Reaction mass of (R*,R*)-7-methoxy-3,7-dimethyl-2-octanol and (R*,S*)-7-methoxy-3,7-dimethyl-2-octanol

Endpoint summary

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 188, it is soluble in water (12.04 g/L at 20°C) and is lipophilic (log Kow = 2.3).

The available evidence suggests that the substance is bioavailable via the oral and dermal routes. The substance is expected to be extensively metabolised and mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

In accordance with the 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 physical 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 multiconstituent, having a relatively low molecular weight around 188 g/mol. The substance is a water soluble liquid (12.04 g/L) and is slightly lipophilic based on the octanol/water partition coefficient (Log Kow = 2.3 at 35°C). The substance has moderate volatility according to its vapour pressure (583 Pa Pa at 20°C).

 

Absorption:

Oral/GI absorption

The physical chemical characteristics described above suggest that the substance could be absorbed in the gastro-intestinal tract by passive diffusion. Water-soluble substances would 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. After 6 weeks of treatment, the mean absolute and adjusted liver weights for males and females receiving 1500, 3500 or 8000 ppm were marginally high. After 2 weeks of recovery, the mean absolute and adjusted liver weights for males and females that previously received 8000 ppm were similar to Control. Dietary administration of the test item to rats for 6 weeks resulted in test item related findings in the kidneys of all treated males. Hyaline droplet accumulation can be seen as a background change in rat kidneys, but the incidence and severity of this change in males and the association with an increased severity of tubular basophilia and the presence of granular casts indicated that this change was related to treatment. Following a 14-day recovery period, full recovery from test item related findings seen in the kidneys was considered to have occurred.

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 occur based on the log Kow (between -1 and 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.

Therefore, 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 = 583 Pa at 20°C) indicated a moderate volatility and inhalability and therefore exposure by inhalation may occur. Thus, at ambient temperature, respiratory absorption is expected under normal use and handling of the substance. Also, when used as a vapour or 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 2.3 at 35°C suggests that the substance would not extensively accumulate. 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 water-soluble therefore elimination of the unchanged form, in urine, may be possible. Biotransformation is expected and elimination of metabolites would most likely occur in urine, although elimination of conjugates in bile is possible. As the parent substance is volatile, elimination via the lungs, in expired air could also be possible.

The registered substance has log Kow=2.3 at 35°C which is below the criterion of 4.5 for bioaccumulation and is believed to be extensively and rapidly metabolised; therefore, it is considered to have no bioaccumulation potential.