p-nitrobenzoic acid, compound with 2,2',2''-nitrilotriethanol (1:1)

Endpoint summary

Description of key information

Physical data as well as information from toxicological data indicate that p-Nitrobenzoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (CAS No 7394-38-9) is absorbed and metabolized in the body. Furthermore, there are no indications for accumulation and the substance or its metabolites are likely eliminated from the body.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

A toxicokinetic assessment based on the physical properties (see ECHA Guidance on Information Requirements and Chemical Safety Assessment, R7c, version 3.0, June 2017) and toxicity data was performed. NOTE: this is mostly a generic assessment based on general statements in the guidance document that are derived from physical parameters.

The substance p-Nitrobenzoic acid, compound with 2,2',2''-nitrilotriethanol (1:1) (CAS No 7394-38-9) is a mixture consisting of p-nitrobenzoic acid (NBA) and 2,2’,2’’-nitrilotriethanol (triethanolamine, TEA) in a ratio of 1:1.

Based on the molecular weight (NBA: 167 g/mol, TEA: 149 g/mol), high water solubility and moderate log P values of the two main components (NBA and TEA) of the substance, absorption through aqueous pores or carriage with the bulk passage of water and absorption by passive diffusion is possible. The structure of both compounds (NBA: nitro- and carboxyl group, TEA: hydroxyl groups) suggest that the compounds may be ionized which could hinder their ability to diffuse across biological membranes. If administered orally the constituentTEA is rapidly absorbed in the gastrointestinal tract (Kohriet. al, 1982). An oral acute toxicity test showed no signs of toxicity for the substance whereas a 14-day oral (gavage) administration of the substance with the highest tested concentration of 1000 mg/kg bw/day resulted in slight and transient depression of body weight and food consumption, changes in haematological parameters and macroscopic as well as weight changes in spleen in male and female rats. These findings suggest an absorption of some constituents of the substance after oral administration. In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening the substance administered at 60, 200 or 600 mg/kg bw/day by oral gavage did not cause signs of systemic toxicity and did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) in parental male and female Hsd.Han: Wistar rats (NOAEL: 600 mg/kg bw/d). Further, the development of the F1 offspring was not impaired from birth to post-natal day 13 at any dose level after repeated oral administration of dams (NOAEL: 600 mg/kg bw/d).

Due to the low volatility (2.7*10-8 Pa at 20°C) and high boiling point (189.9°C) the substance is not present in a gaseous state and absorption through inhalation is therefore unlikely. If the substance should still reach the respiratory tract, the main constituents can cross the alveolar and capillary membranes by passive diffusion. Due to the low vapor pressure no inhalative toxicity study was conducted but the results of the oral toxicity studies suggest that absorption through inhalation will also occur. Based on the high water solubility (782 g/l) of the substance, the substances may retain in the aqueous fluids (mucus) and be transported out of the deposition region.

The physical state (solid) and molecular weight (only <100 g/mol favours dermal uptake) suggest that the substance will not be easily absorbed through skin. Additionally, the high water solubility and low log P values (-0.28 to -1.08) will further decrease the penetration into the stratum corneum and therefore dermal absorption of the substances due to high hydrophilicity will be limited. Due to the low vapour pressure of the substance, evaporation will be low and can result in a higher dermal absorption. Animal studies showed no clinical signs of skin irritation/corrosivity or skin sensitization. Dermal toxicity studies have not been conducted because the substance does not meet the criteria for classification as acute toxicity by the oral route and no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation).

Based on the small size of the main constituents and high water solubility of the substance, wide diffusive distribution in the body is expected. However, the high water solubility will limit the rate of diffusion of the molecules across membranes and therefore their distribution. The low log P values of the main constituents suggest that it is unlikely that the molecules are distributed into cells. A repeated-dose toxicity study with the substance revealed effects on the spleen as well as effects on the hematopoietic system (red blood cell parameters and reticulocytes). The effects on the spleen are not necessarily substance-induced but could be a secondary effect through changes in the hematopoietic system.

None of the substances have a log P value greater than 4 and are unlikely to accumulate in the lipid rich stratum corneum; substances with a log P value <3 are not likely to accumulate in the adipose tissue with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

No experimental data is available on the metabolism of the mixture but there is some information available for the constituent TEA: neither of the hypothetical metabolites (monoethanolamine and diethanolamine) was detected in the urine of mice after dermal administration. Further, 95 % of the triethanolamine in the urine was excreted unchanged (Waechter & Rick, 1988). A small amount of triethanolamine is excreted as glucuronide conjugates (Kohriet. al, 1982).

Due to the low molecular weight (below 200 for each constituent), possible ionization and high water solubility of the substance, elimination via the urine is the most likely pathway of excretion. Though there is no information available for the mixture, there is some information on the excretion of TEA: in 48 h about 60 % of the substance is excreted via the urine, 20 % via faeces and less than 10 % is still found in the skin at the site of application (Waechter & Rick, 1988).

Literature:

Kohri, N., Matsuda, T., Umeniwa, K., Miyazaki, K. & Arita, T. (1982) [Development of assay method in biological fluids and biological fate of triethanolamine]. Yakuzai Gaku, 42, 342–348 (in Japanese).

Waechter, J.M. & Rick, D.L. (1988) Triethanolamine: Pharmacokinetics in C3H/HeJ Mice and Fischer-344 Rats Following Dermal Administration, Midland, MI, Dow Chemical Company.