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 at 20°C, with the 11 major constituents, representing more than 90% of the substance, having a molecular weight between 134 and 222 g/mol. 9/11 of these constituents have limited water solubility (<10 mg/L) with the exception of constituent 4 (268 mg/L) and 6 (80.3 mg/L), accounting for only 4% of the substance. Consequently, most of the constituents are lipophilic with log Kow>4, except for constituent 4 (2.6) and constituent 6 (2.5).

The available evidence suggests that the substance is bioavailable via the oral and dermal routes. The substance is expected to be metabolised and mainly excreted in urine with low potential for bioaccumulation.

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 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 UVCB substance with 11 known constituents accounting for more than 90% of the substance. They hava a relatively low molecular weight between 134 and 222 g/mol. The substance is a limited water-soluble liquid (<10 mg/L exception for 2 constituents with solubilities > 80 mg/L but representing only 4% of the substance). Consequently, it is mainly lipophilic based on the octanol/water partition coefficient (Log Kow >4 at 25°C). The substance has moderate volatility according to its vapour pressure: 209 Pa at 25°C, considering the sum of the partial pressure of known constituents (using molar fraction).

 

Absorption:

Oral/GI absorption

The physical chemical characteristics described above suggest that the substance could slightly be absorbed in the gastro-intestinal tract by passive diffusion. However, some evidence of oral absorption were evidenced in acute oral toxicity study and the OECD 422 study. Adverse clinical signs of toxicity were observed after a single dose from 3000 mg/kg bw in the acute oral toxicity study. Also,

after 6 weeks of dietary exposure in an OECD 422 study, the absolute and adjusted organ weights in the toxicity phase males that received 3500 or 7000 ppm or females that received 7000 ppm had an increase in liver weight when compared to the Controls, with the adjusted weights attaining statistical significance. Moreover, changes considered to be related to administration of the test item were present in the kidneys of male rats only. Males given 1750, 3500 or 7000 ppm had hyaline droplets (minimal to slight severity) in the cortical tubules of the kidneys. Cortical tubular basophilia (minimal to slight severity) was also present in some male rats given 1750, 3500 or 7000 ppm. In this study, tubular basophilia was of minimal to slight severity, but was not present in Control. However, following a 14-day recovery period there were no findings considered to be related to treatment in the kidneys of males examined.

The observation of such 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 limited but to occur based on the Log Kow of most of the main constituents (slightly > 4) and the low molecular weight (< 500 g/mol). This is confirmed by mortality observed at 5000 mg/kg bw in the acute dermal toxicity study.

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 = 209 Pa at 25°C) indicates 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 > 4 at 25°C suggests that the substance could accumulate in fatty tissues. However, distribution and bioaccumulation are highly dependent on the rate of biotransformation and elimination. Some of the main constituents like limonene are expected to be extensively metabolised. This may explain why no evidence of cumulative effects was observed 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. This was confirmed in the OECD 422 study where increased liver weights, a sign of adaptative response to repeated exposure to the substance, were observed after 6 weeks of exposure in males and females at 7000 ppm.

 

Excretion:

The parent substance is of low water solubility therefore elimination of the unchanged form of its constituents, in urine, may be limited. 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 relatively volatile, elimination via the lungs, in expired air could also be possible.

The registered substance has constituents with log Kow>4 at 25 °C and 4 major constituents slightly above the criterion of 4.5 for bioaccumulation. However, these constituents are expected to be extensively metabolised therefore, the registered substance is considered to have low bioaccumulation potential.