Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study according to OECD guideline under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Chemical name: mixture of N,N-Dimethydecan-1-amide and N,N-Dimethyloctan-1-amide
- Physical state: liquid
- Storage condition of test material: roomtemperature

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 19-22 weeks old (at week -1)
- Weight at study initiation: between 6.4-9.0 kg (at week -1)
- Housing:individual cages
- Diet (e.g. ad libitum): ad libitum, ssniff HH complete food for dogs, 12 mm pellets from ssniff Versuchstierdiaten GmbH, Soest, Germany
- Water (e.g. ad libitum): ad libitum, common drinking water quality
- Acclimation period: 17 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 - 23.5°C
- Humidity (%): 25-50%
- Air changes (per hr): forced ventilated room
- Photoperiod (hrs dark / hrs light): Premises illuminated by diffuse daylight, but mainly fluorescents lamps with regulated
the day/night cycle (12h each)
- Cleaning: spray cleaned each afternoon (hot water)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: applied as 0.5% aqueous tylose suspension
Details on oral exposure:
According to guideline
PREPARATION OF DOSING SOLUTIONS:
- suspensions were prepared weekly
- stability ensured for 8 days in range of concetrations used
- Analytical content check of the formulation performed during the course of the study

ADMINISTRATION:
Administration via gavage: Administration volumen: 10ml, Application once daily 2 hours before feeding in the morning

VEHICLE
- Justification for use and choice of vehicle (if other than water): common vehicle
- Concentration in vehicle: 4.0 mg/ml, 20.0 mg/ml and 50.0mg/ml
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical verification of concentration in vehicle via GC, reported recovery >97%
Duration of treatment / exposure:
13weeks
Frequency of treatment:
once daily 2 hours before feeding in the morning
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
40mg/kg bw
Basis:
other: nominal applied as 0.5% aqueous tylose suspension
Remarks:
Doses / Concentrations:
200mg/kg bw
Basis:
other: nominal applied as 0.5% aqueous tylose suspension
Remarks:
Doses / Concentrations:
1000mg/kg bw
Basis:
other: nominal applied as 0.5% aqueous tylose suspension, later reduced to 800 and further to 500 mg/kg bw
No. of animals per sex per dose:
4 male and 4 female per dose
Control animals:
yes, concurrent vehicle
Details on study design:
according to guideline
Positive control:
not necessary

Examinations

Observations and examinations performed and frequency:
According to guideline
Sacrifice and pathology:
According to guideline
Statistics:
In line with the small number of animals per group, a descriptive statistical evaluation was performed

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
- General findings
reflexes, body temperatures, pulse rates, blood pressure and heart rates as well as electrocardiograms did not
yield relevant changes up to and including group III
- Clinical observations
nutritional state were not relevant changed
From group II upwards, vomiting and salivation were observed repeatedly, effects in group III consisted of uncoordinated
movements, nasal discharge, lateral/prone position, and trembling
-mortality
one animal of group III had to be sacrificed on day 3 (showing lateral position)
another animal of group III died in week 7 of the study exhibiting lateral position, bloody nasal and oral discharge
before death
- Feed and water intake
no notable differences could be detected in feed intake between control animals and animals up to and including group III
no descriptions of unusual findings in water intake in the observation records up to and including group III
- Ophthalmoscopic findings
no ocular changes were detected up to and including group II. In group III, a cataractous lens occurred in the right eye of one animal
- Body weights
The mean body weight gain of males and females showed no changes up to and including group III in comparison to the control group
- Haematoloqy
no changes were observed up to and including group III
- Clinical chemistry
APh increased in two animals (group III)
N-Dem: increased in all females of group II and marginally increased in one animal, all animals group III
P 450: increased in two animals (group III)
In all the other clinico-chemical parameters determined no changes were detected up to and including group III
- Urines
no appreciabledifferences were detected between the controls and the animals in the treatment groups up to and including group III
- Gross-pathological and histopathological findings
necropsy and histopathological examination did not reveal toxicologically relevant effects up to and including group III
- Gravimetric organ findings
there was an increase in absolute and relative liver weights in males of group III

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 40 - < 200 mg/kg bw/day (nominal)
Sex:
male/female
Dose descriptor:
LOEL
Effect level:
>= 200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: repeated vomiting and salivation, increased N-Demethylase values; for group III (500-1000mg/kg bw) uncoordinated movements, nasal discharge, lateral/prone position, and trembling, death

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

An unintentional intratracheal application might have been the cause for the effects in the lungs (severe bronchopneumonia in no. B 915/group III and acute edema in no. B 944/group III) leading to premature sacrificing or death of these two animals.

Applicant's summary and conclusion

Conclusions:
As there were only local effects and slightly increased N-DEM values in the absence of any other finding the NOAEL is established at 200 mg/kg bw/d
Executive summary:

To assess the subchronic toxicity of confidential substance namea subchronic test according toOECD Guideline for Testing of Chemicals No. 409 "Subchronic Oral Toxicity - Non rodent", adopted 12th of May 1981 was performed.

Therefore Groups of 4 male and 4 female beagle dogs per dosage were treated once daily by gavage over a period of 13 weeks with following daily oral doses:

Control group: 0 mg/kg b.w.

Group I : 40 mg/kg b.w.confidential substance name

Group II : 200 mg/kg b.w.confidential substance name

Group III : 1000 mg/kg b.w.confidential substance name

From the second day of the study onwards, 1000 mg/kg were reduced to 800 mg/kg, and from the 4th day of the study onwards, 800 mg/kg were reduced to 500 mg/kg due to a markedly reduced health status of some group III-animals.

The official result in the report was:

Tests of the reflexes, body temperatures, pulse rates, blood pressure, and heart rates showed no changes up to and including group III. The same holds true for the electrocardiograms . The nutritional state, feed intake, and body weight gain also yielded no adverse effects up to and including group III. Clinical observations evidenced repeated vomiting and salivation from group II upwards. Additional effects in group III consisted of uncoordinated movements, nasal discharge, lateral/prone position, and trembling. All these effects from group II upwards are considered to be due to treatment with the test compound. Animal no. B 915/group III had to be sacrificed on day 3 of the study showing lateral position, flat breathing, and bloody faeces before sacrificing, and animal no. B 944/group III died in week 7 of the study exhibiting lateral position, bloody nasal and oral discharge before death. Due to the lung findings observed in the histopathological investigations, these two events might be associated with an unintentional intratracheal application.

Ophthalmoscopy showed a lens cataract in one animal of group III. This effect is seen to be treatment-related. Haematology and Differential blood counting showed no changes up to and including group III. Clinical chemistry evidenced a substance-related elevation of APh-values in group III. Increased N-Demethylase values from group II upwards and increased Cytochrome P450-values in group III are seen as treatment-related effects giving evidence for an increased metabolic activity in the liver. In this context the increased liver weights in males of group III are also considered to be treatment-related. Urinalyses showed no changes up to and including group III. Necropsy and histopathological examination did not reveal toxicologically relevant effects up to and including group III. Besides increased liver weights in males of group III (see above), no changes in organ weights were detected up to and including group III.

The author followed that based on the reported effects it can be concluded that 40 mg/kg Testsubstance administered orally by gavage to beagle dogs daily over a period of 13 weeks were tolerated without adverse effects.

In contrast to this conclusion the applicant assessed to effects observed as follow:

The NOEL at 40 mg/kg bw/d (0.4%) reported is based on local effects caused by oral application of the test substance at irritating concentrations (≥2%). At 200 mg/kg bw/d clinical chemistry revealed only slightly increased N-DEM values in the absence of any other finding. The increase of this parameter is an indication for a minimal liver enzyme induction but not for an adverse effect.Therefore the NOAEL is established at 200 mg/kg bw/d