Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Study period:
The assessment was conducted in May 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII (8.8).

Data source

Reference
Reference Type:
other: Review of available data
Title:
Unnamed
Year:
2018

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behaviour has been conducted to the extent that can be derived from the relevant available information. The assessment is based on the Guidance on information requirements and chemical safety assessment R.7c: Endpoint specific guidance (ECHA, November 2014)
GLP compliance:
no
Remarks:
Not relevant for assessment

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Any other information on results incl. tables

TOXICOKINETIC BEHAVIOUR

The substance is a liquid with a molecular weight of156.27g/mol.

The substance has a relatively low vapour pressure and is non-volatile and therefore inhalation is not considered to be a significant route of exposure.

The substance has a moderate log octanol/water partition coefficient (log Pow 3.7) and is water soluble (325.6 mg/L).

The substance caused mortality in an acute oral toxicity study at high doses (3200 mg/kg bw and above). Mortality in an acute dermal toxicity study was observed at 2500 mg/kg and above, plus moderate signs of toxicity.

Oral repeated dose studies, showed some mortality and some possible evidence of absorption.

The substance is a skin irritant and a skin sensitiser.

The substance was non-mutagenic in in-vitro and in-vivo genotoxicity studies, in either the presence or absence of an auxiliary metabolising system.

 

 

Absorption

The test item is a relatively low molecular weight liquid that is readily soluble in water and has a moderate log Octanol: Water partition coefficient (log Pow 3.7). This suggests that the test item has the potential to cross biological membranes, via diffusion, such as those of the gastro-intestinal tract following oral ingestion. The results of the acute oral toxicity study on a source substance showed mortality only at very high concentrations (3200 mg/kg bodyweight).

Repeated dose toxicity studies found that oral administration of a source substance linalool/citronellol mixture in a feeding study in rats at 51 and 56 mg/kg bw/day caused reduced food intake and body weight gain in males, however, the authors attributed this effect to be caused by the palatability of the given mixture and considered these effects to be biologically insignificant. In a limited urine analysis, in haematology, in gross examinations and in liver and kidney weights, no test substance related effects were observed. The NOEL was determined as 51 and 56 mg/kg bw/d (the highest doses tested) citronellol for males and female, respectively.

 Another source substance of geraniol (3,7-dimethyl-2,6-octadienol) and the isomer (3,7-dimethyl-1,6-octadienol) was fed to five male and five female individually housed Osborne-Mendel rats Concentrations of 1000 ppm (= ca. 55 mg/kg bw/day) were administered for 189-169 days and a concentration of 10000 ppm (= ca. 550 mg/kg bw/day) was given for 112 days. No clinical signs, no effects on body weight as well as no histopathological changes were observed, and the NOEL could be estimated as 10000 ppm. Thus the NOAEL would be > 550 mg/kg bw/day.

 Repeated dose toxicity was also analysed in a 13 week oral toxicity study at doses of 250, 500, 1000, 2000 and 4000 mg/kg bw/d of food-grade geranyl acetate (71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5). 1/10 female and 2/10 male of the 4000 mg/kg bw/d group died. Besides mortality, the observed substance related toxic effect was a depressed mean body weight of the animals of the 4000 mg/kg bw/d group compared to control (19% for the males, 8% for the females). Three males showed reddened mucosa of the stomach, however no test substance related histopathological changes were observed. Thus, a NOAEL of 2000 mg/kg bw/d of food-grade geranyl acetate has been set, corresponding to 580 mg/kg bw/d citronellyl acetate. In the same study, also, ten male and female B6C3F1 mice per dose were gavaged at doses of 125, 250, 500, 1000, 2000 mg/kg bw food-grade geranyl acetate for the 13 week study. Seven males and nine females of the 2000 mg/kg bw group died. No other clinical signs of toxicity were noted during the study. The males of the 2000 mg/kg bw group exhibit a delay in body weight gain. Liver, kidney and myocardium of males and females of the 2000 mg/kg bw group displayed cytoplasmic vacuolization with lipid inclusions indicative of fatty degeneration. Furthermore, stomach lesions including inflammation and edema were reported in this group. Thus, the NOAEL was set at 1000 mg/kg bw/d food-grade geranyl acetate corresponding to 290 mg/kg bw/d citronellyl acetate.

In an oral OECD 421 study rats were treated at concentrations 100, 300 and 1000 mg/kg bw/day Nerol/Geraniol. Clinical observations indicated distinct toxicity in the exposed parental animals of the highdose group (1000 mg/kg bw/d) but not in the animals of the mid- and low-dose group.

A reduction of food consumption (up to 10% in males and females during treatment weeks 0-1 as well as females (-34%) during lactation), and decreased body weight in males (up to -5%) had been determined during treatment weeks 2-4. The body weight change in males was reduced from week 0 to 5 (-28% on average in this time period). In females a significant body weight change was observed during lactation leading to a body weight loss (-3%). Consequently, the body weight was decreased in males during treatment weeks 2-5 (-7%) and in females of week 6 (-9%). Therefore the NOAEL for systemic toxicity in adults was 300 mg/kg bw/day. The test compound did not adversely affect fertility of the F0 generation parental animals at all dose levels as there were no changes of male/female mating and fertility indices, time until successful copulation, duration of pregnancy and mean number of implantations. Therefore, the NOAEL for fertility was 1000 mg/kg bw/day.

There is an alert for a dose-dependent adverse effect of the test substance on pre-/postnatal development of the F1 offspring at mid and high-dose level (300 and 1000 mg/kg bw/d) indicated by a decrease in viability and body weight. The NOAEL for the F1 generation was therefore 100 mg/kg bw day. These effectsare likely to be secondary to maternal toxicity as evidenced by clinical observations, empty stomachs in pups and significantly reduced feed consumption and body weights during the lactation period. The developmental NOAEL of 100 mg/kg bw/day is also conservative given that the overall viability of 91% at the mid-dose is not significant compared to the 97% viability reported in the low-dose.

These results would suggest that there is some potential absorption of the test item following oral administration, but not significant toxicity.

Some passage across the dermal barrier may be possible as the substance is a liquid and the Log P value and water solubility favours moderate to high dermal absorption. Skin absorption was predicted to be ≤ 80% by a Skin Absorption Model (SAM), based on a calculated Jmax value. The substance is a skin irritant, and therefore damage to the skin surface may enhance penetration. The substance is also a skin sensitiser, suggesting that some uptake of the substances occurs. An acute dermal toxicity study showed clinical signs of systemic toxicity at doses from 1250 mg/kg bodyweight and above (where 2 animals were reported as weak and unable to stand at 1250 mg/kg bw, ataxia in 4 animals at 2500 mg/kg bw and ataxia and pupillary dilation at 5000 mg/kg bw). A reproductive toxicity screening study via the dermal route on the source substance Geraniol in the rat at doses 150, 300 and 450 mg/kg bw/d found no evidence of systemic toxicity. These results would suggest that there is some potential absorption of the test item following dermal administration.

As the material does not exist as particulates and the material has low volatility (vapour pressure < 0.5kPa), exposure via the inhalation route is limited. The Log P value is favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The results observed in oral toxicity studies on source substances that indicates the potential for absorption following ingestion, also indicates that the substance may also be absorbed if it is inhaled.

 

Distribution

As the test item is of low molecular weight and is water soluble, it can be assumed that any absorbed test item can be readily distributed in the water fraction of circulatory fluids. This may be supported by effects observed in oral repeated dose toxicity studies. As the substance evoked a skin sensitization response, this would suggest the material may bind to circulatory proteins. The limited fat solubility suggests the material is unlikely to accumulate in body fat.

 

Metabolism

The results of the repeated dose toxicity studies and reproductive toxicity screening studies show no evidence of enhanced hepatic metabolism and the fact that the material is already freely water soluble suggests that metabolism may not be required to enhance excretion. Genotoxicity studiesin vitroshow that the genotoxic potential of the test item is neither enhanced nor diminished in the presence of S9 microsomal metabolising system.

 

Excretion

Low molecular weight test items that are water soluble are most likely to be excreted via the kidney although the repeat dose studies give no indication of route of excretion. Following oral ingestion, any test item that is not absorbed is likely to be excreted in the faeces.

Applicant's summary and conclusion

Conclusions:
The test item is a low molecular weight liquid that is water soluble. Any oral ingestion of the test item may lead to absorption and systemic distribution, there may also be some limited adsorption via the dermal and inhalation routes. The test item is unlikely to be metabolised and excretion is most likely to be via the kidney.
Executive summary:

The test item is a low molecular weight liquid that is water soluble. Any oral ingestion of the test item may lead to absorption and systemic distribution, there may also be some limited adsorption via the dermal and inhalation routes. The test item is unlikely to be metabolised and excretion is most likely to be via the kidney.