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Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please find the attached justification.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Details on distribution in tissues:
MICE
- The distribution of radioactivity present in tissue samples from female mice showed that the heart, kidney, liver, lung, and spleen contained higher concentrations of test substance equivalent relative to blood. (Result read-across source CAS No. 102-71-6)
- The average amount of the administered dose remaining in the body at sacrifice was 3.6% of which 1% or less was found in the liver, kidneys and skin. (Result read-across source CAS No. 102-71-6)

RAT
- 0.9% of the dose remained in the tissues 72 hours after dosing (Result read-across source CAS No. 102-71-6)
Details on excretion:
MICE
1) Result read-across source CAS No. 102-71-6
- 26% of the dose was recovered in the urine within 24 hours.
- 40% of the dose was excreted within 24 hours
- An average of 62% of the dose was recovered in the urine within 72 hours after dosing, and 27.6% was recovered in the feces during this time.
- Less than 0.5% of the dose was recovered in carbon dioxide traps, and less than 0.1% was recovered in volatiles traps.
2) Result read-across source CAS No. 102-71-6
- Radioactivity in blood declined in a bi-exponential manner through 24-hour post-dosing with a rapid initial phase (half-life of 0.3 hr) followed by a slower terminal phase (half-life of 10 hr).
- Clearance of radioactivity from blood was calculated to be approximately 1.5 mL/hr/kg and the apparent volume of distribution was estimated to be approximately 11 mL.
3) Result read-across source CAS No. 102-71-6
- Following a 1 mg/kg intravenous dose of 14C-TEA, the radioactivity in the blood was eliminated from the blood by an apparent firstorder process in a biphasic manner. The half-life of the alpha-phase of elimination of radioactivity from the blood was 0.58 hours with a terminal half-life for the elimination of radioactivity of 10.2 hours as estimated by the method of residuals (Gibaldi and Perrier, 1982).
- Urine was the primary route for elimination of radioactivity following intravenous administration of 14C-TEA. Approximately 65% of the administered dose was excreted via this route of elimination within 24 hours post-dosing.
- Faeces was the secondary route of elimination for the route under investigation. The mean percentage eliminated via the faeces ranged from 16.3 to 27.7.
- There were no marked differences observed across dose levels or routes of administration in the amounts of the dose eliminated via the urine and faeces.

RAT (Result read-across source CAS No. 102-71-6)
- The radioactivity was rapidly excreted in the urine, and 90% of the dosed radioactivity was recovered in the urine within 24 hours.
- An average of 98% of the dose was recovered in the urine within 72 hour after dosing, and approximately 0.6% of the radioactivity was recovered in the feces during this time.
- Less than 0.5% of the dose was recovered in carbon dioxide traps, and less than 0.1% was recovered in volatiles traps.
Metabolites identified:
no
Details on metabolites:
Result read-across source CAS No. 102-71-6

Description of key information

Key value for chemical safety assessment

Additional information

No substance-specific data on the toxicokinetic properties of the substance (CAS 29340-81-6) are available. However, according to Article 13 of legislation EC1907/2006, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests, i. e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. CAS 29340-81-6 is a salt manufactured from triethanolamine (TEA, CAS 102-71-6) and citric acid (CAS77-92-9) and dissociates into the respective TEA cation and citrate anion. Therefore it is considered to be acceptable to derive lacking information on toxicological properties of CAS 29340-81-6 by read-across from its starting materials.

Citric acid

Citric acid is an important intermediate of the Krebs cycle (also known as citric acid cycle), and therefore occurs naturally as a metabolite in virtually all living organisms. It is also used as a natural food preservative and a food additive. The average daily intake (ADI) is not limited according to the evaluation of Joint FAO/WHO Expert Committee on Food Additives (1973), which concluded that the substance is non-hazardous to men. Therefore the toxicological behaviour of CAS 29340-81-6 is expected to be governed primarily by the toxicity of TEA.

TEA

In a study by the NTP (2004), groups of four female mice and rats received a single intravenous dose of 3 mg/kg [14C]-TEA. Expired radioactivity was trapped and quantitated and urine and faeces were collected from all B6C3F1 mice and F344/N rats dosed intravenously up to 72 hours after dosing. Tissue samples at 72 hours after dosing were also examined. The distribution of radioactivity present in tissue samples from female mice showed that the heart, kidney, liver, lung, and spleen contained higher concentrations of TEA equivalent relative to blood. The same effect was observed in rats. In mice, 26% of the dose was recovered in the urine within 24 hours. An average of 62% of the dose was recovered in the urine within 72 hours after dosing, and 27.6% was recovered in the faeces during this time. Urine collected 6 to 24 hours after intravenous dosing contained more than 95% radiolabeled components that co-eluted with unchanged TEA, with minor components eluting the same fractions in mice as those in rats. In rats, 90% of the dosed radioactivity was recovered in the urine within 24 hours. An average of 98% of the dose was recovered in the urine within 72 hour after dosing, and approximately 0.6% of the radioactivity was recovered in the faeces during this time. Less than 0.5% of the dose was recovered in carbon dioxide traps, and less than 0.1% was recovered in volatiles traps. 0.9% of the dose remained in the tissues 72 hours after dosing. With only 40% of the dose excreted within 24 hours, mice appeared to excrete intravenously administered TEA much slower than did rats. Considerably more of the dose was recovered in the faeces of mice (28%) than in rats (0.6%). However, it is common for mice to shred and powder their food pellets, and the faeces collections are often contaminated with urine-soaked solids and their associated radiochemical equivalents.

 

In a study by Stott et al (2000) the distribution, metabolism and excretion of 14C-TEA derived radioactivity were determined in male C3H/HeJ mice following intravenous (iv) injection of 1 mg/kg (14)C-TEA. Urine was the primary route of excretion of radioactivity (46-69% of total dose; 58-79% of absorbed dose) followed by faeces (16-28% of total dose; 19-32% of absorbed dose). The body burden of radioactivity was 3.1% of the applied dose. Radioactivity in blood declined in a bi-exponential manner through 24-hour post-dosing with a rapid initial phase (half-life of 0.3 hr) followed by a slower terminal phase (half-life of 10 hr). Clearance of radioactivity from blood was calculated to be approximately 1.5 mL/hr/kg and the apparent volume of distribution was estimated to be approximately 11 mL.

 

In a study by the Dow Chemical Company (1989), the distribution and excretion of 14C-TEA following intravenous administration of 1 mg/kg bw was determined in 27 male C3H/HeJ mice. The average amount of the administered dose remaining in the body at sacrifice was 3.6% of which 1% or less was found in the liver, kidneys and skin. Urine was the primary route for elimination of radioactivity following intravenous administration of 14C-TEA. Approximately 65% of the administered dose was excreted via this route of elimination within 24 hours post-dosing. Faeces was the secondary route of elimination for the route under investigation. The mean percentage eliminated via the faeces ranged from 16.3 to 27.7%. The average amount of the dose remaining in the body at sacrifice was 3.6% for intravenously dosed animals. The average amount of the administered dose found in the liver, kidneys and skin was approximately 1% or less. The radioactivity in the blood was eliminated from the blood by an apparent first-order process in a biphasic manner. The half-life of the alpha-phase of elimination of radioactivity from the blood was 0.58 hours with a terminal half-life for the elimination of radioactivity of 10.2 hours.