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EC number: 915-730-3
CAS number: -
In view of the absence of neurological or behavioural effects in all in
vivo studies performed for OTNE, no neurotoxicity is anticipated: 90
-day oral study via gavage in rat; Extended one generation reproductive
toxicity study, 90 -day dermal studies in rat and mice; 28 -day oral
study via gavage in rat and developmental toxicity via gavage in rat. In
absence of indications for neurotoxicity in adult animals also in off
spring and young animals neurotoxic effects are not anticipated.
Neurotoxicity is regarded as an important and relevant toxicity
endpoint. To evaluate if there are any particular concerns on
neurotoxicity for OTNE, the available in vivo information on this
substance was assessed with regard to neurotoxicity. The findings from
various studies with regard to neurotoxicity are provided below, and do
not indicate any neurotoxic effects of in vivo exposure to OTNE.
ECHA noted in their compliance check there may be an alert for
Neurotoxicity based on information of an analogue. The absence of
neurotoxic effects in the present experimental studies are deemed to be
sufficient to conclude on absence of neurotoxicity for this substance.
For completeness the IFF letter to ECHA presenting the absence of such
an alert is attached to this Endpoint Summary.
Evaluation of neurotoxicity findings in the 13-week oral toxicity
study in rat (OECD TG 408)
A subchronic (13-week) repeated-dose toxicity study was performed
according to OECD TG 408 and GLP principles. Wistar Han IGS rats
(Crl:WI(Han)) were administered daily by oral gavage at dose levels of
30, 120 and 500 mg/ kg bw/day. A control group treated with vehicle
(corn oil) was included. In each dose group 10 male and 10 female
animals were included. Neurotoxicity was examined by performing detailed
clinical examinations (in an arena outside the home cage) on all rats
prior to the first exposure and then once weekly throughout the study
(except for week 12). Behavioral endpoints (Functional Observation
Battery and motor activity assessment) were investigated in all rats at
the end of the study (in week 12 or 13 for females and in week 13 for
males). There was no mortality. There were no other treatment-related
clinical signs. Neurobehavioral observations and motor activity
assessment did not indicate any neurotoxic potential of the test
substance. Therefore, this 13-week oral toxicity study does not indicate
any neurotoxic effects and supports the hypothesis that OTNE is not
Evaluation of neurotoxicity in the Extended One Generation
Reproductive Toxicity study (OECD TG 443): No neurotoxic effects
were seen such as convulsions, tremor, abnormalities in gait or
Evaluation of neurotoxicity findings in the 13-week dermal NTP study
in rats and mice (OECD TG 411)
The study was intended as a subchronic dermal study in which solutions
of OTNE in ethanol were applied to the skin of mice and rats for 5 days
per week for 3 months, without occlusion. For that reason oral exposure
could not be ruled out. 10 rodents were tested in each dose group. Doses
were 6.25%, 12.5%, 25%, and 50% OTNE in ethanol and 100% OTNE, on
approximately 10% of body surface area. These doses correspond
approximately to 125 to 2000 mg/kg bw in mice, and 31.25 to 500 mg/kg bw
in rats. During the course of this study, cage side observations were
performed two times daily.
Bodyweights, food and water consumption and clinical observations were
recorded during the study. Biochemistry samples were taken from all
animals. All animals were killed and subsequently examined
macroscopically; tissue samples (including the brain) were collected
from each animal for histopathology diagnosis. The behavior of the
animals during the study was normal and did not indicate any neurotoxic
potential of the substance. Furthermore, no histopathological
abnormalities were observed in the brain. The results of this study do
not indicate any neurotoxic effects and therefore the hypothesis that
OTNE is not neurotoxic, is supported.
Evaluation of neurotoxicity findings in the 28-day oral toxicity
study (OECD TG 407)
This study was performed to assess the systemic toxicity of OTNE to the
rat, in accordance with OECD TG 407. OTNE was administered by oral
gavage, once daily, to three groups of rats for a minimum of 28
consecutive days, at dosage levels of 15, 150 or 1000 mg/kg/day
suspended in corn oil. Control animals received the vehicle (corn oil).
Cage side observations ware performed three times daily. Animals were
examined for signs of ill health, behavioral changes or toxicity.
Bodyweights, food and water consumption and clinical observations were
recorded during the study. Biochemistry samples were taken from all rats
shortly prior to termination following the four-week treatment and
two-week recovery periods. All animals were killed and subsequently
examined macroscopically; specified tissues were then prepared for
Neurotoxicity: There were no treatment-related mortalities. Evidence of
poor grooming was noted for high dosage group rats during the treatment
period. No further behavioral or neurological effects were observed
during treatment. Furthermore, OTNE induced no effects on organ weight
of the brain. In summary; this 28-day oral toxicity study does not
indicate any neurotoxic effects and supports the hypothesis that OTNE is
Evaluation of neurotoxicity findings in the developmental toxicity
study (OECD TG 414)
A developmental toxicity study was performed in accordance with the US
FDA Guideline on detection of toxicity to reproduction for medicinal
products, which is equivalent to OECD TG 414. The study was performed
under GLP conditions. Groups of pregnant rats (25/dose group) were
gavaged with 0 (control), 96, 240, or 480 mg/kg bw/day on gestation days
7-17 at dosage volumes of 0.5, 0.1, 0.25, or 0.5 ml/kg bw, respectively.
Viability, abnormal clinical signs, body weights, abortions, premature
deliveries, and feed consumption were recorded. Mating performance was
assessed. On gestation day 21, surviving rats were euthanized by carbon
dioxide asphyxiation and Caesarean sections were performed to remove the
foetuses. Rats underwent gross necropsy. Foetuses were assessed for
litter parameters and gross external, soft tissue, or skeletal
malformations. Maternal animals showed reduced body weights and
persistent clinical signs (e.g., increased salivation and urine-stained
abdominal fur) at the highest dose. There were no treatment-related
effects on developmental parameters at any dose. No further behavioral
or neurological effects were described in this study.
Based on the available in vivo dataset for OTNE, no specific concerns on
neurotoxicity were identified after repeated exposure. Based on the
absence of neurotoxicity indications in the studies described, further
neurotoxicity assessments are not deemed necessary.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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