Trichloro(2,4,4-trimethylpentyl)silane

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triethoxy(2,4,4-trimethylpentyl)silane

EC Number:

252-558-1

EC Name:

Triethoxy(2,4,4-trimethylpentyl)silane

Cas Number:

35435-21-3

IUPAC Name:

triethoxy(2,4,4-trimethylpentyl)silane

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Nohon Charles River Co., Hino Breeding Ctr., Gamo-gun, Shigu, JAPAN
- Age at study initiation: 5 wk
- Weight at study initiation: 153-177 g (m); 122-145 g (f)
- Fasting period before study:
- Housing: 1/ stainless steel cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/-2
- Humidity (%): 55 +/- 10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h/12 h

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
TS stirred (no further details) into vehicle. Stability and homogeneity determined by GC testing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): none given
- Amount of vehicle (if gavage): total dose volume 10 ml/kg bw/day

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 8, 40, 200, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

6 (for treatment and recovery groups)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
- Rationale for animal assignment (if not random): none given
- Rationale for selecting satellite groups: recovery groups (14-days post dosing) 0, 1000 mg/kg bw/day
- Post-exposure recovery period in satellite groups: 14 days

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: days -2, 1,3,8,12,17,21,26,28 of administration, and days 1,5,10,14 of recovery

FOOD CONSUMPTION:
- Food consumption: Yes
- Time schedule for examinations: days 3,8,15, 22,28 of administration, and days 4,8,14 of recovery

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of adminstration and recovery
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes (overnight)
- Parameters checked: see table 1

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of adminstration and recovery
- Animals fasted: Yes
- Parameters checked : see table 1

URINALYSIS: Yes
- Time schedule for collection of urine: administration day 28, recovery day 17
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked: see table 1

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)

Statistics:

Results were tested for uniform distribution using Bartlett’s technique, and when confirmed at a significance level of 5% a one-way variance analysis was performed. Significant differences identified in variance analysis were subjected to Dunnett’s technique (vehicle one: each administration group).

When no uniform distribution was observed a Kruskal-Wallis test was performed. When a significant difference was found a non-parametric Dunnets’s technique was performed.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
Salivation in treated and wehicle-treated groups.
1000 mg/kg bw/day (m/f): reduced spontaneous locomoton, lacrimation, reddish tears and moist hair on the lower abdomen with staining.

BODY WEIGHT AND WEIGHT GAIN
1000 mg/kg bw/day: reduced body weight m/f. Not entirely resolved at the end of recovery period.

FOOD CONSUMPTION:
1000 mg/kg bw/day: reduced food intake m/f. During recovery period no difference from controls was noted in males, but females had reduced food intake on day 8
200 mg/kg bw/day: reduced intake in females on day 28.

HAEMATOLOGY
1000 mg/kg bw/day: prolonged activated partial thromboplastin time - suggested secondary to liver effects (m/f); reduced monocyte proportion in differential white blood count - within historical range (m).

No effects reported following recovery period.

CLINICAL CHEMISTRY
8 mg/kg bw/day: reduced sodium (m)
40 mg/kg bw/day: reduced sodium (m)
200 mg/kg bw/day:increased total cholesterol (m), reduced sodium (m)
1000 mg/kg bw/day: increased gamma-GTP (m), increased GPT (f), increasing tendency of total cholesterol (m/f), reduced total protein(m), reduced sodium (m), reduced blood glucose (f), reduced creatine (f), reduced chlorine (f)

Many of the above observations for the 1000 mg/kg bw/day groups (male and female) remained at the end of the recovery period. (Only 0 and 1000 mg/kg bw/day recovery groups were included.)

Several of these findings were suggested to be secondary to effects on the liver.

URINALYSIS
200 mg/kg bw/day: turbid urine (m/f) with granular decayed cell debris (m/f)
1000 mg/kg bw/day: turbid urine (m with granular decayed cell debris (m/f), increased urinary volume (m)

ORGAN WEIGHTS
8 mg/kg bw/day: reduced absolute adrenal gland weight (m)
>=200 mg/kg bw/day: increased relative liver weight (m),
1000 mg/kg bw/day: increased relative liver weight (f), increased relative kidney weight (m/f), reduced absolute brain and spleen weight (m, possibly assocated with reduced body weight)

At the end of the recovery period (0, 1000 mg/kg bw/day groups only retained) increased relative kidney weight (m) and increased relative brain weight (f) were reported.

GROSS PATHOLOGY
1000 mg/kg bw/day:enlarged liver (m/f).
Sporadic reporting of skin scab formation (f, 8 and 1000 mg/kg bw/day), blackish region of mucosa of the glandular stomach (m, 40, 200, 1000 mg/kg bw/day; f vehicle controls) and tubercles of the spleen (m, 40 mg/kg bw/day). With the exception of liver enlargement, in each case 1/6 of each group was affected

At the end of the recovery period (0, 1000 mg/kg bw/day only): changes to the gladular stomach (m, vehicle controls; f 1000 mg/kg bw/day - different groups from those affected during treatment); reduce testis and epididymis (m, 1000 mg/kg bw/day). In each case 1/6 of each group was affected

HISTOPATHOLOGY: NON-NEOPLASTIC
Bladder: diffuse hyperplasia of the transitional epithelium: 200 mg/kg bw/day 1/6 m, 1/6f; 1000 mg/kg bw/day 5/6 m, 6/6 f
1000. No effects reported at 40 mg/kg bw/day.
Liver: centrilobular hypertrophy of hepatocytes: 1000 mg/kg bw/day 2/6 m, 5/6 f. No effects reported at 200 mg/kg bw/day.

After the recovery period bladder effects remained in 4/6 m, 6/6 f, although the severity was reduced in many cases.
There were other sporadic findings

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

LOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: bladder effects, observations in the urine (m/f), relative liver weight (m), blood cholesterol (m)

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A well reported 28-day oral study (with a 14-day recovery period) conducted in the main according to the current guideline and in compliance with GLP, identified a NOAEL value of 40 mg/kg bw/day in male and female rats. Urological and liver effects, possibly reversible, were evident at 200 mg/kg bw/day.