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EC number: 701-188-3 | CAS number: -
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Key value for chemical safety assessment
Effects on fertility
Description of key information
A comparative study in male rate was performed to investigate the potential toxic effect of terpineol multiconstituent when administered by diet versus by gavage over a period of 28 days. No effect on male fertility was observed in animals from the diet group (12000 ppm). Moreover, in a recent study examining the toxicokinetics of alpha-terpineol in male rats, it was demonstrated that terpineol multiconstituent metabolism is rapidely saturated and revealed that the AUC values at the highest dose level (750 mg/kg) were ~2.3-fold higher than the values predicted from a linear relationship, indicating a systemic overexposure of male rats after gavage administration.
Extended One Generation Reproductive Toxicity Study: on-going
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 250 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- GLP study conducted according to OECD Guideline 422 without any deviation (Klimisch score = 1).
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 2 230 mg/m³
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- GLP study conducted according to OECD Guideline 413 without any deviation (Klimisch score = 1).
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The systemic toxic potential, including reproductive effects, of terpineol multiconstituent was assessed in different studies.
1- First it was assessed in rats by oral gavage administration over a period of five weeks at doses of 0, 60, 250 or 750 mg/kg/day.
Overall, general toxicity was essentially seen at the top dose groups but was of moderate intensity:
· Underactive behavior and unsteady reactions, in males and females were observed briefly during week 1 in animals receiving 750 mg/kg/day
· Males receiving 750 mg/kg/day showed slightly lower overall weight gain (weeks 0-5) compared with Control
· Some minor biological changes were also observed as well as some changes in bodyweight adjusted liver and kidney weights
The main feature was the testicular effects observed at the top dose:
·Testis weight was markedly low compared to control in males receiving 750 mg/kg/day and there was also an indication of low epididymal weights at this dose.
·Reduced numbers or complete absence of spermatozoa accompanied by the presence of degenerate spermatogenic cells in ducts were observed in the epididymides of males receiving 750 mg/kg/day at the end of the 5 week dosing period and was still present following the 2 week recovery period.
·Other related abnormalities were also observed in some animals as spermatocele granuloma, moderate to severe seminiferous tubular atrophy/degeneration accompanied by minimal to moderate spermatid giant cells and minimal to slight seminiferous tubular vacuolation.
In summary: a clear testicular toxicity was observed at 750 mg/kg bw/day while no testicular effect was seen at 250 mg/kg bw/day.
2- In order to clarify these effects and test the hypothesis of a metabolism switch at the top dose due to the mode of administration (gavage), a similar study was conducted to compare gavage and dietary route of exposure.
The duration of two weeks was selected for gavage in order to better capture the earliest effects of the substance and have better information on potential mechanism of action. A group (5 male animals) received Terpineol by gavage at doses of 750 mg/kg/day for two weeks.Two further groups (5 male animals/group – Groups 1 and 2) received Terpineol orally, via the diet, at concentrations of 7500 or 10000 ppm.
From Day 11, due to a food intake insufficient to achieve target levels of 500 and 750 mg/kg bw/day, dietary intake was supplemented with Terpineol by gavage for Group 1 animals at 300 mg/kg/day (150 mg/kg/b.i.d) and Group 2 animals at 150 mg/kg/day. In addition exposure of these two groups was extended to three weeks.
In Group 1 (group mean test substance intake: 546 mg/kg), all animals had normal testis and epipidymis weight as well as normal sperm count except animal one who had a testicular weight at about 30% of the other animals of his group and a sperm count at about 1% of the other animals. This animal was the only one among all the groups to have lost weight during the study which may explain its sensitivity to the substance toxicity. However, all animals in this group, with exception of animal 2, had most of their spermatozoids with abnormal shape and no motility. Animal 2 had a normal sperm count with 97% mobiles and 36% with progressive mobility (slightly lower than in group 2) and he was the one who achieved the lowest test substance intake but not much lower than animal one (527 vs. 551 mg/kg as day one to 21 average).
In Group 2 (group mean test substance intake: 602 mg/kg), all animals were normal with the exception of animal 6 who had no motile sperm, close to 100% of abnormal spermatozoids (decapited) but a normal testis /epipidymis /seminal vesicles weight as well as a normal number of spermatozoa in testis and epipidymis. This animal was the one with the highest test substance intake (639 mg/kg for an average of 592 mg/kg for the other four animals).
Results of the second study were indicative of an effect linked with the bolus dose. However they could not be considered as sufficient to prove it due to the insufficient food intake and the obligation to add some part in gavage to achieve a dose level comparable to the top doses of the first study. For this reason an additional two week study was performed in another laboratory with higher dose in the diet.
3- A comparative two week study was conducted where terpineol multiconstituent was adminitered orally either by diet or by gavage to male rats.
Two groups (5 male animals/group) received Terpineol orally by gavage at 500 and 750 mg/kg bw and two others via the diet, at concentrations of 8000 or 12000 ppm for two weeks. There were two control groups, one vehicle control gavage administration and one pure control.:
Gavage groups
G1 Vehicle control
G4 500 mg/kg bw - TERPINEOL
G5 750 mg/kg bw - TERPINEOL
Diet groups.
G18 8000 ppm - Diet Administration - TERPINEOL
G19 12000 ppm - Diet administration -TERPINEOL
G20 Diet Control
Group numbering was not continuous as there were other substances tested in this study.
Immediately after scheduled sacrifice of each male, the left vas deferens, epididymis and testis were removed and the epididymis and testis were weighed.
The following tests were performed:
·Sperm motility
·Sperm morphology, sperm count and homogenisation-resistant spermatids count were to be performed in a second time and will be reported in the final report
All animals were subject to a detailed necropsy. Epididymis, seminal vesicles, testis and prostate were dissected free of adjacent fat and other contiguous tissue and the weights recorded. The bilateral organs were weighed individually. Organ weights were also adjusted for terminal bodyweight, using the weight recorded before necropsy.
The results available to date (November 2010) are the following:
·Sperm motility
o Motile- the percentage of cells which are moving at or above the minimum speed as defined in the set up parameters
o Progressively motile- the percentage of cells moving with both VAP (average path velocity) > progressive minimum VAP and STR (straightness) > S0. (progressive minimum VAP is a delimiter used in determining whether a motile cell is labelled as rapid or medium. Sois the threshold straightness.)
·Body and organ weights.
Results of the study:
- In the gavage groups, feed intake was decreased in both treated groups and at the end of the two weeks treatment period.
- Test substance administration resulted in an initial decreased body weight gain without complete recovery up to the end of the study.
- In the feeding groups, food intake was very low during the first days of the study but increased rapidly and total substance intake in the high dose group remained slightly over 750 mg/kg during all week two.
- This also resulted in a clear decrease in body weight gain and, even for the high dose group in a body weight loss, with only a partial recovery during week 2.
However, effects on sperm mobility clearly confirms the effects previously observed when the substance is administered by gavage while no effects are detected when administration of via diet.
4- Such discrepancies of effects depending on the mode of dose administration were confirmed in a 90-day toxicity study (i.e. a whole period of spermatogenesis).
Terpineol multiconstituent was dissolved in corn oil, mixed in Ssniff powder feed at the dose level of 12000 ppm and fed to male Sprague-Dawley rats (10/dose) dailyad libitumf or 13 weeks. Rats in the control group were fed basal diet only without any test item admixtures. All rats were observed for clinical signs, mortality, and changes in the body weights and food intake. Sperm evaluations were conducted at termination for all the males from each group. Sperm motility, count and morphology were evaluated for all the groups. All rats were subjected to detailed necropsy at termination and organs were weighed. Histopathological examination of the testes and the epididymides were carried out.
No treatment related mortality or signs of toxicity were noted. The body weights were significantly reduced in rats receiving test item at 12000 ppm. This decrease was associated with a decrease in the food intake throughout the treatment period. The Food consumption was significantly reduced in males receiving test item at 12000 ppm dose during the treatment period. The calculated mean daily test item consumption was 0 and 622.65 mg/kg bw/day corresponding to 0 and 12000 ppm, respectively.
A slight significant increase in the percentage of abnormal (4.8 %) sperms was noted at 12000 ppm as compared to the control group. However, the change was considered incidental as it was well within the range of normal biological variation noted among male rats [the range of the in-house historical control data for mean percentage of abnormal sperms: 0.1- 7.4%]. The sperm motility remained unaffected by dietary administration of test item. There were no test item-related changes observed in cauda epididymal weight/sperm count and testicular weight/spermatid count.
There were no test item-related changes in the terminal fasting body weights. Increased liver weights (absolute-13% and relative-20%) were noted in the treatment group. Increased relative weights (paired and unpaired) of testes and epididymides were observed in the treatment group. There were no test item-related histological changes observed in the testis and the epididymis.
No testicular and epididymal toxicity was evidenced in animals receiving terpineol multiconstituent at 12000 ppm, corresponding to 623 mg/kg bw/day, for 90 days .
Discussion
Terpineol multiconstituent when administered at the dose of 750 mg/kg by gavage produced testicular toxicity with absence of spermatozoids and testicular degeneration. None of these effects were observed at 250 mg/kg.
Hypothesis that these effects could only be observed due to the peak of concentration and a possible metabolism switch at this level was tested in studies where the test substance was administered in the diet trying to achieve this same level..
Results demonstrate clearly that, despite a similar exposure level by gavage and by mixed administration (diet + gavage), a much lower level of toxicity was achieved in the diet groups and singularly in the group two where total test substance intake was higher but the proportion by gavage was twice lower.
In a third study, it was possible to feed the rats at a sufficient level to achieve a dosage around 500 and 750 mg/kg during a period long enough to compare pure gavage and pure diet administration. In this case, while effects on sperm motility in the gavage group were clearly reproduced, no effects were observed on this parameter in the diet groups. The absence of toxicity effect on male fertility was further confirmed in a 90 -day oral toxicity study where male rates were feed at the dose level of 12000 ppm (corresponding to 623 mg/kg/day).
In the 90-day toxicity study conducted by inhalation, no toxic effects were observed in male reproductive organs at any tested concentrations (the NOAEC was established at 2.23 mg/L corresponding to an estimated achieved dose of 566 mg/kg/day). There are therefore strong arguments to consider that the effects observed at high dose by gavage are due to a peak effect and are unlikely to occur, even at the highest achievable dose, by either inhalation, dermal or oral route (in the food).
Gavage administration is a normal way to evaluate drug toxicity (which can be administered as one dose/day) or a convenient surrogate (no need to mix with diet) to evaluate toxicity which could occur due to presence of the substance in the food or to extrapolate to different routes of exposure (dermal or inhalation). However, in some cases, it creates pharmacokinetic (and then pharmacodynamic) circumstances which cannot be encountered in real conditions of exposure and can be considered in this case as a non relevant route of exposure (as would be IV or IP mode of administration).
In a recent study conducted by gavage, pharmacokinetic analysis also confirmed the systemic overexposition of the rat after a single dose at 750 mg/kg. The extent of systemic exposure, characterised by AUCall, was shown to increase with increasing dose over the dose range 75 to 750 mg/kg; however, these increases were greater than the proportionate dose increment in both plasma and whole blood. Overall, the AUCall values at the highest dose level (750 mg/kg) were ca 2.3-fold higher than those values predicted from a linear relationship.
Based on the data currently available, there is strong evidence that no specific reproductive effects will occur when animals are exposed through a route relevant for human exposure.
Conclusion
Based on these findings, there is strong
evidence that no reproductive effects are likely to occur by the
realistic routes of exposure and no classification for reproductive
effects is therefore warranted.
Effects on developmental toxicity
Description of key information
A developmental toxicity study was conducted with terpineol multiconstituent according to OECD guideline 414 and in compliance with GLP in the rat and in the rabbit.
NOAEL (No Observed Adverse Effect Level) for maternal toxicity and embryo-foetal development was determined to be 600 mg/kg bw/day and 500 mg/kg bw/day in the rat and the rabbit, respectively.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rabbit
- Quality of whole database:
- GLP study conducted according to OECD Guideline 414 without any deviation (Klimisch score = 1).
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In a GLP-compliant prenatal developmental toxicity study performed according to OECD guideline 414, Terpineol multiconstituent diluted in corn oil was administered by gavage to groups of mated female Sprague-Dawley rats (20 mated females/dose) at the dose levels of 0, 60, 200, 600 mg /kg bw/ day from Days 6 to 19 after mating. Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Detailed observations were recorded daily at the following times in relation to dose administration. A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health. The weight of each adult was recorded on Days 0, 3 and and then daily from Days 6 to 20 after mating. The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 0-2, 3-5, 6-9, 10-13, 14-17 and 18-19 inclusive after mating.
On Day 20 post-coitum, the dams were sacrificed and subjected to macroscopic examination. The gravid uterine weight, number of implantations, live and dead fetuses, early and late resorptions and corpora lutea were recorded. Gross evaluation of the placenta was also performed.
Fetuses were sexed, weighed and examined for external, soft tissue and skeletal malformations.
With the exception of one female in the 200 mg/kg bw/day group (No. 52) which had a total litter resorption, all females were found to be pregnant with live young at scheduled termination on Day 20 of gestation. No mortality was observed.
At scheduled termination on Day 20 of gestation, the adjusted mean liver weight of females receiving 600 mg/kg bw/day was significantly higher than Control (1.10X Control). There were no treatment-related macroscopic abnormalities detected. No relevant clinical signs or signs of reaction to treatment were noted in treated females. Females receiving 60 or 200 mg/kg bw/day showed no treatment-related changes in clinical condition, body weight performance, food intake, liver weight or macropathology.
There was no effect of maternal treatment with Terpineol multiconstituent at any dose level investigated on litter data. Sex ratio, as assessed by the percentage of males per litter, was generally comparable in all groups and in line with expectations. Embryo-fetal growth was slightly reduced by maternal treatment at 600 mg/kg bw/day.
It was considered that there was no adverse effect of maternal treatment on embryo-fetal development; the incidence of major and minor abnormalities and skeletal variants showed no relationship to maternal treatment with Terpineol multiconstituent.
In the 600 mg/kg bw/day group there was a slightly higher incidence of incompletely ossified or unossified 5th and/or 6th sternebrae compared to concurrent control and the Historical Control Data range.
It was considered that this minor finding did not constitute an adverse effect on development.
On the basis of the results obtained in this study, the dosage of 600 mg/kg bw/day was considered to be the NOAEL (No Observed Adverse Effect Level) for maternal toxicity. The NOAEL for developmental toxicity was considered to be 600 mg/kg bw/day.
In a study conducted according to OECD guideline 414 and in GLP conditions, three groups of 22 females received Terpineol multiconstituent at doses of 125, 250 or 500 mg/kg bw/day by oral gavage administration, from Day 6 to 28 after mating at a volume dose of 5 mL/kg body weight. A similarly constituted Control group received the vehicle, 1% methylcellulose, over the same period and at the same volume dose as the treated groups.
Animals were killed on Day 29 after mating for reproductive assessment and fetal examination.
Clinical observations, body weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 29 after mating and the gravid uterus weight recorded. All fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination of the head or skeletal examination.
Administration of Terpineol multiconstituent to pregnant New Zealand White rabbits at dose levels up to and including 500 mg/kg bw/day was well tolerated, with no test item-related premature deaths, clinical signs or post-dosing signs observed.
Females given 500 mg/kg bw/day showed slight mean body weight loss during Days 6-9 of gestation, and a slight reduction in mean food consumption from Day 6 to Day 20 of gestation; these differences from Control were not adverse.
Mean gravid uterine weight and adjusted body weight gain was unaffected by Terpineol multiconstituent administration at all dose levels investigated, and there were no test item-related maternal abnormalities detected at scheduled termination.
There was no effect of maternal treatment with Terpineol multiconstituent on litter data, as assessed by the number of implantations, resorptions, live young, sex ratio and pre- and post-implantation losses. Placental, litter and fetal weights were similar in all groups.
The incidence of major and minor fetal abnormalities and skeletal variants showed no relationship to maternal treatment with Terpineol multiconstituent.
Based on the results obtained in this study of embryo-fetal development, it was concluded that the high dose level of 500 mg/kg bw/day represented the No Observed Adverse Effect Level (NOAEL) for maternal toxicity and for embryo-fetal survival, growth and development.
Toxicity to reproduction: other studies
Additional information
The systemic toxic potential, including reproductive effects, of terpineol multiconstituent was assessed in Sprague Dawley rats by oral gavage administration over a period of five weeks at doses of 0, 60, 250 or 750 mg/kg/day and according to OECD guideline 422. This study indicated that the kidneys, the liver and the testes were the main target organs.
A significant dose-related increase in liver weight was reported in both males and females. Minimal centrilobular hepatocyte hypertrophy was seen in the liver of three toxicity phase females receiving 750 mg/kg/day of Terpineol and accounted for the increases in liver weight at necropsy. Other biochemical findings in this study, such as bile acids and cholesterol levels in females at 750 mg/kg/day may also indicate an alteration of the metabolic function of the liver following administration of Terpineol. However, the changes in liver weight and histopathology findings showed complete recovery after 2 weeks.
Testis weight was markedly low compared to control in males receiving 750 mg/kg/day and there was also an indication of low epididymal weights at this dose.Reduced numbers or complete absence of spermatozoa accompanied by the presence of degenerate spermatogenic cells in ducts were observed in the epididymides of males receiving 750 mg/kg/day at the end of the 5-week dosing period. None of these effects were observed at 250 mg/kg/day.
A new comparative study was performed to investigate the potential toxic effect of terpineol multiconstituent when administered by diet versus by gavage over a period of 28 days. Similar effects on the liver were reported in all treated animals whatever the route of administration (i.e. marked dose-related increase in liver weight). On the contrary, effects on testis weight and sperm motility were observed in the gavage group, but no effects were observed on these parameters in animals exposed to the same dose level by diet. There are therefore strong arguments to consider that the testicular effects observed at 750 mg/kg/day after gavage administration were due to a peak effect of terpineol multiconstituent and are unlikely to occur, even at the highest achievable dose, by either inhalation, dermal or oral route (in the food).
The gavage administration is a normal way to evaluate drug toxicity (which can be administered as one dose/day) or a convenient surrogate (no need to mix with diet) to evaluate toxicity which could occur due to the presence of the substance in food or to extrapolate to different routes of exposure (dermal or inhalation). However, in some cases, it creates pharmacokinetic (and then pharmacodynamic) circumstances which cannot be encountered in real conditions of exposure and can be considered in this case as a non-relevant route of exposure (as would be intravenous or intraperitoneal modes of administration).
In the recent in vivo toxicokinetic study, results obtained after administration of single doses of terpineol multiconstituent revealed the non-linear pharmacokinetics of alpha-terpineol. The AUC values at the highest dose level (750 mg/kg) were ~2.3-fold higher than the values predicted from a linear relationship. These results indicate a systemic overexposure to alpha-terpineol and its metabilites after gavage administration. Further investigations after repeated dosing should confirm this effect and would probably indicate a much higher systemic exposure at 750 mg/kg/day than the one obtained after a single dose.
Based on the complementary information provided in the dossier, the driving hypothesis is that the saturation of alpha-terpineol metabolism led to disproportionately high systemic concentrations that should be considered as unrelated to human exposure, especially after gavage administrations of high dose of terpineol multiconstituent (750 mg/kg/day). After single dose of terpineol multiconstituent, the AUCs increased more than dose-proportionally, leading to much higher systemic exposure than expected. This should be considered as non-relevant plasmatic concentrations compared to real conditions of exposure.
Moreover, a 90-day inhalation study, requested by ECHA, was conducted at dose levels up to 2.23 mg/L (corresponding to an estimated achieved dose of 566 mg/kg/day) and no toxicity was reported in male reproductive organs at top dose.
Justification for classification or non-classification
-The effects on testes are reported at top dose (750 mg/kg/day) and only after gavage administration;
-No effects on testes were observed by dietary administration while the effects on the liver were reported after both gavage and diet administrations;
-No effects on male reproductive organs were reported after 90 days exposure by inhalation at top dose (2.23 mg/L, corresponding to an estimated achieved dose of 566 mg/kg/day).
-Oral gavage with terpineol multiconstituent has shown to result for alpha-terpineol in
o higher peak in plasma (Cmax)
o higher area under concentration-time curve in plasma (AUC)
In the context of terpineol multiconstituent dossier, oral gavage at high dose clearly resulted in much higher systemic exposure than expected, leading to biologically non-relevant effects that should not be considered for classification purposes.
Based on the available data, classification for reproductive effects is then not warranted at this stage.
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