Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Remarks:
expert statement
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Well documented expert statement. This expert statement has been based on a series of physicochemical, environmental and toxicology studies with THEIC performed according to technical guidelines and in compliance with GLP in internationally recognized contract research organizations. In addition, this expert statement has been based on read-across with cyanuric acid giving due consideration to the safety evaluation of cyanuric acid by a joint FAO/WHO expert committee.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Expert statement based on a series of physicochemical, biodegradation, ecotoxicological and toxicology studies. Technical guidelines followed in these experimental studies are cited in the respective endpoint study records.
GLP compliance:
no
Remarks:
Considered unnecessary for expert statement

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tris(2-hydroxyethyl)-1,3,5-triazinetrione
- Physical state: solid white powder / granules
- Composition of test material: 99% (according to SIDS information), > 96% (substance to be registered)
Radiolabelling:
no

Test animals

Species:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement
Strain:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement
Sex:
male/female
Details on test animals and environmental conditions:
Detailed in the endpoint study records of in-vivo studies referred to in the present expert statement.

Administration / exposure

Route of administration:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement
Vehicle:
other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement, if appropriate
Details on exposure:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.
Duration and frequency of treatment / exposure:
Detailed in endpoint study records referred to in the present expert statement.
Doses / concentrations
Remarks:
Doses / Concentrations:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.
No. of animals per sex per dose:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.
Control animals:
other: Detailed in endpoint study records referred to in the present expert statement, if applicable
Positive control:
Detailed in endpoint study records referred to in the present expert statement, if applicable
Details on study design:
Detailed in endpoint study records referred to in the present expert statement, if applicable
Details on dosing and sampling:
Detailed in endpoint study records referred to in the present expert statement, if applicable
Statistics:
Detailed in endpoint study records referred to in the present expert statement, if applicable. Not applicable for the present expert statement.

Results and discussion

Preliminary studies:
Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Based on the physical-chemical properties of THEIC [water solubility quite high (572 g/L at 20°C) and a moderately low molecular weight of 261 with hydrolytic stability (stable > 5 d at 50°C, pH 4, 7 and 9 according to OECD 111)] it is expected that after oral dosing the substance is absorbed in the gastro-intestinal tract and becomes systemically available. However, there was no indication of systemic exposure, since no effects were observed in the acute and repeated dose oral toxicity studies. The quasi-inert behavior of THEIC in the oral toxicity studies is consistent with the absence of any cytotoxic effects in the in vitro mutagenicity tests with various cell lines and the absence of any effects on algae, daphnia and fish in ecotoxicology studies. In addition, THEIC was not readily biodegradable in the standard laboratory test.

In view of the high water solubility of THEIC and on average only 1.1 mass percent of its particles < 10 µm, inhalable particles predominantly will settle in the nasopharyngeal region being trapped in the mucus lining and becoming systemically available by passage across the respiratory tract epithelium and/or by mucus transport and swallowing. Inhalation exposure is expected to result in 100% absorption of the inhalable fraction.

Dermal absorption of THEIC is considered to be low. With water solubility quite high (572 g/L at 20°C) and the n-octanol/water partition coefficient quite low (log10 POW = – 1.63 at 23°C, pH 7.5) THEIC is considered to be too hydrophilic to cross the lipid rich environment of the stratum corneum (1).

Reference:
ECHA (2008) Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance.
Details on distribution in tissues:
There are no data on the distribution of THEIC in tissues. However, read-across with the structurally similar substance cyanuric acid (EC No. 203-618-0, CAS No. 108-80-5) revealed that this substance was not metabolized in toxicokinetic studies with rats and dogs and 7 days after oral dosing no radioactivity of the 14C-labelled cyanuric acid was detected in the animals (1).

Reference:
WHO (2004). Evaluation of Certain Food Additives and Contaminants. Sixty-first report of the Joint FAO/WHO Committee on Food Additives. WHO Technical Report Series 922.
Details on excretion:
There are no data on the excretion of THEIC. However, read-across with the structurally similar substance cyanuric acid (EC No. 203-618-0, CAS No. 108-80-5) revealed that this substance was excreted unchanged preferably via the urine at higher doses also via the faeces in toxicokinetic studies with rats and dogs (1, 2). Excretion of cyanuric acid unchanged via the urine was also demonstrated in 2 human volunteers.

Reference:
(1) - WHO (2004). Evaluation of Certain Food Additives and Contaminants. Sixty-first report of the Joint FAO/WHO Committee on Food Additives. WHO Technical Report Series 922.
(2) - OECD (1999) SIDS initial assessment report for 9th SIAM: isocyanuric acid. Paris, Organisation for Economic Co-operation and Development, SIDS Initial Assessment Meeting, Screening Information Dataset for High Production Volume Chemicals (108-80-5).

Metabolite characterisation studies

Metabolites identified:
not specified

Applicant's summary and conclusion

Conclusions:
Interpretation of results : No bioaccumulation potential. Conclusion of submitter from the present expert statement.