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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study with GLP
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
Unnamed
Year:
2000
Reference Type:
other company data
Title:
Unnamed
Year:
1997
Reference Type:
other: monograph provided by ECHA
Title:
Endpoint record:Repeated toxicity
Author:
ECHA
Year:
2010
Bibliographic source:
Document from ECHA

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Principles of method if other than guideline:
There is no need to add in this field.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
75 - 95% (typical 88%, verified by UV/visible spectrum, Infrared (IR) spectrum, Nuclear Magnetic Resonance (NMR), and Mass spectrum.)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Rat/Sprague Dawley Crl:CD

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
400
Details on oral exposure:
0, 15, 150, 1000 mg/kg/day for 28 consecutive days followed by a 14 day treatment free (recovery) period
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
28 consecutive days followed by a 14 day treatment free (recovery) period.
Frequency of treatment:
0, 15, 150, 1000 mg/kg/day for 28 consecutive days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 15, 150, 1000 mg/kg/day
Basis:
no data
No. of animals per sex per dose:
5/sex/group; 3 test groups, 1 control group, 2 recovery groups (high dose and vehicle)
Control animals:
yes
Details on study design:
Nothing to add in this field.
Positive control:
no data

Examinations

Observations and examinations performed and frequency:
Clinical Observation
YES
Clinical Chemistry/Haematology: yes
Blood chemistry:ALT,AST
Urinalysis:urine volumes, urine specific gravity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Nothing to add in this field.
Statistics:
no data

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):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
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 observations
There were no deaths during the study period.One control male developed a scab in the dorso-cervical region from day 7 to day 16, which
was attributed to injury. A female in the 150 mg/kg/day group had clinical signs including hunched posture and pilo-erection but these were not considered to be treatment-related since these effects were not detected at 1 000 mg/kg/day.
Clinical Chemistry/Haematology
Blood chemistry
A statistically significant reduction or increase in alanine amino transferase (ALT) was detected in males at 15 or 150 mg/kg/day, respectively, compared with controls. In the absence of adverse effects at the high dose level of 1000 mg/kg/day, and that the values were within the normal range for this strain of rat, these findings were not considered to be treatment-related.
Males treated with 15 or 1000 mg/kg/day also showed a statistically significant reduction in aspartate amino transferase (AST). As these levels were also in the normal range, they were not considered to be toxicologically important.

Urinalysis
Recovery 1000 mg/kg/day females showed a statistically significant reduction in urine volumes and increase in urine specific gravity compared with controls. Since no such changes were detected following 28 days of treatment, they were not considered to be toxicologically important.

Organ weights
The statistically significant increases in absolute ovary weight detected for females treated with 1000 or 150 mg/kg/day and the reduction in absolute liver weight detected in recovery 1000 mg/kg/day females were not reflected in the relative weights. These effects were therefore not considered to be treatment-related.

Necropsy
The incidental findings recorded for one recovery control male and one non-recovery control female, identified as hydronephrosis of the right kidney or dark patches on all lobes of the lung, respectively, showed no dose-response relationship and were consistent with normally expected low findings for this strain of rat. These effects were therefore not considered to be treatment-related.

Histopathology
The reported microscopic cardiac, hepatic and renal findings were consistent with normally expected low findings for this strain of rat. There were also microscopic changes in the lung of one non-recovery female, associated with macroscopic findings and more probably representing an artefactual, procedure-related lesion. These effects were therefore not considered to be treatment-related.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Oral administration of the chemical to rats for a period of 28 consecutive days at dose levels up to 1000 mg/kg/day produced no treatment-related changes in the parameters measured.

Result: The test chemical was considered to have a “No Observed Adverse Effect Level” (NOAEL) of 1000 mg/kg/day.

Applicant's summary and conclusion

Conclusions:
The results of the study allowed an NOAEL of 1000 mg/kg/day (highest dose tested) to be clearly established.
Executive summary:

In a 28-day repeat dose oral toxicity study in rats there were statistically significant findings related to clinical chemistry, organ weight parameters, and macroscopic and microscopic changes in the kidney and lung. However, the findings were not dose-related and were

considered not to be treatment-related.