Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: assessment based on available information
Adequacy of study:
key study
Study period:
2012-11-07
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non GLP-assessment report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Objective of study:
other: toxikocinetic assessment
Principles of method if other than guideline:
Assessment of all available data
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
CYANOX® 1790 Antioxidant
IUPAC nomenclature - Tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate
Synonym - [tris(4-t-butyl-3-hydroxy-2,6-dimethyl-benzyl)-s-triazine-2,4,6-(1H,3H,5H) trione]

Appearance - White powder, odorless
CAS No. 40601-76-1
Molecular Formula - C42H57N3O6
Molecular Weight - 699.92 g/mole
Purity > 99%
Radiolabelling:
no

Test animals

Species:
other: none
Strain:
other: none

Administration / exposure

Route of administration:
other: oral, dermal and inhalation
Vehicle:
unchanged (no vehicle)
Details on exposure:
see assessment

Results and discussion

Main ADME results
Type:
other: see conclusions

Applicant's summary and conclusion

Conclusions:
Once absorbed in the gastro-intestinal tract, Cyanox 1790 might be metabolized. Excretion of Cyanox 1790 and its metabolites will occur via the bile (high molecular weight) or the urine (low molecular weight). Based on the high partition coefficient, Cyanox 1790 may accumulate in adipose tissue. For risk assessment purposes, the oral absorption for Cyanox 1790 is set at 10%, the dermal absorption at 10% and the inhalation absorption at 100%.
Executive summary:

In general a substance needs to be dissolved before it can be taken up from the gastro-intestinal tract. The very low water solubility (less than 100 ppb) and partition coefficient of 15.3 indicate that this substance will not readily dissolve in the gastro-intestinal fluid. The relatively high molecular weight (MW = 699.92 g/mole) is also indicative for limited passage through biological membranes. The presence of an ionisable group will further impair the absorption as ionised substances do not easily pass the gastro-intestinal wall. It is therefore unlikely that Cyanox 1790 will show a high systemic exposure after oral administration.

Based on the available physico-chemical properties of Cyanox 1790, for risk assessment purposes the oral absorption of Cyanox 1790 is set at 10%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor. Although a LOAEL of 25-84 mg/kg bw/day has been observed in the short-term repeated dose toxicity study, it should be noted that the effects observed in the toxicity study are related to the parent compound Cyanox 1790 including metabolites of Cyanox 1790. As the present assessment is based on the physico-chemical properties of the parent compound, no conclusion can be drawn on the biological availability of the substance after metabolisation.

Once absorbed in the gastro-intestinal tract, Cyanox 1790 might be metabolized. Excretion of Cyanox 1790 and its metabolites will occur via the bile (high molecular weight) or the urine (low molecular weight). Based on the high partition coefficient, Cyanox 1790 may accumulate in adipose tissue.

In humans, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Based on the particle size of Cyanox 1790, particles <100 µm which have the potential to be inhaled, are present. For the particles that have the potential to be inhaled, they will be settled in the nasopharyngeal region (larger particles <100 µm), thoracic region (particles <50 µm) or alveolar region (particles <15 µm). Part of the deposits in the nasopharyngeal region will be coughed or sneezed out of the body, or swallowed, while a part will dissolve into the mucus lining of the respiratory tract epithelium. For risk assessment purposes the inhalation absorption is set at 100%.

According to the criteria given in the REACH Guidance (e.g. guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. European Chemical Agency, May 2008), 10% dermal absorption will be considered in case MW > 500 and log Pow< -1 or > 4, otherwise 100% dermal absorption should be used. As the physico-chemical properties of Cyanox 1790 meet the criteria for limited dermal absorption, for risk assessment purposes dermal absorption is set at 10%.

Based on the present available data, no additional conclusions can be drawn on the distribution, metabolism and excretion of Cyanox 1790 after dermal and inhalation absorption.