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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study obtained through inquiry process; SNIF file obtained from ECHA.

Data source

Reference
Reference Type:
other: SNIF
Title:
Unnamed
Year:
1992

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
A mixture of: esters of C14-C15 branched alcohols with 3,5-di-t-butyl-4-hydroxyphenyl propionic acid; C15 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate; C13 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate
EC Number:
413-750-2
EC Name:
A mixture of: esters of C14-C15 branched alcohols with 3,5-di-t-butyl-4-hydroxyphenyl propionic acid; C15 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate; C13 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate
IUPAC Name:
413-750-2
Constituent 2
Reference substance name:
reaction mass of: esters of C14-C15 branched alcohols with 3,5-di-t-butyl-4-hydroxyphenyl propionic acid; C15 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate; C13 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate
IUPAC Name:
reaction mass of: esters of C14-C15 branched alcohols with 3,5-di-t-butyl-4-hydroxyphenyl propionic acid; C15 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate; C13 branched and linear alkyl 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoate
Test material form:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
not specified

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 d
Frequency of treatment:
Dosing regime: 7 days/week
No. of animals per sex per dose:
- Male: 10 animals at 10 mg/kg bw/day
- Male: 4 animals at 100 mg/kg bw/day
- Male: 5 animals at 1000 mg/kg bw/day
- Female: 10 animals at 10 mg/kg bw/day
- Female: 4 animals at 100 mg/kg bw/day
- Female: 5 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
Throughout the study period no clinical changes were observed in animals of either sex which received the low or the intermediate dosages of the test substance (10 or 100 mg/kg/day).
With the high dose of the test article (1000 mg/kg/day) episodes of salivatioin were observed just after treatment in some rats of both sexes starting from the third week of the study onwards. This symptom, which generally lasted a few minutes after each dosing, was no longer observed after discontinuation of treatment.
No other clinical changes were seen in any groups including the controls.

BODY WEIGHT AND WEIGHT GAIN
Body weights of both males and females were found to have been unaffected by the oral administration of the test substance up to and including the highest dosage administered of 1000 mg/kg/day.
At the statistical analysis of body weight data no significant variations emerged between the treated and control groups at any dose.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No treatment-related changes in food consumption were seen during the study period in any group of either sex. Statistical analysis only revealed an incidental statistically significant decrease in food intake as compared to controls, in males of the lowest dosage group; this change, which was slight in degree, appeared to be confined to the 2nd week of dosing. No other significant variations were seen at any time.

OPHTHALMOSCOPIC EXAMINATION
No eye changes were seen in any of the animals tested.

HAEMATOLOGY
No variations of toxicological relevance were seen at hematology tests in either sex at any dose, after 4 weeks of treatment.

CLINICAL CHEMISTRY
No treatment-related changes in blood chemistry parameters were seen at the end of the dosing period in animals of either sex which received the low and intermediate dosage of the test article.
For these groups only incidental slight variations from control data i.e. increase in urea serum levels for males of group 3 and decrease iin alkaline phosphatase activity for females of group 2 were highlighted by the statistical analysis.
At the highest dosage tested the only slight effect was a trend towards a decrease in the glucose serum levels which involved both sexes. This change did not achieve the statistical significancy. No other variations were seen.
At the end of the withdrawal period the above modification in the glucose serum levels were no longer observed in the recovered groups.
An incidental statistically significant increase in creatinine values was seen in the recovered females.

URINALYSIS
Evaluation of urine parameters statistically examined performed at the end of the administration period did not reveal major variations between the treated and control groups of either sex. Only a slight increase in the specific gravity, as compared to control data, was noted in ANOX BF-dosed males of all groups.
At the semiquantitative analysis and microscopic examination of the sediment a slight increase in frequency of leukocytes, compared to controls, was observed in individual males and females of the high dosed group.
On discontinuation of treatment a slight increase in frequency of Leukocytes was still evident at the semiquantitative analyses in some males of the recovered group.
No notable changes were seen for females.

ORGAN WEIGHTS
The only observed modification of compound-related origin was a slight increase in absolute and relative mean weights of liver in group 4 males and females killed at the end of the treatment period, statistically significant in males. A very slight trend to increase was also present in group 3 animals. However ail these changes were characterized by individual values comprised in the range of control rats of the same age and strain used in other experiments.
Group 4 females killed at the end of the recovery period had mean relative liver weights significantly higher than controls: this change was considered of incidental origin because all individual values fell within the normal variability of control rats of this age, and was considered mainly caused by the final fasting body weight in group 4 that was slightly lower than that of the controls.
No changes were noted in males at the end of the recovery period.
No other differences induced by treatment were noted at either periods.
In particular, the statistically significant decrease in mean relative weight of pituitary seen in group 3 males at the final killing was of incidental origin because it was unrelated to the dosage.

GROSS PATHOLOGY
No changes induced by treatment were noted at either killings.
All the observed modifications were of incidental origin, not infrequently presen in control rats of this age. They were slight aspects of incidental spontaneous pathology, as gastric glandular mucosa erosion, congestion in various organs and increase size of mandibular iymph nodes, or aspects of various estrual phases in females (ovarian cyst, fluid within the uterine lumen, with increased size).

HISTOPATHOLOGY:
Treatment induced hepatic centrilobular hypertrophy in males and females of group 4 and in males of group 3. This change was generally slight and was dosage related in males for degree (in one male of group 4 it was moderate) and diffusion (in group 4 it appeared generally diffuse, while in group 3 centrilobular hypertrophy was multifocal).
Complete recovery was achieved after the withdrawal period.
No other compound-related modifications were observed.
All other variations were generally seen with similar frequency and degree in treated and control rats, and/or are not infrequently seen in rats of the same age used as controls in other trials in our Laboratory.
Among the most frequent spontaneous pathology were inflammatory aspects of various organs and tissues, vacuolation consistent with fatty change in the liver and renal tubules, hematopoiesis in the spleen, basophilia of renal tubules, foci of degeneration with or without inflammation in the heart and gastric glandular mucosa erosions.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL = 1000 mg/kg bw/day
The test substance, when daily administered to Sprague Dawley rats by oral route for 4 weeks, was on the whole well tolerated up to and including the highest dosage administered because no signs of toxicity were observed.
Executive summary:

The oral repeated dose toxicity of the structural analogue has been determined in a subacute GLP study with rats (3 groups of males and 3 groups of females) according to EU Method B.7 (28-days, 7 days a week, of oral gavage exposure at doses of 10, 100 and 1000 mg/kg bw/d).

The test substance was on the whole well tolerated up to and including the highest dosage administered because no signs of toxicity were observed. The most important change, which proved reversible, was a slight hypertrophy of hepatocytes in rats treated with 1000 and 100 mg/kg/day, which was considered of adaptative origin. At 100 mg/kg/day these signs were mostly limited to males. A NOEL of 10 mg/kg bw/day and a NOAEL of 1000 mg/kg bw/day have been determined. Since EC 700-397-7 is a near analogue to the test substance (EC 413-750-2), the experimental data from this substance were used in a read-across approach.