Reaction mass of 2,2',2''-nitrilotriethanol and disodium succinate and sodium acetate and sodium bromide

Endpoint summary

Description of key information

Reaction mass of CXN1-55 is readily absorbed by oral intake. Dermal absorption is extensive for trietanolamine as well as for succinimide, whereas acetate, succinate and NaBr have less evident skin penetration properties. The components of reaction mass of CXN1-55 are evenly distributed in the organism. The compound mixture is not sensitizing, therefore no evidence could be assumed for protein-binding properties. The components like trietanolamine and NaBr do not undergo extensive biotransformation and are mainly excreted as parent compounds. Acetate, succinate and succinimide unchanged or metabolized are part of citrate cycle and produces endogenous metabolites. It is assumed, that water-soluble and at physiological pH ionised components of Reaction mass of CXN1-55 are eliminated mainly via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No ADME for Reaction mass of CXN1-55 is available.

 

The constituents of this multi-constituent substance all have relatively low molecular weights ranging from 82 (sodium acetate) to 162 g/mol (sodium succinate), i.e. < 500 g/mol. The log Kow is less than -1 (-6 at 20 °C) indicating that the substance mixture is very hydrophilic (water solubility > 999.5 g/L at 20 °C). This multi-constituent substance is a solid at 20 °C and 1013 hPa with a melting point > 300 °C, therefore is considered as non-volatile substance and inhalation exposure may be neglected. A dermal dose of 2000 mg/kg bw in rat acute toxicity study shows no systemic or local effects. In addition, no systemic toxicity was observed in acute oral toxicity study when administered via oral gavage up to 2000 mg/kg bw Reaction mass of CXN1-55.

 

Absorption

- oral

Triethanolamine (2,2’,2”-nitrilotriethanol):

Absorption in the gastrointestinal tract of triethanolamine administered orally to Wistar rats is rapid; 63% of the dose disappeared from intestines within 65 min (IARC, 2000).

 

Acetate, succinate:

Acetate was absorbed partially by non-ionic diffusion in the rat jejunum (Watson et al., 1990).

It is expected that succinate will be absorbed as well in the upper part of the intestinal tract by non-ionic diffusion.

 

NaBr:

Sodium bromide is readily absorbed. The pharmacokinetics of oral and intravenous bromide was studied in 7 adult volunteers, who served as their own controls. They received 1 mL/kg of 3% sodium bromide, equivalent to 30 mg/kg bromide. Oral bioavailability ranged between 75-118% with a mean of 96 +/- 6% (Vaiseman 1986). In rats (strain not given) bromide is completely absorbed from the gastrointestinal tract (ESIS 2010).

 

Succinimide:

The pharmacokinetic of succinimide was tested in man and rats (Schulte 1978 A, B &C). Succinimide is readily absorbed via the gi tract. Comparison of the absorption rates show that in man absorption is faster than in rats.

 

- dermal

Triethanolamine (2,2’,2”-nitrilotriethanol):

Triethanolamine is absorbed extensively following dermal application to mice at dosages relevant to toxicity testing (Stott WT et al., 2000). Data from various studies in mice and rats (1000-2000 mg/kg bw) suggest that absorption of dermally administered triethanolamine is almost complete in 24 hr (IARC, 2000).

 

Acetate, succinate:

Succinate and acetate are ionized at pH 5.0 (skin) as well as at pH 7.4 (physiological). Even though the molecular weight of both substances is low, because of the ionization the absorbance via the skin is assumed to be very low, but a possibly recognizable.

 

NaBr

Dermal uptake should be low, due to the anionic nature of the substance and the high tendency to dissociate.

Succinimide:

No data is available on dermal absorption. But as the molecule is small and non-ionized both at a pH of 5.0 (skin) and 7.4 (physiological) a significant dermal absorption rate cannot be ruled out.

 

Distribution

Triethanolamine (2,2’,2”-nitrilotriethanol):

In dermal toxicity studies, the peak blood levels of 14(C)triethanolamine were observed 2 hr after its application in C3H/HeJ mice (2000 mg/kg bw), whereas in Fischer 344 rats (1000 mg/kg bw), the blood levels (expressed as radioactivity) indicated that triethanolamine was absorbed less rapidly than by mice (IARC, 2000).

 

Acetate, succinate:

Acetate and succinate are common metabolites in the mammalian body. Their distribution throughout the body as well as within organs and cells is well regulated as long as the levels stay within physiological ranges.

 

NaBr:

In the experiments with human volunteers elimination T1/2 was 11.9 +/- 1.4 days after oral administration and 9.4 +/- 1.5 days after iv administration (P > 0.10) (Vaiseman 1986). Sodium bromide is readily distributed via the blood stream and reaches all organs of the mammalian organism. The autoradiographic analysis of (82)Br-distribution in mice 24 hr after administration showed high Br levels (compared to blood levels) in the following organs: gastric mucosa, gastric contents, urinary bladder contents, blood vessel walls, and retina. High concentrations, but not exceeding the concentration in blood, were in: cartilage, tendons, lungs, compact bone, and thyroid (ESIS 2010). Other studies showed a different quantitative distribution, but also showed distribution throughout the whole body (ESIS 2010). In the rat (strain not given) bromide is distributed mainly in the extracellular fluid, and penetrates the blood-brain barrier, gastro-entrally recirculated (ESIS 2010).

 

Succinimide:

In the rat experiment succinimide was evenly distributed throughout the body.

 

Reaction mass of CXN1-55:

Reaction mass of CXN1-55 is not sensitizing therefore showing no evidence for protein-binding properties.

 

Metabolism

Triethanolamine (2,2’,2”-nitrilotriethanol):

It was concluded that triethanolamine does not undergo extensive biotransformation in mice, since greater than 95% of the radioactivity recovered from the urine was identified as the parent compound (Snyder, 1990).

 

Acetate, succinate

Other compounds of the reaction mass, sodium acetate and sodium succinate are involved in physiological depletion mechanisms of TCA (Tricarboxylic acid cycle or Citric acid cycle) cycle and are transformed to endogene components of physiological conversions.

 

NaBr:

Sodium bromide is stable in the mammalian body and not metabolised.

 

Succinimide:

No specific data on the metabolism of succinimide are available. In the rat experiment maleimide was identified as one of the metabolites of succinimide in urine. As 17 % of the administered dose was exhaled as labelled CO2, it can be expected that some succinimide is extensively metabolised. Hydrolysis of the amido group and subsequent desamidation would yield succinate which is a key metabolite in the citrate cycle.

 

Excretion

Triethanolamine (2,2’,2”-nitrilotriethanol):

24 hr after oral administration of triethanolamine (single dose of 2-3 mg/kg), 53% and 20% of the administered dose was recovered as the parent compound in the urine and feces, respectively (Snyder, 1990). After multiple oral administration to male and female rats, triethanolamine was mainly excreted unchanged. A small amount of triethanolamine (1.4-2.7%) was excreted as glucuronide conjugates (IARC, 2000).

 

Acetate, succinate:

From TCA cycle acetate is eliminated as CO2 with biological half-life of 4 to 6 hours, followed by a much slower rate of elimination (half-life of about 25 hours) (ECHA). Succinate readily metabolized when administered to animals, but may be partly excreted unchanged in urine if large doses are fed. Succinic acid occurs normally in human urine (1.9-8.8 mg/L).

 

NaBr:

Bromide half-life varied from 2.5 days during high chloride intake to 25 days during low chloride intake. It was concluded that chloride had a marked influence on the no-effect-level of bromide (ESIS 2010). In the rat (strain not given) bromide is excreted mainly via the kidney in competition with chloride for tubular reabsorption (ESIS 2010).

 

Succinimide:

In the rat experiment about 4 % of the administered dose of succinimide was found in the feces, 50 % in urine and 17 % as CO2 in the exhaled air. Excretion is fast as maximum blood concentrations were seen after 2 h in rats. In comparison elimination is slower in man, but with a Tmax in blood of Tmax: 1.25 h, it is still rather fast.

 

Reaction mass of CXN1-55:

It is assumed, that water-soluble and at physiological pH ionised components of Reaction mass of CXN1-55 will be eliminated mainly via urine.

 

 

References

ECHA: http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d88da58-6a18-7479-e044-

00144f67d249/AGGR-f9c68c6c-9945-4257-be6c-cde0b4b7286f_DISS-9d88da58-6a18-7479-e044-00144f67d249.html#ADMIN_DATA

 

European Commission, ESIS; IUCLID Dataset, Sodium bromide (7647-15-6) p.40 (2000 CD-ROM edition). Available from, as of June 1, 2010:http://esis.jrc.ec.europa.eu/

 

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php p. V77 389 (2000)

 

Schulte KE, Henke G. Pharmacokinetics of orally administered succinimide in man. European Journal of Drug Metabolism and Pharmacokinetics, July–September 1978, Volume 3, Issue 3, 161-163.

 

Schulte KE, Rendić S, Henke G,. Pharmacokinetics and disposition of orally administered [2,3-14C] succinimide in the rat. European Journal of Drug Metabolism and Pharmacokinetics, January–March 1978, Volume 3, Issue 1, 31-38.

 

Schulte KE, Rendić S, Henke G,. Malimide: A urinary metabolite of succinimide in the rat. European Journal of Drug Metabolism and Pharmacokinetics, October–December 1978, Volume 3, Issue 4, 249-250.

 

Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents.--: Elsevier, 1990., p. 443.

 

Stott WT et al; Food Chem Toxicol 38 (11): 1043-51 (2000)

 

Vaiseman N et al; J Toxicol Clin Toxicol 24 (5) 1986: 403-413.

 

Watson AJ et al. Acetate absorption in the normal and secreting rat jejunum. Gut 31(2), 1990: 170-174.