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EC number: 701-188-3 | CAS number: -
- Degenerative/necrotic germ cells in testes at 750 mg/kg bw/day were considered to be adverse.
- At 600 mg/kg bw/day, considering the low magnitude, incidence and nature of the changes (minimal microvacuolation in a single animal only), this was not considered to be adverse in the experimental conditions of the study.
- Hypertrophy of epithelial cells in epididymides was observed at 600 and 750 mg/kg bw/day and correlated with the higher weight at necropsy (at 600 mg/kg bw/day only). Due to a few degenerated cells seen in one animal at 750 mg/kg bw/day, it was considered as adverse at this dose level. The associated decreased size of the lumen was considered to be secondary to the hypertrophy of epithelial cells.
- Centrilobular hepatocellular hypertrophy correlated with the higher weight at 750 mg/kg bw/day. This was not considered as adverse.
- Periportal/midzonal vacuolation in the liver of most of the animals, including controls was suggestive of a vehicle effect (corn oil).
In a repeated dose toxicity study, Terpineol multiconstituent was administered to six groups of male Sprague-Dawley rats via oral (gavage) at doses of 0 (vehicle), 100, 250, 400, 600 or 750 mg/kg bw/day. Each group was composed of three subgroups: subgroups A and B (six males in each subgroup) corresponded to principal animals and subgroup S (three males) corresponded to satellites animals, especially for toxicokinetics investigations in the testes and in blood samples. The rats from subgroup A were treated for 7 days, those from subgroups B and S for 14 days. During the study, morbidity, mortality, clinical signs, body weight, food consumption, organ weights, gross and histopathology investigations were undertaken.
There were no unscheduled deaths during this study. Ptyalism was observed on several occasions in animals treated from the dose level of 250 mg/kg bw/day, in both subgroups A and B. Slightly lower mean body weight, body weight gain and food consumption were recorded in animals given 600 or 750 mg/kg bw/day of test item, when compared to control group. This tendency was observed in both subgroups (A and B).
At the dose level of 750 mg/kg bw/day for 14 days (subgroup B), adverse changes were noted in testes and consisted in micro and/or macrovacuolation and degeneration/necrosis of germ cells in stages VII and VIII. Epithelial hypertrophy in epididymides was also observed along with decreased size of the lumen. At 750 mg/kg bw/day for 7 days (subgroup A), only slight vacuolated changes were seen in testes of a single animal and minimal hypertrophy of epithelial cells was seen in the epididymides. At 600 mg/kg bw/day for 14 days (subgroup B), minimal vacuolation of germ cells was seen in a single animal and hypertrophy of epithelial cells was noted in epididymides along with reduced lumen. In the liver, minimal hepatocellular hypertrophy was seen after 14 days of treatment at 750 mg/kg bw/day (subgroup B).
Therefore, the test item was clinically well tolerated up to 750 mg/kg bw/day.
Clinical signs were limited to ptyalism. Slightly lower mean body weight and mean food consumption were recorded at the dose levels of 600 and 750 mg/kg/day and were not considered adverse.
At microscopic examination, effects were observed on male genital tract at 600 and 750 mg/kg/day and were considered adverse at 750 mg/kg/day only, as degeneration/necrosis was noted at this dose.
Table 7.1.1/1: Plasma intensity (count) of alpha-terpineol glucuronide following single oral administration of Terpineol Multiconstituent at 100, 250, 600 and 750 mg/kg bw/day in male Sprague-Dawley rats
Dose (mg/kg bw/day)
Plasma intensity (count)
Sampling time (hours)
3 840 304
7 570 038
Table 7.1.1/2: Mean toxicokinetic parameters (median for Tmax) of alpha-terpineol glucuronide following oral administration of Terpineol Multiconstituent at 100, 250, 600 and 750 mg/kg bw/day for 1, 7 or 14 days in male Sprague-Dawley rats
AUC0-∞ Extrap %
Table 7.1.1/3: Dose proportionality assessment of alpha-terpineol glucuronide following oral administration of Terpineol Multiconstituent at 100, 250, 600 and 750 mg/kg bw/day for 1, 7 or 14 days in male Sprague-Dawley rats
Treatment ratio compared with
100 mg/kg bw/day
A toxicokinetic study was conducted to evaluate the toxicokinetics of test item Terpineol multiconstituent, and its metabolite alpha-terpineol glucuronide, following daily oral administration (gavage) to male Sprague-Dawley rats for 1, 7 and 14 days.
The toxicokinetics of Terpineol multiconstituent after oral administration on Day 1, 7 (750 mg/kg group only) and 14, to 12 male Sprague-Dawley rats (n=3 per dose group) were characterised using mean plasma concentration vs. time data. The animals received either 100, 250, 600 or 750 mg/kg bw/day of Terpineol multiconstituent by daily gavage administration. Three additional samples from external animals were allocated to the initial groups: 3 blood samples were added to group 100 mg/kg bw/day at 12 h.
Blood samples for the determination of plasma levels of the test item and its metabolite were taken on all groups: on Day 1; on Day 7 for 750 mg/kg bw/day group only; at the end of the treatment period (Day 14). At each occasion, the animals were sampled as follows: 0 (predose), 0.5, 1, 2, 4, 6, 12 and 24 h after test item administration. Three animals / subgroup were sampled at each time-point, and each animal was sampled four times during each period.
Bioanalysis for the determination of Terpineol multicojstituent concentration in plasma was performed using a validated GC-FID method. Conversely, Terpineol multiconstituent glucuronide concentration could not be determined as no commercial standard was available. Consequently, no validated method could be performed and only the peak intensity (in count), obtained by LC-MS, could be reported.
The toxicokinetic parameters were estimated using Phoenix WinNonlin® software v6.4 (Pharsight Corporation, Mountain View, California 94040/USA).
The following toxicokinetic parameters were determined: AUC0-24h, tmax, λz(t½). Parameters were compared in order to evaluate dose-proportionality and time effect.
Based on the data obtained, the following conclusions can be made:
- No contamination was observed in pre-dose samples collected on Day 1 from all treated and vehicle groups as their respective plasma concentrations of alpha-terpineol and alpha-terpineol glucuronide were either below the Lower Limit of Quantification (LLOQ: 1.00 µg/mL for alpha-terpineol) or not detected (S/N<5 for alpha-terpineol glucuronide).
- Following oral administration of Terpineol multiconstituent to male Sprague-Dawley rats at 100, 250, 600 and 750 mg/kg bw/day, alpha-terpineol concentrations were below the limit of quantification (BLQ < 1.00 µg/mL) for all animals at all sampling times.
- The male rats were exposed to alpha-terpineol since all animals have detectable alpha-terpineol glucuronide amounts in plasma at all times (except at day 1 predose) for all doses.
- Rapid oral absorption and metabolism rate were noted with a metabolite Tmax observed at 0.5 h for all test item doses with the exception of the 100 mg/kg bw/day group at day 1 (Tmax at 1 h). The mean terminal half-life values of the metabolite were highly variable ranging from 1.70 to 20.0 h.
- Mean concentration versus time profiles of the alpha-terpineol glucuronide suggest either an enterohepatic recycling and/or a saturable absorption.
- Both on Days 1 and 14, exposure to terpineol glucuronide (AUC0-24h) increased almost dose-proportionally from 100 mg/kg to 600 mg/kg, whilst at 750 mg/kg a more than dose-proportional increase can be observed.
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