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
Study period:
1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles.

Data source

Reference
Reference Type:
other: study report, used in EPA assessment
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
none

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
groups of 10 male and 10 female Sprague Dawley rats were administered via gavage 0, 50, 200, or 600 mg/kg 1,3,5-TMB in corn oil 5 days/week for 90 days. An additional group of rats (10/sex) were administered 600 mg/kg 1,3,5-TMB for 90 days and retained without treatment for 28 days.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days and 90 days with 28 day recovery
Frequency of treatment:
once a day; 7 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 200, or 600 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Groups of 10 male and 10 female Sprague Dawley rats were administered via gavage 0, 50, 200, or 600 mg/kg 1,3,5-TMB in corn oil 5 days/week for 90 days. An additional group of rats (10/sex) were administered 600 mg/kg 1,3,5-TMB for 90 days and retained without treatment for 28 days.
Positive control:
none

Examinations

Observations and examinations performed and frequency:
Physical examinations, clinical observations, opthamological examinations, body weights, food consumption, hematological and clinical chemistry, organ weights, and gross and histopathology were assessed.

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):
not examined
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
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No Deaths were recorded. Abnormal clinical observations consisted of discolored and/or wet inguinal fur and salivation in the highest dose group of both sexes.

BODY WEIGHT AND WEIGHT GAIN
A non-significant decrease in cumulative body weight gain (11 percent lower than controls) was observed for the high dose males.

CLINICAL CHEMISTRY
Clinical chemistry parameters were ascertained at 30 days post-dosing and at the end of the 28-day recovery period. At the 30-day time point, statistically significantly affected parameters in treated animals versus controls consisted of increased albumin levels and albumin/globulin ratio, decreased globulin and cholesterol levels in high dose males; decreased cholesterol levels in mid dose males; and decreased blood urea nitrogen levels in high dose females. At the termination of dosing, significantly affected parameters occurred only in the high dose group. These consisted of increased alkaline phosphatase and phosphorus levels and decreased glucose levels in high dose males, and increased cholesterol and phosphorus levels and decreased sodium and chloride levels in high dose females. The 30-day differences were not considered treatment-related since they were not present post-dosing. The post-dosing differences, with the exception of increased serum phosphorus levels, were either within normal parameters or due to high values in two individual animals and were not statistically significant. The increased serum phosphorus levels were considered treatment-related but these effects were reversible with in the post-dosing recovery period.

GROSS PATHOLOGY
No abnormalities were noted to be treatment related

Effect levels

Dose descriptor:
NOAEL
Effect level:
600 mg/kg bw/day (actual dose received)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on a lack of adverse effects at the highest dose level (reversible effects such as increased serum phosphorus levels and liver and kidney weights), the no-observed-adverse-effect level (NOAEL) for this study is therefore considered to be 600 mg/kg-day.
Executive summary:

In the subchronic study on the oral toxicity of 1,3,5-TMB, groups of 10 male and 10 female Sprague Dawley rats were administered via gavage 0, 50, 200, or 600 mg/kg 1,3,5-TMB in corn oil 5 days/week for 90 days. An additional group of rats (10/sex) were administered 600 mg/kg 1,3,5-TMB for 90 days and retained without treatment for 28 days. Based on a lack of adverse effects at the highest dose level (reversible effects such as increased serum phosphorus levels and liver and kidney weights), the no-observed-adverse-effect level (NOAEL) for this study is therefore considered to be 600 mg/kg-day.