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EC number: 939-457-4
CAS number: 1469983-50-3
The objective of the study was to obtain preliminary information on the
toxic potential of the Test Item administered to Wistar rats at three
dose levels (150, 300 and 600 mg/kg bw/day) after daily oral gavage
administration for 14 consecutive days, in preparation of a main 90-day
study to be conducted.
The Test Item formulations had concentrations of 96-97% of the nominal
concentrations. These results and stability of the aqueous solutions
acceptable. General clinical and mortality observations were performed
twice daily, and detailed clinical observation was performed weekly
during the study. Body weight was measured on Day 4, 8, 11, on Day 14,
fasted body weight was recorded prior to scheduled necropsy (Day 15).
Food consumption was recorded weekly. Following repeated dose
administration daily for 14 consecutive days, gross macroscopic
examination was performed at necropsy. The stomach was retained from all
animals. No histopathology was required.
There was no mortality in the study. There were no clinical signs
recorded during the study. There were no Test Item related effects
observed on the animal body weights or body weight gain values. Slightly
lower food consumption was noted in Mid and High dose on Day 14. As
there were no effects on body weight or body weight gain values, this
was considered to be a non-adverse effect.
At necropsy, multifocal thickness at the non-glandular stomach mucosa
were noted for 3/4 High dose females and red, single focus was described
in the glandular mucosa of the stomach for 1/4 High dose females. These
were considered as local irritation effects of the Test Item.
In conclusion, under the conditions of this study, 14-days oral gavage
treatment at 600 mg/kg bw/day (High dose) was associated with local
irritation effects of the Test Item in the mucosa of non-glandular and
glandular stomach. There were no adverse effects of treatment in the Mid
or Low dose group and therefore, the systemic NOAEL (no observed adverse
effect level) was considered to be 600 mg/kg bw/day (High dose). It was
considered that suitable dose levels for the 90-day study are 66.6, 200
and 600 mg/kg/day.
Samples for Test Item concentration determination of the dosing
formulations were collected four times during the treatment period.
Formulation stability was established before this study. The Test Item
concentration was analysed at the Test Site using an LC-MS method.
The mean concentration of all formulations were found to be in
the range of 95.1-107.6%of their nominal concentrations (13.3,
40 and 120 mg/mL). No Test Item was detected in the vehicle
control formulations.Based on these results, Test Item formulations were
considered suitable for the study purposes.
Table 1 - Summary of the dose formulation analysis:
(week of sampling)
Measured concentrations with the 95% confidence intervals(mg/mL)
Measured concentration in percentage of the nominal
08 Dec 2017
22 Dec 2017
15 Jan 2018
07 Febr 2018
Table 2 -
were no adverse effects observed on haematology parameters.
in High dose males were minor (<6% difference from the Control) and
similar (MCH) or slightly out (MCV) of the historical control range for
these parameters. There were no statistical differences see in females.
Dose group (mg/kg bw/day)
Mean Cell Volume (flitre)3
Mean Cell Haemoglobin (pg)4
Dunnett 2 Sided p < 0.01
were no Test Item related effects on the clinical chemistry parameters
evaluated at the completion of the 90-day treatment period.
Dunn-Test 2 Sided p < 0.05
Dunnett 2 Sided p < 0.05
Table 4 - Organ
were Test Item related findings in organ weight data.
absolute and relative to body weights and brain weight of the kidneys
increased statistically significantly both in male and female High dose
animals and was considered asTest Item-related. Based on the
histopathology examination, the increase of female's kidney weights was
supported by a non-adverse Test Item-related increased vacuolation of
tubular cells although there was no histopathologic change in males.The
kidney weight differences were considered as not being adverse.
Body weight (g) Day 91 (fasted)
Kidney (absolute g)
Kidney (relative to body weight %)
Kidney (relative to brain weight %)
Dunnett 2 Sided p < 0.01
The purpose of this study was to obtain information on the toxicity of
the registered substance when administered daily for 90 days by oral
gavage to the rat at 3 dose levels selected in agreement with the
Sponsor, based on previous data available, including the results of a
14-day DRF study by oral gavage in rats (Citoxlab study
code:17/133-101PE (see section 7.5.1).
Male and female Wistar rats were treated once daily for 90 days by oral
gavage administration according to the following Experimental Design:
The first day of dosing of each animal was regarded as Day 1. Control
animals received the vehicle only.
Analysis of Test Item formulations for concentrations were performed and
no Test Item was detected in the Control solution samples. All
formulations were found to be acceptable for the study purposes.
The Test Item is known to have strong surfactant properties, so the
gavage treatment was performed very carefully to try to prevent any Test
Item being deposited in the upper oesophagus area, from where it can
enter the upper respiratory tract.
During the study, observations for mortality were performed twice a day,
clinical signs and detailed clinical observations were also performed at
least daily and weekly, respectively. Body weight and food consumption
measurements were performed in weekly intervals.
Ophthalmoscopy was conducted before randomisation and in the last week,
and neurological assessment including FOB (functional observation
battery), locomotor activity (SMART), landing foot splay and grip
strength were performed during Week 12 of the treatment.
Clinical pathology examinations (haematology, clinical chemistry,
coagulation and urinalysis) were conducted prior to necropsy on all
surviving animals on Day 91
followed by necropsy with macroscopic examination and selected organ
weight measurements. Full histopathology was performed for all Control
and High dose
animals, on lesions from other animals found at necropsy and on the
kidney and stomach from the Low and Mid dose groups.
Two High dose animals (one male on Day 32 and one female on Day 57) died
during the study. Severe broncho-alveolar pneumonia was considered to be
cause of death for the male.
The macroscopic and microscopic findings did not indicate a specific
cause of death for the female. There were Test Item related clinical
signs recorded during the study in Low, Mid and High doses (noisy
respiration), these were considered to reflect a local irritation
effect, and not adverse in the context of a systemic toxicity study.
There were no significant adverse effects noted on body weight or body
weight gain, food consumption, neurological assessment however, in
female High dose, the grip strengths of the hind limb were statistically
significantly lower (-23.4%), this was considered to Test Item related
non-adverse finding. There were no significant adverse effects noted on
ophthalmoscopy or oestrus cycle, in the animal behaviour, general
physical condition, in the reactions to different type of stimuli, in
haematology, clinical chemistry or urinalysis parameters.
The absolute and relative to body weights and brain weight of the
kidneys increased statistically significantly both in male and female
High dose animals and was
considered as Test Item-related. Based on the histopathology
examination, the increase of female’s kidney weights was supported by a
non-adverse Test Item-related increased vacuolation of tubular cells
although there was no histopathologic change in males. The kidney weight
differences were considered as not being adverse.
Gastric irritation was observed as a local adverse effect in High dose
males and females and a few Mid dose males. Test item-related
focal/multifocal/diffuse thickness of the non-glandular gastric mucosa
(minimal to moderate hyperkeratosis) was observed in both sexes at the
High dose and in 2/10 Mid dose males. Additionally, a dark red depressed
area was seen in 1/10 High dose females. In 2/7 High dose females,
focal/multifocal erosion/ulcers were observed. These changes were
considered as local irritation effects of the Test Item.
An increase in severity of the tubular cell vacuolation when compared to
controls was observed in High dose females. No Test Item-related
increase vacuolation was seen in High dose males or in Mid or Low dose
females. The increase of vacuolation in High dose females was not
associated with any degenerative or inflammatory responses, hence
considered to be non-adverse.
In conclusion, under the conditions of this study, the oral
administration of C8-18 alkylamidopropyl hydroxysultaine to Crl:WI
Wistar Rats for 90 days caused no effects in body weight, food intake,
neurological assessment, ophthalmology, haematology, clinical chemistry
or urine parameters. Local irritation effects were observed at all dose
levels, with pulmonary symptoms, probably caused by minor reflux into
the respiratory tract. In the most severe cases, mortality occurred in 2
High dose rats. The pulmonary changes were considered to reflect a local
irritation effect of this surfactant substance, and not adverse in the
context of a systemic toxicity study.
The High dose groups of both sexes showed signs of gastric irritation
with multifocal hyperkeratosis of the non-glandular mucosa (not
accompanied with epithelial
hyperplasia). A similar effect was observed in some Mid dose males. In a
few High dose females, the gastric changes included focal/multifocal
erosion/ulcers. These changes were considered as local irritation
effects of the Test Item.
Increased kidney weights in both sexes at the High dose and an increased
incidence and severity of the tubular cell vacuolation in the kidneys in
High dose females (not in males or Mid dose females) was observed. The
histopathology changes were not associated with any degenerative or
inflammatory responses; hence the renal observations were considered to
It is concluded that local irritation in the stomach was an adverse
effect, with a local effect NOAEL of (66.7 mg/kg bw/day). However, the
systemic NOAEL was considered to be the High dose (600 mg/kg bw/day).
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