Trimethyl-3-[(1-oxo-10-undecenyl)amino]propylammonium methyl sulphate

Endpoint summary

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

Reference

Reference 1

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

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study 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 or test system 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:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: neoplastic

histopathology: non-neoplastic

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

water consumption and compound intake

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).

Reference 2

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

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study 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 or test system 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.