Resinoid of Canarium luzonicum (Burseraceae) obtained from the exudate by cyclohexane extraction

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 paste at 20°C with known constituents having a molecular weight between 134 and 240 g/mol. The substance has a broad range of water solubility (from 5.66 to 1488 mg/L for limonene and elemicin, respectively). Consequently, the knwon constituents have also a broad range of log Kow (2.6-4.6 for elemicin and limonene, respectively).

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 known constituents which have a relatively low molecular weight between 134 and 240 g/mol. The substance is a paste with known constituents with broad range of water solubilities (5.66 -1488 mg/L). Consequently, it also has a broad range of octanol/water partition coefficients (2.6 -4.6 at 25°C). The substance is volatile according to its vapour pressure: 887 Pa at 25°C.

 

Absorption:

Oral/GI absorption

The physical chemical characteristics described above suggest that the substance could partly be absorbed in the gastro-intestinal tract by passive diffusion. Some evidence of oral absorption was evidenced in the OECD 422 study. After 6 weeks of exposure through diet, changes considered to be related to administration of the test item were present in the adrenal glands of males and females and kidneys of males. There was an increase in zona glomerulosa hypertrophy seen in the adrenals of males and females treated at 8000 ppm and in males treated at 4000 ppm, and was persisted in males after 14 days of recovery. Vacuolation of the adrenal gland cortex was increased in males given the test item at 2000 ppm and above in a dose related incidence. This persisted after 14 days of recovery. There was an increase in renal cortical tubular hyaline droplets in males treated with the test item at 8000 ppm.

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 knwon constituents (slightly > 4 or below) and the low molecular weight (< 500 g/mol). This is confirmed by mortality observed at 2000 mg/kg bw (1/10 animal) and clinical signs 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 dipentene 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:

Only slight evidence of attenuation of cytotoxicity in the presence of S9 which may indicate biotransformation into less cytotoxic metabolites by microsomal enzymes was evidenced only in the Ames test with the pre-incubation technique. This was confirmed in the OECD 422 study where the analysis of absolute and adjusted organ weights in the toxicity phase males and females that received the test item had an adaptative increase in adrenal and liver weights, when compared to the Controls, with statistical significance being attained for adjusted liver weights for animals that received 8000 ppm.

 

Excretion:

The parent substance is potentially mainly 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 between 2.6 and 4.6 at 25 °C therefore only 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.