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Effects on fertility

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No data for toxicity to fertility are available for tetrahydrolinalool. However, there are reliable studies which were conducted with the structurally similar test substance linalool (CAS 78-70-6) and dehydrolinalool (CAS 29171-20-8). Recently an expert panel assessed the category of non-cyclic terpene alcohols (including tetrahydrolinalool and linalool) 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). Furthermore, comparable toxicity profiles were noted for linalool and dehydrolinalool 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 reproduction/developmental toxicity and teratogenicity studies for linalool and dehydrolinalool were adopted to tetrahydrolinalool by read-across.

In a repeated dose study according to OECD 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). No macroscopically or microscopically remarkable findings regarding male or female reproductive organs have been reported up to the highest dose tested, indicating an absence of toxicity to fertility. This is confirmed by studies with structurally related substances, i.e. after oral administration of 72.9 % linalool in essential oil in a repeated dose study according to OECD 407 and GLP (HLA642-460). Furthermore, oral administration of dehydrolinalool in a repeated dose study according to OECD 407 and GLP to Wistar rats (200 -1000 mg/kg bw/d) did not lead to test substance related findings regarding male or female reproductive organs, further supporting an absence of adverse effects on fertility (DSM B-158’884).

In a reproductive and developmental toxicity screening test (similar to OECD 421, acc. to GLP) (Lorillard 412-005). Female Crl:CD (SD)BR rats were orally (gavage) administered 0, 250, 500 and 1000 mg/kg/day of coriander oil (containing 72.9% linalool) throughout the 7-day premating period, mating, gestation and lactation (post-natal day 4; Lorillard 412 -005). Controls were treated with the vehicle only and males were not dosed. The rats were observed for clinical signs, weight, feed consumption and were necropsied and examined for gross lesions. Mating performance, duration of gestation/parturition and number of implantation sites were recorded. Litter (F1) were examined for number, viability, weight, sex ratio and external morphology. Delivered pups were additionally examined for viability, clinical signs and body weight during a 4-day postparturition period.

Excess in salivation was noted in all groups being significant for mid and high dose group. A significant number of rats in the 1000 mg/kg/day group had urine-stained abdominal fur during the premating period and 1-2 rats in this group showed ataxia and/or decreased motor activity infrequently during the premating and/or gestation periods.

Biologically remarkable decreases in body weight gain and feed consumption occurred in the 1000 mg/kg/day dose group during premating (significant after first dosage). During gestation, biologically remarkable increase in weight and feed consumption occurred for each group given the test article. Statistically significant increases in body weight gain occurred for the low and high dosage group rats and statistically significant increases in absolute and relative feed consumption values occurred for each group given the test article. These effects decreased in severity during lactation.

No adverse effects on mating, fertility or the durations of gestation or parturition occurred for female rats given dosages of linalool up to 1000 mg/kg/day, indicating the absence of adverse effects of linalool on female fertility.

Pup mortality was significantly increased for litters of dams given 1000 mg/kg/day linalool. When comparing implantation averages to delivered litter size in the 1000 mg/kg/day, the litter size was more decreased as compared to other groups. This indicates an increase in resorptions in the high dosage group. No other test substance related adverse effects were noted in the offspring.

The maternal NOEL for coriander oil was below 250 mg/kg/day based on clinical signs (salivation), increased body weight gains and feed consumption. These changes were not considered to be evidence for severe adversity, hence the NOAEL was set at 500 mg/kg/day. The high-dose group (1000 mg/kg/day) showed reduced litter sizes, indicating in utero deaths, and significant increases in pup mortality in the first four days postpartum. No adverse effects regarding mating, fertility or duration of gestation or parturition occurred in any treatment group up to 1000 mg/kg/day. Clear adverse effects on reproductive performance and pup development occurred at 1000 mg/kg/day, that also resulted in significant maternal clinical signs, significant inhibition of average maternal weight gain before mating and significant increases in maternal weight gain and feed consumption during gestation. In the absence of significant toxicity to the dams, the test substance did not affect the reproductive performance or the developmental parameters of pups. The effects observed on reproduction and development are not, therefore, uniquely reprotoxic or developmentally toxic effects but seen to be a consequence to general toxic effects.

The maternal and developmental NOAELs were established to be 500 mg/kg/day corresponding to a NOAEL of 365 mg linalool/kg bw/day.

Dehydrolinalool was tested in a preliminary reproductive toxicity screening test according to OECD 421 and GLP in Fü-Albino (RORO) rats (DSM B154967). Twenty animals per sex and group were given the test article formulated in rape seed oil at doses of 0 (control), 50, 200 or 750 mg/kg/day (administration volume 5 ml/kg/day). The administration period for both sexes was through premating (2 weeks), mating (up to 2 weeks) and gestation up to day 4 of lactation.

Three females died/were sacrificed during pre-mating period and 3 females died/were sacrificed with delivery complications at the highest dose group. Body weight development and food consumption was comparable in all experimental groups. Hypersalivation was observed in males and females at 750 mg/kg throughout the study. However, this was not considered relevant for NOAEL derivation. Females at the highest dose groups showed sedation/ataxia during gestation and lactation. The duration of gestation, mean number of implantations, resorption rate, mean number of pups per litter, mean pup weight, sex ratio were not significantly affected by the treatment in either dose group. In addition, no signs of teratogenic action were observed in any pup of dams which survived the scheduled date of necrospsy in any dose group.

However, at 750 mg/kg the pup live birth index and pup viability index was slightly reduced, when compared with the concurrent control. Moreover, dams with delivery complications were observed at the dose of 50 mg/kg (1 dam) and at 750 mg/kg (3 dams). No delivery complications were noted in the mid dose group (200 mg/kg) and therefore the finding at low dose level was not considered adverse due to missing dose-response relationship. The incidence of abnormalities in the urinary system and of renal and testicular development was increased at 750 mg/kg mainly due to pups of dams which died or were sacrificed during the delivery. Reduced live birth index is as well to a great extent realted to delivery problems.

It is concluded, that dehydrolinalool does not adversely affect mating and fertility of males and females when administered in rape seed oil by oral gavage to rats from 2 weeks premating through day 4 of lactation up to 750 mg/kg/day. Delivery complications were noted at 50 and 750 mg/kg/day. The pup live birth index and pup viability index was slightly decreased at the maternally toxic dose of 750 mg/kg/day. An increased incidence of abnormalities of the urinary system and of impaired renal and testicular development was noted in pups of mothers treated with 750 mg/kg/day. However, most of the observed abnormal pups belong to those dams which died or were sacrificed moribund during delivery. No adverse effects on the reproductive indices and on the developing conceptus/pup were noted up to 200 mg/kg/day. The no-observed-adverse-effect-levels (NOAEL) were set at 200 mg/kg/day for the offspring and dams. The NOAEL was 750 mg/kg bw/day for males.

Taken together, linalool, which was tested for female fertility, and dehydrolinalool, which was tested for male and female fertility showed no adverse effects. With regard to developmental toxicity / teratogenicity, it is concluded that both substances are neither developmental toxic nor teratogenic at doses not being maternally toxic. However, at maternal toxic doses, reduced litter sizes and increased pup mortality was noted for both substances. In a weight of evidence and analogy to linalool and dehydrolinalool, tetrahydrolinalool is not considered to affect fertility.

Short description of key information:
Read across (linalool CAS 78-70-6): Reproductive and developmental toxicity screening test similar to OECD 421, (acc. to GLP):
Maternal NOAEL = 500 mg/kg bw/d (equivalent to 365 mg/kg bw/d linalool)
Developmental NOAEL = 500 mg/kg bw/d (equivalent to 365 mg/kg bw/d linalool)

Read across (dehydrolinalool CAS 29171-20-8): Reproductive and developmental toxicity screening test according to OECD 421, GLP:
Maternal NOAEL = 200 mg/kg bw/d
Developmental NOAEL = 200 mg/kg bw/d

Effects on developmental toxicity

Description of key information
Developmental toxicity study (OECD 414, GLP, oral, rat, gestation day 7-17): NOEL maternal toxicity = 500 mg/kg bw/d linalool; NOEL developmental toxicity and fetotoxicity = 1000 mg/kg bw/d linalool
Additional information

As stated in the section “effects on fertility” linalool and dehydrolinalool was tested in reproductive and developmental toxicity screening tests, resulting in reduced litter sizes and increased pup mortality at maternally toxic doses. The effects on the offspring observed are not uniquely developmentally toxic effects but are considered to be a consequence to general toxic effects.

In the key study according to OECD 414 and GLP the developmental toxicity of the structurally related linalool was evaluated in presumed pregnant Sprague-Dawley rats (25/group; Politano 2008). Oral dosages of 0, 250, 500, or 1000 mg/kg bw/day linalool were administered by gavage on gestational days 7 to 17. The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. There were no maternal deaths, clinical signs, or gross lesions that were considered related to linalool. During the dosage period, mean relative feed consumption was significantly reduced by 7 % and mean body weight gains were reduced by 11 % at 1000 mg/kg/day. During the postdosage period, feed consumption values at 1000 mg/kg bw/day were significantly higher than vehicle control values, which corresponded to the increase in body weight gains during this period. Caesarean section and litter parameters, as well as fetal alterations, were not affected by linalool at any of the three dosages tested. On the basis of these data, the maternal no observed effect level of linalool is 500 mg/kg bw/day, whereas the developmental no observed effect level is1000 mg/kg/day.

Taken together, in analogy to linalool, tetrahydrolinalool is not considered to be a developmental toxicant.

Justification for classification or non-classification

The present data on reproductive toxicity do not fulfill the criteria laid down in 67/548/EEC and 272/2008/EEC, and therefore, a non-classification is warranted.

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