Quaternary ammonium compounds, benzyl C12-C16 (even numbered)-alkyldimethyl chlorides

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-benzyl-N,N-dimethyltetradecan-1-aminium chloride

EC Number:

939-253-5

Cas Number:

68424-85-1

Molecular formula:

C12-14H25-29-(CH3)2-C6H5-N.Cl

IUPAC Name:

N-benzyl-N,N-dimethyltetradecan-1-aminium chloride

Constituent 2

Reference substance name:

Water

EC Number:

231-791-2

EC Name:

Water

Cas Number:

7732-18-5

Molecular formula:

H2O

IUPAC Name:

water

Test material form:

liquid

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Continuous

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 500, 1500 and 3000 ppm of test substance (or 0, 250, 750 or 1500 ppm a.i.) in the diet. From week 8, the concentration of the test substance was reduced to 1250 ppm in the high-dose female group, due to low food intake among these animals.

The mean achieved dosages of active substance, based on food consumption and body weight information were as follows:
males: 0, 8, 25 and 50 mg/kg bw/day
females: 0, 9, 26 and 45 mg/kg bw/day

Doses were chosen on the basis of results obtained in a 2phases range finding study (500, 1000, 2000 and 5000 ppm of the test substance for 4 days, then 2000 ppm (corresponding to 43-53 mg a.s. /kg bw/day) for 14 days. At 2000 and 5000 ppm in the 1st phase and at 2000 ppm in the 2nd one, a marked to moderate reduction of food consumption was reported throughout the study. In addition some haematological parameters were modified, very likely as consequence of reduced food consumption.
A GLP- and TG-compliant 28-day dietary toxicity study is also available: dogs were treated with 500, 1000 and 2000 ppm of the test substance, corresponding to 8.4, 16.9 and 35.3 mg a.s./kg bw/day in males and slightly higher values in females. In this study, no significant effects on food consumption and body weight were recorded at all the dose tested, neither any other relevant effects attributable to the treatment.

No. of animals per sex per dose:

4 males and 4 females per dose group

Control animals:

yes, plain diet

Details on study design:

Post-exposure period: none

Examinations

Observations and examinations performed and frequency:

Observations included: Clinical signs, mortality, body weight, food consumption, Ophthalmology, haematology, clinical chemistry and urinanalysis.

Sacrifice and pathology:

Pathology of all animals (organ weight, gross pathology) and histopathology on the control and high dose animals.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

One out of 4 female dogs in the high dose group (1500 ppm) showed emaciated appearance and soft faeces. No other clinical signs were attributed to treatment with the test isubstance.

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A mean body weight loss was noted in females from the high-dose group when given 1500 ppm a.i. of the test substance (19% less than the corresponding control, statistically significant value). Among the females of that dose group a body weight loss (-27%) was reported, being correlated to the decrease of food consumption. When the dosing was reduced to 1250 ppm a.i., a mean body weight gain similar to that noted in the control females was recorded.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In the 250 and 750 ppm dose group, the food consumption was uneffected in males and females. A markedly lower (-27 %) food consumption was noted in females at the high dose group of 1500 ppm. After reduction of the dose-level to 1250 ppm test substance, the food consumption was only slightly lower (-6 %).

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no treatment related findings.

Haematological findings:

no effects observed

Description (incidence and severity):

No variations in hematology that could be ascribed to the treatment with the test substance

Clinical biochemistry findings:

not examined

Description (incidence and severity):

Slightly lower mean protein (54 g/L vs 58 g/L in controls) and cholesterol levels (2.2 mmol/L vs. 3.7 mmol/L in controls) were noted in females from the high-dose group when given 1500 ppm a.i., consistently with the decrease of food intake. These differences were no longer recorded at the end of the treatment period (after dose reduction). No other variations in blood chemical parameters could be ascribed to the treatment with the test substance.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related findings among the qualitative or quantitative parameters in week 7 or at the end of the treatment period.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No treatment-related effects on organ weights were noted. Differences in organ weights were slight, not dose-related, often of opposing trends in the different groups and sexes, and were without relevant histopathological abnormalities, they were considered to be of no toxicological importance. The differences in the genital organs were mainly due to the variations in sexual maturity in the males and in the different phases of the estrous cycle in the female dogs. Consequently, they were also considered to be of no toxicological importance.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No relevant findings.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

No signs indicative of toxicity were observed in any dose group.
The mean achieved dosages of the test substance, remained stable during the study in all groups and increased in a dose-proportional manner. Based on food consumption and body weight information, the dose levels for 0, 250, 750 and 1500 and/or 1250 ppm of the test substance were as follows:
males: 0, 8, 25 and 50 mg a.i./kg/day females: 0, 9, 26 and 45 mg a.i./kg/day

No unscheduled deaths occurred during the study. No treatment-related clinical signs were observed. There was no direct effect of treatment with the test substance on the body weight. No treatment-related ophthalmological findings, no treatment-related relevant differences in hematology and blood biochemistry, no urinary findings among qualitative or quantitative parameters, no effects of toxicological importance on organ weights, no treatment-related necropsy or microscopic findings were observed at any of the dose groups.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 3 000 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No toxicologically significant effect

Remarks on result:

other: equivalent to 1500 ppm a.i.

Remarks:

equivalent to 50 mg a.i./kg bw/day

2

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 2 500 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No toxicologically significant effect

Remarks on result:

other: equivalent to 1250 ppm a.i.

Remarks:

equivalent to 45 mg a.i./kg bw/day

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

For result tables, kindly refer to the attached background material section of the IUCLID.

Applicant's summary and conclusion

Conclusions:

Under the study conditions, the 90-d NOAEL for systemic effects in Beagle dogs was established at the highest adjusted test dose of 1500 or 1250 ppm a.i., corresponding to 50 or 45 mg a.i./kg bw/day, respectively)

Executive summary:

A 90-day study was conducted to determine the repeated dose oral toxicity of the test substance, C12-16 ADBAC (49.6% active in water) in Beagle dogs according to OECD Guideline 409, in compliance with GLP. The test substance was administered to four animals per sex per dose group at dietary doses of 0, 500, 1500 and 3000 ppm (i.e., equivalent to 0, 250, 750 or 1500 ppm a.i.). From Week 8, the concentration of test substance was reduced to 2500 ppm (i.e., 1250 ppm a.i.) in the high dose female group due to low food intake and reduced body weight among these animals (up to 20%). The mean achieved dosage of active substance, based on food consumption and body weight, were 0, 8, 25 and 50 mg a.i./kg bw/day for males and 0, 9, 26 and 45 mg a.i./kg bw/day for females. One out of 4 female dogs in the high dose group (1500 ppm a.i.) showed emaciated appearance and soft faeces. No other clinical signs were attributed to treatment with the test substance.Themean body weight gain were recorded to be similar to the control females following reduction of the high dose group to 1250 ppm a.i. Consequently, the prior effects on body weights at 1500 ppm a.i. were considered to be due to reduced palatability. Also, slightly lower clinical chemistry parameters (i.e., mean protein and cholesterol levels) were noted in females from the high-dose group when given 1500 ppm a.i., consistently with the decrease of food intake. These differences were no longer observed at the end of the treatment period and after dose reduction to 1250 ppm a.i. Under the study conditions, the 90-d NOAEL for systemic effects in Beagle dogs was established at the highest adjusted test dose of 1500 or 1250 ppm a.i., corresponding to 50 or 45 mg a.i./kg bw/day, respectively) (Guillaumat, 2006).