Registration Dossier

Administrative data

Description of key information

The NOEL in a 90 day sub-chronic dietary study in the rat was 3000 ppm. The NOEL in a 90 day sub-chronic study with a similar substance (methyl trimethyl-3-[(1-oxododecyl)amino]propylammonium sulphate) in the dog was 75 mg/kg (top dose limited by the palatability of the substance in the diet).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Remarks:
The study is very similar to a standard guideline study. However it was conducted prior to OECD guideline and GLP. No analysis of test substance in diet was conducted. There was no statistical analysis of the results. Full details of the study are not reported.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
No ophthalmological examination and no functional observations. Limited haematology, clinical chemistry and pathology.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Carworth Farms, Rockland, NY
- Weight at study initiation: Average body weight for both sexes of 42g
- Housing: Individual cages
- Water (e.g. ad libitum): Ad libidum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 73
- Humidity (%): 40-60
- Air changes (per hr): 10

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Wayne Lab-Blox of Allied Mills Inc, Chicago, Illinois

Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
Continuosly in diet
Remarks:
Doses / Concentrations:
3000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1500 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
750 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
20 males and 20 females
Control animals:
yes, plain diet
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule for examinations: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule for examinations: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 45 and 90 days
- How many animals: 5 males and 5 females
- Parameters examined: Haematocrit %, total haemoglobin concentration, total and differential leukocyte counts, RBC morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 45 and 90 days
- How many animals: 5 males and 5 females
- Parameters examined: urea nitrogen, alkaline phosphatase, glutamic oxaloacetic transaminase, fasting glucose

URINALYSIS: Yes
- Time schedule for collection of urine: 45 and 90 days
- Parameters examined: pH, specific gravity, glucose, protein, haemoglobin, presence of cells, casts and crystals

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
ORGAN WEIGHTS: Yes - thyroids, liver, kidneys, adrenals, testes
GROSS PATHOLOGY: Yes - skin, eyes, ears, mouth, fat, skeletal muscle, bone and marrow, salivary glands, thyroid, trachea, oesophagus, lung, heart, aorta, thymus, spleen, lymph nodes, pancreas, liver, stomach, small intestine, large intestine, caecum, adrenals, kidneys, urinary bladder, ovaries, testes, vagina, pituitary and brain
HISTOPATHOLOGY: Yes - skin, fat, skeletal muscle, bone and marrow, thyroid, parathyroid, trachea, oesophagus, lung, heart, aorta, spleen, pancreas, liver, stomach, small intestine, large intestine, adrenals, kidneys, urinary bladder, ovaries, testes, vagina, pituitary and brain
Statistics:
Not reported
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
There were no treatment related effects reported.
Dose descriptor:
NOEL
Effect level:
3 000 ppm
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Critical effects observed:
not specified
Conclusions:
There were no treatment related effects following dietary dosing of the substance for 90 days to rats. Therefore the NOEL is 3000 ppm (calculated to be approximately equivalent to 279 mg/kg for males and 293 mg/kg for females).
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Remarks:
The study is very similar to a standard guideline study. However it was conducted prior to OECD guideline and GLP. There was no statistical analysis of the results. Full details of the study are not reported.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents)
Deviations:
yes
Remarks:
No ophthalmological examination. Limited clinical observations, haematology, clinical chemistry and pathology.
GLP compliance:
no
Limit test:
no
Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Antec Corporation, Leesburg, Virginia
- Age at study initiation: 6 months
- Housing: Individual cages
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One month

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 73
- Humidity (%): 46-65
- Air changes (per hr): 10


Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The substance was incorporated into the diet then each dog was offered 30g/kg bw of basic diet, moistened with an equivalent amount of water containing the proper quantity of substance.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Daily for 90 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
75 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
25 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
10 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
4 males and 4 females.
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to initial feeding and after 12 weeks
- How many animals: All animals
- Parameters checked: haematocrit %, total haemoglobin concentration, total and differential leukocyte counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to initial feeding and after 12 weeks
- How many animals: All animals
- Parameters checked: blood urea nitrogen, alkaline phosphatase, glutamic oxaloacetic transaminase, fasting glucose

URINALYSIS: Yes
- Parameters checked: appearance, protein, sugar, WBC, RBC

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
ORGAN WEIGHTS: Yes - thyroids, liver, kidneys, adrenals, testes
GROSS PATHOLOGY: Yes - skin, eyes, ears, mouth, fat, skeletal muscle, bone and marrow, salivary glands, thyroid, trachea, oesophagus, lung, heart, aorta, thymus, spleen, lymph nodes, pancreas, liver, gall bladder, stomach, small intestine, large intestine, caecum, adrenals, kidneys, urinary bladder, ovaries, testes, vagina, pituitary and brain
HISTOPATHOLOGY: Yes - skin, fat, skeletal muscle, bone and marrow, thyroid, parathyroid, trachea, oesophagus, lung, heart, aorta, spleen, pancreas, liver, stomach, small intestine, large intestine, adrenals, kidneys, urinary bladder, ovaries, testes, vagina, pituitary and brain
Statistics:
Not reported
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:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
There were no treatment related effects reported.
Dose descriptor:
NOEL
Effect level:
75 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: The top dose used in the study was limited by palatability
Critical effects observed:
not specified
Conclusions:
There were no treatment related effects following dietary dosing of the substance for 90 days to dogs. Therefore the NOEL is 75 mg/kg. The dose level was limited by the palatability of the substance in the diet.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
286 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Sufficient to meet data requirements. The study is Klimisch 2.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are two 90 day sub-chronic studies available on a structurally related substance (methyl trimethyl-3-[(1-oxododecyl)amino]propylammonium sulphate; CAS 10595-49-0), in the rat and dog. There were no treatment related effects in a 90 day sub-chronic feeding study in the rat at doses of up to 3000 ppm in diet (calculated to be approximately equivalent to 279 mg/kg for males and 293 mg/kg for females). Similarly there were no treatment related effects in a 90 day sub-chronic feeding study in the dog at doses of up to 75 mg/kg (top dose limited by the palatability of the substance in the diet). Both of the individual studies have limitations, for example they both precede standard protocol guidelines and GLP. In addition some aspects of the investigations are limited compared to current protocol standards. However taken together they provide a consistent picture of absence of repeated dose toxicity for this substance.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two studies are available, both on a structural analogue. The selected study was conducted in the rat and there is a larger toxicology database available in the rat. In addition the dose levels in the dog study were limited by the palatability of the substance in the diet rather than by toxicity.

Justification for classification or non-classification

No treatment related effects were seen in 90 day sub-chronic studies in both the rat and the dog. Therefore there is no justification for classification of the substance for repeated dose toxicity.