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Description of key information

Two repeated dose toxicity studies are available, a 28-day and a 90-day dietary study in rats at dose levels up to the limit dose of 1000 mg/kg body weight per day. No treatment related adverse effects were observed in both studies up to the highest dose tested. The NOAEL is consequently > 1000 mg/kg bw. The studies confirm the low bioavailability of the substance as also demonstrated in the toxicokinetic study. Due to the low water and anticipated low lipid solubility it can reasonably assumed that the substance is unlikely to exert adverse effects by other routes of exposure or studies of longer duration. Due to the absence of effects at the limit dose of 1000 mg/kg bw in both repeated dose and developmental toxicity studies, the derivation of DNEL values for repeated dose toxicity is not warrantend according to the ECHA guidance on information requirements, Part B, version 2.1, 2011.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was performed prior to international guidelines and GLPs. The parameters investigated largely conform to current methodologies. The lack of adverse effects is consistent with the lack of toxicity observed in modern prenatal developmental studies in 2 species.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
daily for 90 days followed by 46 d recovery period
Frequency of treatment:
daily in the feed for 90 days followed by 46 d recovery period
Remarks:
Doses / Concentrations:
0, 0.01, 0.1, 1% of the diet
Basis:
nominal in diet
No. of animals per sex per dose:
15/sex/group
Control animals:
yes, concurrent no treatment
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):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
dermal irritation
body weight and weight gain
food consumption and compound intake
food efficiency
water consumption and compound intake
haematology
clinical biochemistry
urinalysis
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology
neuropathology
histopathology: non-neoplastic
histopathology: neoplastic
other:
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
1 ppm
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
no

See attached background material for Tables of Results.

Conclusions:
The 90-day NOEL was 1% of the diet or approximately 1000 mg/kg bw.
Executive summary:

EBTBP was administered to four groups of Sprague Dawley rats (n=15/sex/group) at 0, 0.01, 0.1 and 1.0% of the diet for 90 days followed by 46 days during which the rats were fed control diet. No changes in hematology or serum chemistry values related to treatment were detected on study days 0, 45, 92. No effect of treatment was found on urinalysis (d 0, 45 and 90). The mean relative and absolute organ weights of the liver, kidney, heart, and thyroids from the control and 1.0% groups were statistically comparable. Several animals died on test from non-test article related causes (most deaths were related to collection of blood for hematology and serum chemistry evaluations).  Gross necropsy from animals dieing on test and sacrificed on days 92, 134, 135 and 136 revealed no test article-related gross lesions. No test article related lesions were detected on histopathology. The 90-day NOEL was 1% of the diet. This is estimated to be ~ 1,000 mg/kg/d using the assumption of consumption of 25 g diet per 250 g rat per day. This study was performed prior to the adoption of Good Laboratory Practices or EPA/OECD guidelines. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The overall data base with a subacute, a subchronic, two developmental toxicity studies in two species as well as a toxicokinetic study allows the conclusion that the substance has a low hazard potential after repeated exposure.

Additional information

Two repeated dose toxicity studies are available, a 28-day and a 90-day dietary study in rats at dose levels up to the limit dose of 1000 mg/kg body weight per day. No treatment related adverse effects were observed in both studies up to the highest dose tested. The NOAEL is consequently > 1000 mg/kg bw. The studies confirm the low bioavailability of the substance as also demonstrated in the toxicokinetic study. Due to the low water and anticipated low lipid solubility it can reasonably assumed that the substance is unlikely to exert adverse effects by other routes of exposure or studies of longer duration. The substance is unlikely to have any local irritation effects as no indications of irritation were observed neither in the skin and eye irritation studies nor in the repeated dose studies. Due to the absence of effects at the limit dose of 1000 mg/kg bw in both repeated dose and developmental toxicity studies, the derivation of DNEL values for repeated dose toxicity is not warrantend according to the ECHA guidance on information requirements, Part B, version 2.1, 2011.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The repeated dose study of longest duration was selected. it is corroborated by the 28-day study as well

Justification for classification or non-classification

Due to the absence of any adverse effects in the repeated dose studies, no classification for repeated dose toxicity is warranted.