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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Results based on OECD SIDS on tetramethylammoniumhydroxide (April 2006), which is considered to be peer-reviewed.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tetramethyl ammonium hydroxide 20.19%
- Physical state: aqueous solution
- Lot/batch No.: 81029

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 5 weeks
No further details are given on animals or environmental conditions.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
aqueous solution
Details on oral exposure:
Volume: 10 ml/kg
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
5, 10, 20 mg/kg bw/ day
Basis:
actual ingested
No. of animals per sex per dose:
5 (5 and 10 mg/kg bw), 10 (0 and 20 mg/kg bw)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Not reported
- Rationale for selecting satellite groups: Not reported
- Post-exposure recovery period in satellite groups: 14 days (0 and 20 mg/kg bw)

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: not reported

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not reported

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to dosing, on Day 5, and twice a week thereafter.

FOOD CONSUMPTION: YES
- Food consumption was monitored

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: right before autopsy
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: not reported
- Parameters examined: no details reported

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: right before autopsy
- Animals fasted: No
- How many animals: not reported
- Parameters examined: no details reported

URINALYSIS: Yes
- Time schedule for collection of urine: Collected for 4 and 24 hours in the 4th week of the administration period and the 2nd week of the recovery period.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: no details reported

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, organ weights of heart liver and kidney were determined. No data on other organs.
HISTOPATHOLOGY: Yes
Histopathological examinations by hematoxylin eosin staining were carried out on heart, liver, kidneys, spleen, adrenals, stomach, testes, epididymis and ovary of all the animals in the control and high dose groups, and on all gross lesions of all animals. Because treatment-related changes were observed in the kidney of male rats, histopathological examination was further performed on the kidney of all the male animals in the low and middle dose groups.
Statistics:
Dunnett's test, Student's t-test, Aspin-Welch t-test,Mann-Whitney U-test, Fisher test

Results and discussion

Results of examinations

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):
effects observed, treatment-related
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality was observed. On the 6th day of administration and later, incidences of salivation were found in males and females at 10 and 20 mg/kg bw/day.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
A significant decrease in food consumption was observed in the 1st week of administration in male animals at 10 mg/kg bw/day, and male and female animals at 20 mg/kg bw/day. A significant increase in food consumption was observed in the 1st week of the recovery period, however, in the male animals at 20 mg/kg bw/day. The decrease in food consumption was considered to be related to the alkalinity of the substance.

URINALYSIS
There were no treatment-related changes observed in urinalysis, but a significant increase in urinary electrolyte excretion was noted in the 2nd week of the recovery period in the male animals at 20 mg/kg bw/day.

ORGAN WEIGHTS
Decreases were observed in the heart weights in male animals: a significant decrease in the absolute weights at 5 mg/kg bw/day and higher and that in the relative heart to body weights at 10 mg/kg bw/day and higher. The effect was not clearly dose-dependent. On the other hand, no treatment-related changes in organ weights were observed in female animals at any doses at the end of administration or male and female animals at the end of the recovery period. As no histopathology was observed, for now the decrease in heart weight is considered to be not toxicologically relevant, awaiting further data.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on decreases in food consumption seen at 10 mg/kg bw.
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on decreases in food consumption seen at 20mg/kg bw/day in females.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a 28-days oral repeated dose exposure assay, the NOAEL was established to be 5 (males) and 10 (females) mg/kg bw/d.
Executive summary:

A 28-days oral repeated dose experiment was conducted according to OECD guideline 407 and GLP principles. No deaths were observed at the concentrations tested (5, 10 and 20 mg/ kg bw/d). A significant decrease in food consumption was observed in the first week of administration in male animals at 10 mg/kg bw/day, and male and female animals at 20 mg/kg bw/day. A decreased absolute and relative heart weight without dose-response and no correlated histopathological findings was observed at 10 mg/kg bw/day and higher in males only. This effect was not seen at the end of the recovery period. Therefore, this effect was not considered to be toxicologically relevant for the time being, awaiting further data.

The NOAEL for repeated dose oral toxicity was considered to be 5 mg/kg bw/day for males and 10 mg/kg bw/day for females.