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EC number: 915-730-3
CAS number: -
The effects reported in this study need to be evaluated in light of the
used route of exposure. The study was intended as a sub-chronic dermal
study; however, the animals were dermally exposed to OTNE in ethanol
without occlusion of the treated site. Oral absorption (voluntarily or
involuntarily), is expected as a result of oral grooming by the animals.
In the present study, the grooming could have a contributed to an
unknown extent to the systemic exposure and toxicity. Furthermore, also
the local effects observed as a result of dermal exposure are
confounded, a , as grooming by the animals can have influenced the
actual dermal dose, dermal exposure time and could have given te
opportunity for the animals to scratch, rub or lick the exposed site. As
a result of these methodological limitations, the derivation of a dose
descriptor for systemic or local effects due to dermal exposure is
Introduction: In the rat study, OTNE was
tested in a sub-chronic dermal toxicity study according to OECD
Guideline 411. The study is rated Klimisch 2, because the substance was
administered through dermal application without coverage resulting in
oral exposure (due to grooming), which is not in line with the required
coverage according to the guideline and a real systemic dermal NOAEL
cannot be derived.
Method: Male and female F344/NTac rats were
administered OTNE dermally for 3 months. Groups of 10 male and 10 female
rats received no treatment (untreated control) or dermal application of
OTNE in 95% aqueous ethanol at concentrations of 0% (vehicle control),
6.25%, 12.5%, 25%, 50%, or 100% (neat) 5 days per week for 3 months
(31.25, 62.5, 123, 250 and 500 mg/kg bw). Animals in the 100% OTNE
groups were compared to untreated controls, and the remaining dose
groups were compared to the vehicle controls. Formulations were
administered at a volume of 0.5 mL/kg body weight, on approx. 10% of
body surface area (25 cm2).
Local dermal effects: For the local irritant
effects the dose in concentration will be used because concentration is
a better indicator for irritancy than the dose. In male and female rats
administered 12.5 to 100% OTNE, the incidences of minimal to mild
hyperplasia and hyperkeratosis (except in 12.5% OTNE males) at the site
of application were significantly greater than those in the vehicle
control groups. The dermal exposure and effects are confounded for the
following reasons: 1) grooming by the animals decreased the actual
dermal dose; 2) dermal exposure time is decreased and; 3) the scratch,
rubbing and licking of the exposed site may have enhanced the dermal
penetration. In view of these confounders a dose descriptor for local
effects via the dermal exposure route is deemed inappropriate.
Clinical signs and body weight: All rats
survived to the end of the study. There were no biologically significant
clinical or behavioural effects. Final mean body weights and body weight
gains of dosed male and female rats were similar to those of the
respective control groups with the exception of the 500 mg/kg bw/day
OTNE male rats, which had a statistically significant but minor decrease
in mean body weight gain (-6%) compared to the untreated control.
Clinical chemistry: Alanine aminotransferase
and Alkaline phosphatase are significantly decreased becoming dose
depending from 125 mg/kg bw onwards (starting with a decrease of 25%) in
all dosed groups of males and in 125 to 500 mg/kg bw/day OTNE females.
In general, the toxicological relevance of a decrease of these enzymes
is generally doubtful but it is consistently seen.
Liver: Relative liver weights at 250 and 500
mg/kg bw/day OTNE were significantly increased (> 10-31%) compared to
the control. At 250 mg/kg bw this increase is considered adaptive at 500
mg/kg bw these may be considered adverse.
Kidney: The relative kidney weights of the 500
mg/kg bw/day OTNE male and female rats were significantly increased by
10 and 8%, respectively. These increased are not considered adverse.
Other effects: There were no neurotoxic and
immunological effects seen. There were no biologically significant
neoplastic findings found.
A local long-term repeated dose NOAELcould not
be established because the concentration to which the animals are
exposed doubtful due to oral grooming
A systemic dermal repeated dose NOAEL cannot
be established because beside dermal exposure the oral exposure route is
a major route e.g. the relative liver weights in the oral and dermal
studies is similar increased (ca 50% at 500 mg/kg bw) in the oral 90-day
IFF study as in this NTP study. Only a combined systemic dermal/oral
NOAEL can be established. This can be set at 250 mg/kg bw considering
the relative liver weight increase of < 30% as an adaptive effect in
absence of other liver related findings of toxicological relevance.
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