, Paris, France, 26-28 March 2002, Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate Staples, C.A., 2003, Phthalate Esters, The Handbook of Environmental Chemistry, Springer Verlag Berlin, Heidelberg, New York

Staples, C.A., 2003, Phthalate Esters, The Handbook of Environmental Chemistry, Springer Verlag Berlin, Heidelberg, New York

Various reviews of different phthalate esters by the Australian National Industrial Chemicals Notification and Assessment Scheme (NICNAS) are available. The data on the toxicokinetics indicate that phthalates in general are likely to be rapidly absorbed as the monoester from the gut and excreted via the urine.

Some tests are conducted with the substance named 1,2,4-Benzenetricarboxylic acid, decyl octyl ester (old CAS-no.: 67989-23-5). In these cases the same test item was used, only the name and the CAS-Nr. was different.