1,3-Propanediol, 2-methyl-, reaction products with ethenyltrimethoxysilane

Endpoint summary

Description of key information

NOAEL (subacute, rat) = 100 mg/kg bw/day (males and females)

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: RccHanTM: WIST

Sex:

male/female

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

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

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

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)

Critical effects observed:

yes

Lowest effective dose / conc.:

300 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

bladder

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

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.

Details from the histopathology report: “In main study, transitional cell hyperplasia was observed in 5 males (slight to moderate) and 4 females (minimal to moderate) of the high-dose group and 5 males (minimal to slight) and 1 female (minimal) of the mid-dose group. The incidence/ severity of the lesion increased dose dependently. Inflammatory cell infiltration (mostly composed of mononuclear cells) in the submucosa was observed in 5 males (slight) and 4 females (minimal to slight) of the high-dose group and 5 males (minimal to slight) and 1 female (minimal) of the mid-dose group. The incidence/ severity of the lesion increased dose-dependently. In recovery study, transitional cell hyperplasia was observed in 5 males (minimal to moderate) and 5 females (minimal) of the high-dose group. Minimal inflammatory cell infiltration in the submucosa was observed in 3 males and 4 females of the high-dose group.”

 

Incidence and Mean Severity Grade of Main Findings in Urinary Bladder

Finding	Group 1		Group 2		Group 3		Group 4
Main Study Animals	5 M-	5 F	5 M	5 F	5 M	5 F	5 M	5 F
Transitional cell hyperplasia	-	-	-	-	5/1.4	1/1.0	5/2.6	4/1.8
Inflammatory cell infiltration	-	-	-	-	5/1.2	1/1.0	5/2.0	4/1.8
Recovery Animals	5 M	5 F					5 M	5 F
Transitional cell hyperplasia	-	-					5/2.2	5/1.0
Inflammatory cell infiltration	-	-					3/1.0	4/1.0

 

 

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.

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

A reliable study is available (Klimisch 1).

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Two consecutive 7-Day range-finding gavage studies were performed in Wistar rats to determine suitable doses for treatment with the test substance Y-15866 in a subacute toxicity study (Simon, 2011). Based on the results of these preliminary tests, doses of 100, 300 and 1000 mg/kg bw/day were selected for the assessment of subacute toxicity in rats.

In a subsequent 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/day, respectively (Simon, 2011). 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 during the treatment period, which was considered to be test item-related. During recovery, food consumption increased again in all animals. The decline in food consumption during the study correlated with a decrease in body weight gain and mean body weights in both sexes at 300 and 1000 mg/kg/day and was considered to be of adverse nature. In haematology parameters, significantly decreased haematocrit was noted in males at 1000 mg/kg bw/day. The observed increase in mean corpuscular volume in females at this dose persisted up to the end of the recovery period. 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 bw/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. The changes in haematology and clinical biochemistry parameters as well as effects on organ weights of thymus and adrenal glands showed no correlation with macroscopic or microscopic findings and were not considered to be adverse. Based on the study results, the NOAEL for rats was established at 100 mg/kg bw/day.

It was considered that there were no urinary tract related clinical signs, there were no test item-related changes in urinalysis parameters and there were no test item-related macroscopic findings evident for the urinary tract.  Histopathological effects were observed only in the urinary bladder.  The changes observed in the urinary bladder during microscopic exam (transitional cell hyperplasia) are local (not systemic), generally slight or minimal to moderate and show tendency for reversibility (at the end of recovery the number of positive animals generally decreased, and the grading of severity decreased) and mononuclear infiltrates decreased. Taking this into account it is concluded that classification of Y-15886 with STOT RE 2 (urinary bladder as a target organ) is not warranted.

Justification for classification or non-classification

The available data on subacute toxicity of Y-15866 do not warrant classification STOT RE according to Regulation (EC) 1272/2008.