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Description of key information

Repeated dose toxicity - oral: 90 d, rat, feeding: NOAEL = 5000 ppm; 316/384 mg/kg bw/day in males/females (according to OECD 408, GLP; BASF 2019; 50C0267/10C194)
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
316 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Study duration:
subchronic

Additional information

Repeated dose toxicity: oral

In the chosen key study, i.e. a subchronic repeated dose toxicity study in rats according to OECD TG 408 and GLP, tetrahydrolinalool was administered orally via the diet to groups of 10 male and 10 female Wistar rats at concentrations of 0, 1500, 5000 and 15000 ppm (94/113, 316/384, 982 /1118 mg/kg bw/d in males/ females, respectively) over a period of 3 months (BASF 2019; 50C0267/10C194).

Food consumption and body weight were determined weekly. The animals were examined for signs of toxicity or mortality at least once a day. Detailed clinical examinations in an open field were conducted prior to the start of the administration period and weekly thereafter. Ophthalmological examinations were performed before the beginning and towards the end of the administration period. A functional observational battery and measurements of motor activity were carried out towards the end of the administration period. Clinico-chemical and hematological examinations as well as urinalyses were performed towards the end of the administration period. After the administration period all animals were sacrificed and assessed by gross pathology. Organ weights were determined followed by histopathological examinations.

The various analyses confirmed a homogeneous distribution of the test substance in the diet, a general correctness of the prepared concentrations and the stability at room temperature for a period of 4 days during the study. In addition, stability analyses revealed a stability of the test substance in the diet after a storage of 12 days in the freezer followed by 2 days at room temperature.

With regard to clinical examinations, signs of general systemic toxicity were observed in decreased body weight changes at 15000 ppm in male (982 mg/kg bw/d) and female (1118 mg/kg bw/d) animals, the highest concentration tested. Body weight changes were decreased in males (-15.6% on study day 7) and females (up to -12.7% on study day 56) when compared to controls.

Regarding clinical pathology, a shortened prothrombin time in high dose rats of both sexes (15000 ppm) indicated an increased synthesis of coagulation factors by the liver cells. In high dose males, lower glucose values combined with lower chloride levels and higher potassium levels were found, most probably due to a changed energy metabolism coupled with a potential metabolic acidosis. This metabolic acidosis is partly compensated by renal excretion of acids, as seen by a lowering of the urinary pH value.

Increased incidences of transitional epithelial cells and granulated and epithelial casts were observed in the urine sediment of high dose males (15000 ppm). These changes - occurring only in the male sex of this age - indicated an alpha-2µ-globulinuria, which was observed also in histopathological examinations and which is regarded as species-specific finding in male rats without human relevance.

Regarding pathology, all findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered as incidental or spontaneous in origin and without any relation to treatment.

Low and mid dose group animals (1500 and 5000 ppm) did not show any treatment-related adverse effects in clinical examinations, clinical pathology and pathology.

In conclusion, the oral administration of tetrahydrolinalool via diet over a period of 3 months revealed adverse effects in male and female Wistar rats. Under the condition of this study the no observed adverse effect level (NOAEL) was 5000 ppm in males (316 mg/kg bw/d) and females (384 mg/kg bw/d) based mainly on effects in clinical pathology.

 

In support of the key study, repeated dose toxicity studies conducted with the structurally similar test substances linalool (CAS 78-70-6) and dehydrolinalool (CAS 29171-20-8) are included for further assessment.

In a 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 treatment 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-2µ-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.

 

Overall, comparable toxicity profiles after repeated administration were noted for tetrahydrolinalool and linalool, leading to disturbances in clinical pathology and alpha-2µ-globulin nephropathy in kidneys. Alpha-2µ-globulin nephropathy was also observed after repeated administration of dehydrolinalool, although, clinical toxicity at the limit dose appeared to be more severe when compared to the findings seen after subchronic treatment with tetrahydrolinalool. Stomach lesions and indicative signs for gastro-intestinal intolerance are observed in studies with linalool and dehydrolinalool only. These findings are considered to result from bulk administration via gavage, which was not performed in the subchronic study with tetrahydrolinalool. The comparability of these findings confirm the assessment of the category of non-cyclic terpene alcohols (including tetrahydrolinalool and linalool) by an expert panel in terms of their toxicologic properties. The panel concluded that all assessed non-cyclic terpene alcohols have close structural relationships and similar biochemical and toxicity profiles (RIFM EXPERT Panel 2008).

 

Repeated dose toxicity: dermal

Only a short russian abstract with limited validity is available for repeated dose toxicity of tetrahydrolinalool after dermal administration (Melceva 1990). According to the authors, an irritation effect of the skin was observed after application of the test material which was dose-dependent. According to the authors, the cutaneous limit concetration was 10 % (no further information available). As stated above, data for dermal repeated dose toxicity of a structurally related test substance, i.e. linalool (CAS 78-70-6) was adopted to tetrahydrolinalool by read-across as supporting study.

In this 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 until 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/EEC, and therefore, a non-classification is warranted.