Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

The available evidence suggests that Trimellitic anhydride mono-chloride (TMAC) may be bioavailable via the oral and dermal routes. Regarding the inhalation, no exposure to dusts or to vapour could occur and therefore, bioavailability is considered negligeable.

The substance is expected to be very quickly hydrolysed in Trimellitic anhydride (TMA) that is instantaneouly converted in Trimellitic acid (TMLA) and conjugated in the liver, distributed in the whole body and then excreted mainly in urine.

The toxicity of TMAC, TMA and TMLA is qualitatively assumed to be similar for systemic toxicity following the same pathway of absorption, distribution, metabolism and excretion with these chemicals being presented as analogues. Therefore, a read-across of TMAC (target substance) with TMA and TMLA as source substances, is considered as relevant as decribed in the RAAF document

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In accordance with the section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the target substance, trimellitic anhydride mono-chloride (TMAC) was derived in a read-across approach from the relevant available information on the target substance, collected in the dossier, and information on Trimellitic anhydride (TMA) and Trimellitic acid (TMLA) as source substances. The physical chemical properties of TMAC and both TMA and TMLA, the results obtained from the acute, the repeated-dose and reproductive toxicity studies from TMA and TMLA, as well as information gained from genotoxicity assays were used to predict the toxicokinetic behaviour of the target substance.

 

Structure and physical-chemical properties:

The registered substance trimellitic anhydride mono-chloride (TMAC) has a molecular weight of 210.6 g/mol.

The substance is a dense solid at ambient temperature, with low melting and low volatility. Generation of dusts is unlikely based on hygroscopic property of the solid. Properties involving contact with water (i.e. solubility, partition coefficient or surface tension) cannot be determined, due to rapid hydrolysis into Trimellitic anhydride (TMA), itself instanstaneously hydrolysed into Trimellitic acid (TMLA) as described in section 5.1.2. Therefore, TMAC rapidly forms TMA and then TMLA under the conditions used to test its toxicity.

TMAC has no potential to bioaccumulate due to its ready biodegradability and quick hydrolysis.

Absorption:

Oral/GI absoprtion:

Based on the chemical structure of TMAC (target substance) and its product of degradation following hydrolysis, TMA has been identified as a relevant analogue (source substance) for the target substance (see the read-across justification document, section 13). Indeed, TMA and then, TMLA could be generated almost instantaneously following the acidic hydrolysis of TMAC.

The physical chemical characteristics described above suggest that TMAC is of adequate molecular size (< 500 g/mol) to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract.

At acidic pH value, the oral absorption may be potentiated by the ability of TMAC to dissolve into gastro-intestinal fluids, hydrolysed into TMA rapidly converted to TMLA which, in contact with the mucosal surface, can induce irritation, as demonstrated in the acute oral toxicity study with TMA. Moreover, mortality observed in the acute oral studies performed with TMAC and TMA showed systemic effects at high doses (> 2000 mg/kg bw).

At lower dose, systemic effect with TMAC is not expected as supported by oral systemic effects observed in the 90-day repeated dose toxicity study performed with TMA in rats exposed by diet. The NOAEL for systemic effect in male rats was set to 404 mg TMAC equivalent/kg bw/day in the 90-day repeated dose toxicity study with TMA. The observation of clinical effects indicates the oral bioavailability of TMAC via its hydrolysed products, i.e.TMA and TMLA.

Given the available data, TMAC has been assumed to be bioavailable by oral route.

Dermal absorption:

The uptake of TMAC into the stratum corneum is forseen, considering its corrosivity. The transfer of TMAC between the stratum corneum and the epidermis is thus anticipated.

In light of these data, a dermal absorption of 100% is conservatively assumed.

Respiratory absorption:

The vapour pressure of the target substance (VP = 0.017 Pa at 20°C) indicates an absence of volatility and therefore no exposure by inhalation is anticipated. Moreover, no dust is generated (hygroscopic properties). Thus, at ambient temperature, no respiratory absorption is expected. In light of these data, no significant bioavailability of TMAC is expected by inhalation.

However, the potential for inhalation toxicity was evaluated in an acute toxicity by inhalation with the source substance (TMA) (as dusts) showing severe pulmonary irritation inducing mortality at concentrations lower to the limit of classification (5 mg/L). As TMAC (target substance) is a skin corrosive, corrosivity or strong irritation to respiratory tract at low concentrations might be expected, which may increase inhalation absorption of TMAC in case of unlikely respirable dust formation.

 

Distribution:

Systemic distribution of TMAC can be predicted from its physical chemical characteristics. Considering that TMAC is quickly hydrolysed in TMA which is instantaneously converted in TMLA, it is suggested that, upon systemic absorption by oral and dermal routes, TMAC may be transported through the circulatory system as TMLA. Afterwards, TMAC (as TMLA form) may cross cellular barriers without potential to accumulate into fatty tissues.

 

Metabolism:

Following oral or dermal absorption, quick hydrolysis of TMAC in TMA and then in TMLA is expected. Then, TMLA might be conjugated with acid glucuronic or sulfate in the liver.

 

Excretion:

The target substance, having a molecular weight lower than 500 g/mol, is expected to be mainly excreted in urine as TMLA or as TMLA conjugated to glucuronide and to sulfate following oral or dermal exposure. No more than 5-10% may be excreted in bile as such or as metabolites following metabolism in the liver.