Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

There were no studies available in which the toxicokinetic properties of the registered substance were investigated.

The registered substance is a liquid with a molecular weight around 196, it is slightly soluble in water (34.51 mg/L at 20°C) and is lipophilic (log Pow = 3.98).

The available evidence suggests that the substance is bioavailable via the oral and dermal routes. Systemic absorption of this substance via inhalation route is possible but to a limited extent due to its low volatility (Vp=6.58 Pa at 25°C). The substance is expected to be mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

In accordance with section 8.1.1 of Annex VIII of Regulation (EC) No 1907/2006 (REACH), the toxicokinetic profile of the substance (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information collated in the dossier. The physico-chemical characteristics of the substance, the results obtained from acute, repeated-dose, and reproductive toxicity studies on the substance were used to predict its toxicokinetic behaviour.

 

Physico-chemical properties:

The substance is a monoconstituent, having a relatively low molecular weight around 196 g/mol. The substance is a slightly water soluble liquid (34.51 mg/L) and is lipophilic based on the octanol/water partition coefficient (Log Kow = 3.98). The substance has low volatility according to its vapour pressure (6.58 Pa at 25°C).

 

Absorption:

Oral/GI absorption

The physico-chemical characteristics described above suggest that the substance could be partly absorbed in the gastro-intestinal tract by passive diffusion. Slightly water-soluble substances would partly dissolve into the gastrointestinal fluids. There are no ionisable groups in the parent substance so pH would not affect absorption.

These hypotheses are supported by oral adaptative systemic effects observed in the combined toxicity study with the reproduction/developmental toxicity screening test performed on the registered substance in rats by dietary administration. In this study, only slight adaptative changes were observed in in males receiving 7500 ppm, the highest dose tested, and a slight but not statistically significant lower level for males receiving 2500 or 1000 ppm when compared with Controls. Statistically significantly higher mean cell haemoglobin levels for males receiving 7500 ppm and slightly but statistically significant higher mean cell volume levels for males receiving 1000 ppm or above. Mean cell haemoglobin concentration was slightly but statistically significant higher for females receiving 1000 ppm or above. Haematological parameters examined in Week 2 of recovery were similar to that of the Controls. Organ weights for males and toxicity phase females killed after 6 weeks of treatment indicated that the adjusted group mean kidney weights for animals that received 7500 ppm and the adjusted group mean liver weights for females that received 7500 ppm were slightly but statistically significantly higher than that of the Controls. Organ weights taken following the two week recovery period for animals that received 7500 ppm, were similar to Controls indicating no persistent effects. No significant and relevant histopathological findings were recorded.

The observation of slight systemic effects indicates the oral bioavailability of the registered substance and/or its metabolites.

In light of these data, and the lack of specific information on oral absorption, the substance was assumed to be 100% bioavailable by oral route for the purposes of human health risk assessment.

 

Dermal absorption

Regarding dermal absorption, systemic absorption by the dermal route is expected to be moderate to high based on the log Kow (close to 4) and the low molecular weight (< 500 g/mol). The absence of effects in the actue toxicity study by dermal route probably indicates low toxicity rather than the absence of absorption.

In light of these data, the substance was conservatively assumed to be 100% bioavailable by dermal route for the purposes of human health risk assessment.

 

Respiratory absorption

The potential for inhalation toxicity was not evaluated in vivo.

The vapour pressure of the substance (Vp = 6.58 Pa at 25°C) indicated a low volatility and inhalability and therefore no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance.

However, when used as a vapour in aerosol, the substance is expected to be directly absorbed across the respiratory tract epithelium by passive diffusion.

In light of these data, and the lack of specific information on respiratory absorption, the substance was conservatively assumed to be 100% bioavailable by inhalation for the purposes of human health risk assessment.

 

Distribution:

There is no experimental evidence to indicate distribution but the physico-chemical data suggests that wide distribution could occur. The log Kow value of 3.98 at 25°C suggests that the substance would not extensively accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may partly accumulate if exposures are continuous. Distribution and bioaccumulation are highly dependent on the rate of biotransformation and elimination. There is, however, no evidence of cumulative effects from the repeated dose oral toxicity study.

  

Metabolism:

All three in vitro genotoxicity tests showed some evidence of attenuation of cytotoxicity in the presence of S9 which may indicate biotransformation into less cytotoxic metabolites by microsomal enzymes.  

 

Excretion:

The parent substance is slightly water-soluble therefore some elimination of the unchanged form, in urine, might be possible but limited. Biotransformation is expected and elimination of metabolites would most likely occur in urine, although elimination of conjugates in bile is possible. The parent substance is not sufficiently volatile for any appreciable elimination via the lungs, in expired air.

The registered substance has log Kow = 3.98 at 25°C which is below the criterion of 4.5 for bioaccumulation; therefore, it is considered to have a low bioaccumulation potential.