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Administrative data

Description of key information

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; 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.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

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 neurotoxic.

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 histopathological examination.

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 not neurotoxic.

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.

Justification for classification or non-classification

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.