Amino functional alkoxysilanes

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2001.06.11 to 2001.07.16

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Test material

Test material information

Constituent 1

Test material form:

other: liquid

Test animals

Species:

rat

Strain:

other: HanBrl:WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd.
- Age at study initiation: 6 weeks
- Weight at study initiation: males 143-160g females 112-130g
- Housing: five per cage in Makrolon type-4 cages with wire mesh tops and standard softwood bedding (Lignocel)
- Diet: Pelleted standard Provimi Kliba rat maintenance diet (batch 07/00) ad libitum
- Water: Community tap water ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 11 June to 16 July 2001

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Prepared daily, Y-15167 weighed into a tared glass beaker and vehicle added. Mixture prepared using a magnetic stirrer and used at room temperature.

VEHICLE
- Concentration in vehicle: 0, 10, 40, 200 mg/mL
- Amount of vehicle (if gavage): 5mL/kg
- Lot/batch no.: 9.3.01 SCO / 7.3.01 SCO

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration, homogeneity and stability (after 2 hours) were determined at teh start of the study. Concentration and homogeneity also determined during Week 3 (according to NMR method)

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

Doses / concentrations 4

Dose / conc.:

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

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on results of non-GLP 5-day dose range finding study
- Rationale for animal assignment: random (computer-generated algorithm)

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily days 1-3, once daily thereafter

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 4
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All
- Parameters checked in table No. 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 4
- Animals fasted: Yes
- How many animals: All
- Parameters checked in table No.2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Week 4
- Dose groups that were examined: All
- Battery of functions tested: sensory activity, grip strength, motor activity

Sacrifice and pathology:

ORGANS WEIGHTS: Yes (see table 3)
GROSS PATHOLOGY: Yes (see table 4)
HISTOPATHOLOGY: Yes (see table 4)

Statistics:

The following statistIcal methods were used to analyze the body weight, organ weights and ralios. as well as clinical laboratory data:
• The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) was applied insteadof the Dunnett-test when the data could not be assumed to follow a normal distribution.
• Student's t-test was applied to grip strength and locomotor activity.
• Fisher's exact-test was applied to the macroscopic findings.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Description (incidence):

A male at 1000 mg/kg/day was found dead on Day 4. The cause of death was considered to be a dosing error.

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:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Reduced locomotor activity was noted at 1000 mg/kg/day, most clearly seen in males.

Immunological findings:

not examined

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

Description (incidence and severity):

Necrotic tracheitis was noted in the 1000 mg/kg/day male which died on Day 4 and was considered consistent with a dosing error.

Histopathological findings: neoplastic:

no effects observed

Effect levels

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Reduced motor activity was noted at 1000 mg/kg bw/day

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Oral administration to Wistar rats at 0, 50, 200 or 1000 mg/kg bw/day for 28 days resulted in no test item-related mortality (a sinlge male died from suspected dosing error), no clinical signs during daily observations or weekly behavioural observations, no findingsduring functional observation battery observations, no effects upon haematology or clinical chemistry parameters, no changes in absolute or relative organ weights and no macro- or microscopic changes.
Treatment-related changes were noted for locomotor activity which was slightly reduced at 1000 mg/kg/day.
Based on the results of this study the NOAEL was concluded to be 200 mg/kg bw/day.