Trichloro(phenyl)silane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Study period:

2009-01-14 to 2009-10-20

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, using a closely related test material.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Principles of method if other than guideline:

OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Trimethoxyphenylsilane

EC Number:

221-066-9

EC Name:

Trimethoxyphenylsilane

Cas Number:

2996-92-1

IUPAC Name:

trimethoxy(phenyl)silane

Test animals

Species:

rat

Strain:

other: Han Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Labs Ltd., Wölferstrasse 4, 4414 Fűllinsdorf, SWITZERLAND
- Age at study initiation: 11 wk
- Weight at study initiation: 294-330 g (m), 178-213 g (f0
- Housing: 1/Makrolon type 3 cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 6 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±3
- Humidity (%): 20-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h/12 m

IN-LIFE DATES: From: 2009-01-14 To: 2009-04-06

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Prepared weekly. Homogeneous suspension maintained with magnetic stirrer during dosing .
VEHICLE
Dried deacidified corn oil
- Justification for use and choice of vehicle (if other than water): none given
- Concentration in vehicle:
- Amount of vehicle (if gavage): dose volume 5 ml/kg bw
- Lot/batch no.: 37899577

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

CG-FID. Stability and homogeneity verified at start of study and during 2nd last week of dosing.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: 2 wk
- Proof of pregnancy: vaginal plug / sperm in vaginal smear]referred to as day 0 of pregnancy

Duration of treatment / exposure:

toxicity males: from 2 weeks prior to mating for at least 4 wk
toxicity/reproductive females: from 2 weeks prior to mating for at about 7 wk

Frequency of treatment:

daily, 7 days/wk

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 250, 500 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: prior range finding study (Harlan B88762)
- Rationale for animal assignment (if not random): random with consideration for body weight

Examinations

Maternal examinations:

The number of implantation sites and corpora lutea was recorded for all dams with litters. The uteri of non-pregnant females were treated to visualize possible hemorrhagic areas of implantation sites.

Histological examination of ovaries was carried out on any females that did not give birth. In addition, microscopic examination of the reproductive organs of all infertile males was made, if necessary.

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (18 h)
- How many animals: 5

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Animals fasted: Yes (18 h)
- How many animals: 5

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION/FOB: Yes
- Time schedule for examinations: just prior to sacrifice
- Dose groups that were examined: 5/sex, all groups
Cage-side observations: unusual body movements (e.g. tremors, convulsions), abnormal behavior (e.g. circling, stereotypy) and posture as well as resistance to removal.
Hand-held observations: palpebral closure, pinna reflex, lacrimation, pupil size, pupil reactivity, salivation, muscle tone, extensor thrust response, righting reflex and reaction to handling.
Open field observations: level of ambulatory activity including rearing (one minute evaluation), responsiveness to sharp noise, paw pinch, gait evaluation, quantity of urine and fecal pellets voided.
Categorical observations (can be made any time during the FOB): hair coat, behavior, respiration, muscle movements, eyes, hearing ability (Preyer’s reflex), urine or feces, soiling, general abnormalities, posture.
Measurements / Counts: hind limb / fore limb grip strength, landing foot splay, rectal temperature.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

The litters were examined for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually (without identification) on days 0 (if possible), 1 and 4 postpartum.

Statistics:

Means and standard deviations of various data were calculated. 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 instead of the Dunnett test when the data could not be assumed to follow a normal distribution. Fisher's exact-test was applied to breeding data and the macroscopical findings.

Indices:

Litter size (birth index), post-natal loss (PND0-4) (viability index).

[Also gestation time, gestation index, precoital time, conception index, corpora lutea count, implantation rate, post implantation loss.]

Historical control data:

provided and relevant to comment on organ weight changes (below)

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
ORGAN WEIGHTS
In females at 500 mg/kg bw/day, thymus weight was reduced (absolute, relative to body and relative to brain), although these values were within the range of historical controls. Female liver and kidney weights (relative to body) were also increased at the top dose; again within the range of historical controls. [The report incorrectly notes increased thymus and reduced liver weights for this group.]
GROSS PATHOLOGY
The urinary bladder was thickened at all doses. This finding in the urinary bladder was said mainly to correlate with transitional cell hyperplasia observed at microscopic level.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys: >=250mg/kg bw/day multifocal tubular degeneration/regeneration, tubular simple dilation,increased incidence of focal tubular degeneration/regeneration, transitional cell hyperplasia, renal pelvic dilation.
Urinary Bladder: >=100 mg/kg bw/day perivascular lymphoid cell infiltration, minimal to moderate transitional cell hyperplasia. Hyperplastic lesions were accompanied by minimal to slight dilation Minimal to moderate bladder with slight hemorrhage.
Jejunum: >=250 mg/kg bw/day, multifocal lymphangiectasis of villi
Liver and thyroid: 500 mg/kg bw/day, liver cell hypertrophy (the consequent increase of follicular cell hypertrophy in the thyroid gland was considered to be an adaptive effect and not adverse)

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

LOAEL

Effect level:

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

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The mean number of pups at first litter check was not affected by the treatment with the test item. The sex ratio was also not affected. No abnormal pups were noted at any dose level. During the lactation period, pup weight gain at 500 mg/kg bw/day was reduced compared to the controls, but did not attain statistical significance. The reaction was due primarily to lower weight gain which occurred in two litters. Excluding the lower pup weight which occurred in these two litters at 500 mg/kg bw/day, mean pup weight gain was not considered to be affected by the treatment with the test item.

At necropsy of the pups, the incidence of pups with no milk in the stomach did not give any indication of a test item-related effect.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A well reported oral combined repeated dose/reproductive and developmental screening study, conducted according to the current guideline and in accordance with GLP, reported a NOAEL for developmental effects at the highest tested dose of 500 mg/kg bw/day for trimethoxy(phenyl)silane. General systemic parental effects were reported at the lowest tested dose of 100 mg/kg bw/day.