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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
Study period:
15 Feb - 24 May 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Y-15866
- Physical state: clear colourless liquid
- Analytical purity: 72%
- Lot/batch No.: 3710-10
- Expiration date of the lot/batch: 2013-07-16
- Storage condition of test material: at room temperature (20 ± 5 °C) and light protected
- Other: Correction for purity: 1.389

Test animals

Species:
rat
Strain:
other: RccHanTM: WIST
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days and 14 days post-exposure observation period (satellite control and test groups)
Frequency of treatment:
once daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 (main study)
5 (satellite control and high dose groups)
Control animals:
other: yes, bidistilled water at the same dose volume as the high dose group

Results and discussion

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
LOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: reduced absolute and relative adrenal weights (non-adverse)
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on food consumption, body weights, haematology, clinical chemistry, histopathology; reduced absolute and relative adrenal weights (f, non-adverse)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

All animals survived the scheduled treatment and recovery periods. No test item-related clinical signs were noted at the daily observations and no findings were observed at the detailed behavioural observations. No findings were evident at the functional observational battery performed during the fourth week of treatment. No test item-related changes in urinalysis parameters were evident. In males and females, slightly reduced food consumption was noted at 300 and 1000 mg/kg bw/day, which correlated with a decrease in body weight gain and mean body weights in both sexes at the respective dose levels. In haematology parameters, significantly decreased haematocrit was noted in males and increased mean corpuscular volume in females at 1000 mg/kg bw/day. Several plasma clinical chemistry parameters were statistically significantly altered after treatment with 1000 mg/kg bw/day in males (increased triglyceride and alanine aminotransferase (ALAT), decreased calcium, protein, albumin and globulin levels) and females (decreased protein, globulin and urea levels, increased albumin/globulin ratio and chloride levels). At necropsy, no macroscopic findings related to treatment were observed. At 300 and 1000 mg/kg bw/day, reduced absolute and relative thymus weights in males and females, which were not fully reversible at the end of recovery were observed. In females of all dose groups, reduced absolute and relative adrenal weights were seen. Although no clear dose-response was noted, this finding was considered to be test item-related, as the reduction in organ weights persisted up to the end of recovery and reached statistical significance at 1000 mg/kg/day. Histopathological examination revealed treatment-related adverse effects on urinary bladder as observed by transitional cell hyperplasia and inflammatory cell infiltration in all males treated with 300 and 1000 mg/kg bw/day as well as in one female at 300 mg/kg bw/day and four females at 1000 mg/kg bw/day.

Applicant's summary and conclusion

Conclusions:
Based on the results of the subacute toxicity study, the NOAEL for Y-15866 in male and female rats was established at 100 mg/kg bw/day.
Executive summary:

In a 28-day oral toxicity study according to OECD guideline 407 and GLP, Y-15866 was administered undiluted once daily by gavage to 5 Wistar rats per sex and group at dose levels of 100, 300 and 1000 mg/kg bw/d, respectively. A control group of 5 male and 5 female animals received bidistilled water as control. Additional 5 rats per sex in the control group and 1000 mg/kg bw/day dose group were treated for 28 days and then allowed a 14-day treatment-free recovery period. All animals survived the scheduled treatment and recovery periods. No test substance-related clinical signs were noted at the daily observations and no findings were observed at the detailed behavioural observations. In males and females, slightly reduced food consumption was noted at 300 and 1000 mg/kg bw/day, which correlated with a decrease in body weight gain and mean body weights in both sexes at the respective dose levels. In haematology parameters, significantly decreased haematocrit was noted in males and increased mean corpuscular volume in females at 1000 mg/kg bw/day. Several plasma clinical chemistry parameters were statistically significantly altered after treatment with 1000 mg/kg bw/day in males (increased triglyceride and alanine aminotransferase (ALAT), decreased calcium, protein, albumin and globulin levels) and females (decreased protein, globulin and urea levels, increased albumin/globulin ratio and chloride levels). At necropsy, no macroscopic findings related to treatment were observed. At 300 and 1000 mg/kg bw/day, reduced absolute and relative thymus weights in males and females, which were not fully reversible at the end of recovery were observed. In females of all dose groups, reduced absolute and relative adrenal weights were seen. Although no clear dose-response was noted, this finding was considered to be test item-related, as the reduction in organ weights persisted up to the end of recovery and reached statistical significance at 1000 mg/kg/day. Histopathological examination revealed treatment-related adverse effects on urinary bladder as observed by transitional cell hyperplasia and inflammatory cell infiltration in all males treated with 300 and 1000 mg/kg bw/day as well as in one female at 300 mg/kg bw/day and four females at 1000 mg/kg bw/day. After recovery, these findings were found to be irreversible in male and female animals treated with 1000 mg/kg bw/day. Based on the study results, the NOAEL for rats was established at 100 mg/kg bw/day.