Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: estimation
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: estimation of toxicokinetic and metabolism of trimethylolpropane based on information given by the experimental animal data

Data source

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

Materials and methods

Principles of method if other than guideline:
assumtions based on the available experimental data with amimals and physico-chemical data
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Propylidynetrimethanol
EC Number:
201-074-9
EC Name:
Propylidynetrimethanol
Cas Number:
77-99-6
Molecular formula:
C6H14O3
IUPAC Name:
2-ethyl-2-(hydroxymethyl)propane-1,3-diol
Details on test material:
as described in the respective tests
Radiolabelling:
no

Administration / exposure

Route of administration:
other: assumtions based on the available experimental data with amimals and physico-chemical data
Vehicle:
other: assumtions based on the available experimental data with amimals and physico-chemical data
Duration and frequency of treatment / exposure:
assumtions based on the available experimental data with amimals and physico-chemical data
Doses / concentrations
Remarks:
Doses / Concentrations:
assumtions based on the available experimental data with amimals and physico-chemical data
No. of animals per sex per dose / concentration:
assumtions based on the available experimental data with amimals and physico-chemical data

Results and discussion

Any other information on results incl. tables

The following remarks on the toxicokinetics of trimethylolpropane are based on the available studies which were recorded within the process of registration according to the Regulation (EC) No. 1907/2006 (REACH). Experimental toxicokinetic studies were not available.

Trimethylolpropane (TMP, Molecular weight 134.18) is a white, crystalline, hygroscopic solid with a meltingpoint of 58°C at 25 °C, a vapour pressure of 0.0062 Pa at 25°C and log Pow of - 0.47 at room temperature.TMP dissolves readily in water(>100 g/L at room temperature), glycerol, ethanol and other low-molecular alcohols, but is somewhat less soluble in acetone, ethyl acetate and benzene and virtually insoluble in aliphatic, aromatic and chlorinated hydrocarbons (Criteria Group for Occup Standards 1995).

ABSORPTION

The physico-chemical characteristics of TMP (readily soluble in water,log Pow-0.47) and the molecular mass are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion. This assumption of an oral absorption is confirmed by the data on acute and subchronic oral toxicity. 1-2 hours following single oral administration of 1000, 2150, 4640, 10000 or21500 mg/kg bw, rats appeared depressed, exhibited lacrimation, slow and labored respiration from 2150 mg/kg bw onwards and mortality occurred at 21500 mg/kg bw. Gross autopsy of the dead animals showed pathological changes in lungs, stomach, intestine. Changes in the kidneys were seen in surviving rats dosed with 4640 and 10000 mg/kg bw (Celanese Corp. 1956). Repeated application of up to and including 1 % TMP in the diet (corresponding to max 667 mg/kg bw/d) for 90 days led to changes in red blood parameters and effects on liver, spleen and kidneys(de Knecht van Eekelen 1969). All these findings indicate absorption from gastrointestinal tract and systemic availability after oral application.

Water solubility, n-octanol/water partition coefficient and molecular weight of TMP are in ranges which favor dermal absorption. However, applied to the shaved back of rabbits in doses up to 10000 mg TMP/kg bw as paste for 24 hours followed by a 7 days post exposure observation, only mild irritational effects and no deaths were reported and at autopsy effects only on the kidneys were reported (Celanese Corp 1956). In acute skin and eye irritating studies in rabbits no systemic intolerance reactions have been reported (Bayer 1979) and no sensitizing effect has been identified in the Local Lymph Node Assay (Bayer AG 2010).

Water solubility and low molecular weight are suggestive for inhalation absorption but due to the vapour pressure of 0.02 Pa it is unlikely to occur at workplace. In animal experiments, acute exposure did not lead to signs of intoxication and/or mortality. In an early study, at autopsy following repeated exposure up to 1800 mg/m³ daily for 4 hours over a period of 3.5 months, there is some evidence of absorption shown in only slight disturbance of blood circulation, slight disturbance of the permeability of the vessel walls, interstitialpneumonia, focal emphysema in lungs and parenchymatous degeneration of the liver but individual animal data were not shown (Stankevich 1967).

DISTRIBUTION and METABOLISM

As a small molecule with the given water solubility a wide distribution is expected. This assumption is confirmed by the changes shown in the repeated dose toxicity studies following oral application or inhalation exposure (see section Absorption). However, histopathological changes in spleen and liver only at the highest test doses in the 90-day feeding study (de Knecht-van Eekelen 1969) reveal limited distribution into cells.

Based on the results of the in vitro genotoxicity tests (Ames test, with and without metabolic activation, MHLW ) and HPRT test with and without S9 -mix (Harlann CCR 2010) and

Chromosome Aberration tests with and without metabolic activation (MHLW ) it is concluded that DNA-reactive metabolites of TMP will most probably not be generated in mammals in the course of hepatic biotransformation. The polar structure of TMP suggests that it will preferably be either directly conjugated in a phase-II reaction or undergoes further oxidation in the alcohol moieties of the molecule.

ELIMINATION

The n-Octanol/water partitition coefficient (log Pow of 0.47) is not suggestive of accumulation of unchanged TMP in fatty tissues subsequent to absorption from GI tract or from lungs. On the basis of the molecular structure, the molecular size and the water solubility excretion into urine in the unchanged form and/or as glucuronide/sulfate is assumed to be a preferred route of elimination

Applicant's summary and conclusion