Linalyl acetate

Endpoint summary

Description of key information

Repeated dose toxicity - oral:  28 d, rat, gavage: NOAEL = 117 mg/kg bw/day (similar to OECD 407, GLP; HLA642-460; Read-Across to CAS No. 78-70-6)
Repeated dose toxicity - oral: 28 d, rat, gavage: NOAEL = 200 mg/kg bw/day (according to OECD 407, GLP; (DSM B-158`884)  Read-Across to CAS No.29171-20-8
Repeated dose toxicity - dermal: 90 d, rat, open: NOAEL = 250 mg/kg bw/d (Similar to OECD 411, GLP; T&O 79-201; Read-Across to CAS No. 78-70-6)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

117 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Repeated dose toxicity: oral

A repeated dose oral study is available that were conducted with the structurally similar metabolite linalool (CAS 78-70-6). Since linalyl acetate is expected to be hydrolysed to linalool in the gastro-intestinal tract, repeated dose studies on the hydrolysis product linalool were included in this assessment via read-across. Furthermore, comparable toxicity profiles were noted for linalool and dehydrolinalool (CAS 29171 -20 -8) in acute toxicity studies and repeared dose studies, leading to alpha-2u-globulin nephropathy, metabolic enzyme induction in the liver, hypersalivation and sedation / ataxia after repeated application. Therefore the available repeated dose studies for linalool and dehydrolinalool were adopted to linalylacetate by read-across.

In the key study similar to OECD TG 407 and according to GLP, the toxicity of coriander oil (containing 72.9% linalool) was evaluated in Sprague-Dawley rats when administered daily by gavage to achieve dosage levels of 160, 400, and 1000 mg/kg of body weight per day (HLA642-460). A concurrent control group received only the vehicle. Criteria evaluation for signs of compound effect included survival, clinical observations, body weights, food consumption, clinical pathology, gross pathology, organ weights, and histopathology.

No treatment-related effects on survival, clinical observations, body weights, or food consumption were observed. Treatment-related increases in total protein and serum albumin were observed in the mid- and high-dose males and the high-dose females. Serum calcium was also increased in these treatement groups, apparently as a secondary response to the increase in albumin, its major serum binding protein. The pathogenesis of these increases, however, is unknown. Treatment-related lesions were noted histopathologically in the kidneys (necrosis of tubules) of the high-dose males, in the nonglandular region of the stomach (inflammation and acanthosis) in the mid- and high-dose females, and in the liver (periportal cytoplasmic vacuolization) of the high-dose females. Similar lesions of the liver were also noted in the low- and mid-dose females, but at a lower incidence. The findings in liver of females were considered to be slight and unlikely to influence liver function. Liver enzymes like AST and ALT were not changed and the histopathological findings were therefore considered rather adaptive than adverse. Kidney lesions were seen in males only and are related to alpha-2u-globulin nephropathy which is not of relevance for humans. Stomach lesions are considered to be result of bulk administration of an irritant substance via gavage.

Taken together, the No Observed Adverse Effect Level (NOAEL) was established to be 160 mg/kg/day, which corresponds to a NOAEL of 117 mg/kg bw/day linalool.

In a repeated dose study according to OECD 407 and GLP, dehydrolinalool was administered to 10 - 14 male and female Wistar rats for a period of 4 weeks (DSM B-158`884). Doses of 0 mg/kg/d, 200 mg/kg/d, 600 mg/kg/d and 1000 mg/kg/d were given daily by oral gavage (400 mg/kg/d at the mid-dose in the first week, 900 mg/kg/d at the high-dose for 2 days). Four animals per sex were allocated for recovery (43 days).

Clinical symptoms referring to gastro-intestinal intolerance (hypersalivation) were observed in all treated animals which may be related to irritant properties of the test material. At the high-dose some animals showed sedation. These symptoms are considered to be compound-related. Two females of the high-dose died spontaneously. Both deaths occurred in animals showing increased salivation and sedation. Five females (4 controls, 1 low-dose animal) died due to anemia shortly after bleeding. A slight, dose-related increase in the relative adjusted liver weight occurred in males and females of the mid- and high-dose level without histopathological correlate. The increase was less apparent after the recovery period. A slight increase in relative adjusted kidney weight was seen in mid- and high-dose males. Major treatment-related changes were confined to the kidney of the male animals. Tubular accumulation of hyaline droplets, with dose-dependent increase, were noted in nearly all treated males. However, similar severity of hyaline droplets accumulation was seen in 3 control males maintained up to termination of recovery and low-dose males sacrificed at treatment end. Distinct signs of tubular degeneration, which led to the diagnosis "hyaline droplets nephropathy" were seen only in males of the mid- and high-dose, with a clear trend towards reversibility. The hyaline droplet nephropathy is well known not to be relevant for human health.

It is concluded that dehydrolinalool is of low subacute toxicity in rats concerning hematological and clinical chemistry parameters. It induced treatment- related hypersalivation and sedation in the high-dose group. In males, dehydrolinalool induced hyaline droplet nephropathy at mid- and high-dose levels. This type of nephropathy is known to be specific in male rats with no predictive value for man. The NOAEL is considered to be at 200 mg/kg/d.

Repeated dose toxicity: dermal

For repeated dose toxicity after dermal application, a repeated dose study from the structurally related linalool was included in this assessment via read-across.

In the key study similar to OECD TG 411 and according to GLP, linalool was administered topically to male and female Sprague Dawley rats for 91 consecutive days at doses of 250, 1000 and 4000 mg/kg (T&O 79-201). Groups of saline treated animals served as the concurrent control.

Mortality apparently related to treatment occurred in females treated with the highest dose of the test material. Depressed activity was the most common and significant toxic sign. Several other deaths occurred during the study but there was no clear relationship to treatment. Slight redness of the skin was noted in all treated groups. It cleared after 3 to 6 weeks at the lower doses but persisted to week 13 in the high dose group. Body weights in high-dose group and in mid-dose females were lower than control. Food consumption was depressed in high-dose males early in the ongoing study. Hematology, clinical chemistry and urinalysis findings were unremarkable. Liver weight in males and females of the high-dose group appeared to be increased compared controls. Kidney weight in females of the high dose group appeared to be increased above controls. However, histopathologically no changes were seen in these organs. A test substance related increase in squamous epithelial hyperplasia from very slight in the controls to slight/moderate in the high dose group was observed.

Taken together, a dermal No Observed Adverse Effect Level (NOAEL) of 250 mg/kg bw/day was established for linalool.

 

Repeated dose toxicity: inhalation

no data available

Justification for classification or non-classification

The present data on repeated dose toxicity do not fulfill the criteria laid down in 67/548/EEC and 1272/2008/EC, and therefore a non-classification is warranted.