Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

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 156, it is moderately soluble in water (1.2 g/L at 20°C) and is moderately lipophilic (log Pow = 2.91).

The available evidence suggests that the substance is bioavailable via the oral and dermal routes. Systemic absorption of this substance via inhalation route is expected but to a limited extent. 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 in the dossier. The physico-chemical properties 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 substance, composed of of 2 different cis-trans isomers, having a relatively low molecular weight around 156 g/mol. The substance is a water soluble liquid (1.2 g/L) and is moderately lipophilic based on the octanol/water partition coefficient (log Kow = 2.91). The substance has low volatility according to its vapour pressure (10.4 Pa at 25°C).

 

Absorption:

Oral absorption

The physico-chemical properties described above suggest that the substance is absorbed in the gastro-intestinal tract by passive diffusion. Water-soluble substances will readily dissolve into the gastrointestinal fluids. Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. 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.

Analysis of serum after six weeks of exposure indicated high urea and low chloride concentrations in animals receiving 15000 ppm. Bile acid was significantly lower than control in females at all dose levels and males at the intermediate and low dose. Cholesterol was higher than Control for males and females receiving 15000 ppm with an indication of a dose trend at 5000 ppm in males. Calcium was significantly higher than Control in males and females at 15000, at 5000 ppm in males only. Females receiving 15000 ppm had slight but significantly higher total protein higher at 15000 ppm neither albumin or albumin globulin ratios were significantly affected. At analysis during recovery week two none of the above changes were apparent. 

At necropsy the liver and adrenal weights for males and females at 15000 ppm and males at 5000 ppm (liver only) were higher than Control. After 14 days recovery these differences were not apparent.

Findings seen in the kidneys of male animals comprised of hyaline droplets in the cortical tubules, cortical tubular basophilia and corticomedullary granular casts, all at generally minimal or slight severity. Hyaline droplet formation was seen in all treated male groups after six weeks of treatment but not following 14 days of recovery. Cortical tubular basophilia and corticomedullary granular casts were seen in males given 5000 and 15000 ppm of Dihydroterpineol multiconstituent. After cessation of treatment for 14 days in males given 15000 ppm there was a slight reduction in the incidence or severity of these findings, which may indicate partial recovery.

The observation of 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 and the water solubility values. The absence of effects in the toxicity studies 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 = 10.4 Pa at 20°C) indicated a low volatility 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. However, the log Kow value of 2.91 suggests that the substance would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may 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

In vitro chromosome aberration test showed some evidence of attenuation of cytotoxicity in the presence of S9 which might indicate biotransformation by microsomal enzymes (but less evident with Ames and HPRT tests).  

 

Excretion

The parent substance is moderately water-soluble therefore some elimination of the unchanged form, in urine, might be possible. Biotransformation is expected, however, and elimination of metabolites would most likely occur in urine, although elimination of conjugates in bile is possible. The repeated exposre induced species and sex-specific renal toxic effects in male rats due to alpha2microglobulin accumulation which confirms renal excretion of the parent substance and/or its metabolites. The parent substance is not sufficiently volatile for any appreciable elimination via the lungs, in expired air.

The registered substance has log Kow=2.91 which is below the criterion of 4.5 for bioaccumulation; therefore, it is considered to have a low bioaccumulation potential.