Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In line with ECHA final decision number TPE-D-2114455990-41-01/F, there is an ongoing extended one-generation reproductive toxicity study with the registered substance, triethoxy(2,4,4-trimethylpentyl)silane. The study results will not be available in time to meet the ECHA deadline of 8th February 2021. The study results will therefore be submitted at a later date.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A dose range-finding study has been conducted with triethoxy(2,4,4-trimethylpentyl)silane for the ongoing extended one-generation reproductive toxicity (EOGRT) test. This range finder was not conducted according to OECD Test Guidelines or in compliance with GLP. Doses of 0, 100, 300 or 1000 mg/kg bw/day triethoxy(2,4,4-trimethylpentyl)silane in corn oil were administered daily by oral gavage to F0 female rats for 2 weeks prior to pairing for matin, throughout mating, gestation and lactation until termination on post-natal day (PND) 21. On weaning day 21, 10 F1 males and 10 F2 females per group were selected for post-weaning evaluation, during which the animals were given daily oral gavage administration of 0, 100, 300 or 1000 mg/kg bw/day triethoxy(2,4,4-trimethylpentyl)silane in corn oil.

The following parameters and end points were evaluated in F0 females: clinical observations, body weights, food consumption, mating performance, observations of females with litters during lactation, gross necropsy findings, organ weights and histopathological examinations.

The following litter examinations were made to F1 offspring: number and sex of pups, stillbirths, live births, presence of milk in the stomach up to PND 4, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.

The following parameters and end points were evaluated in F1 animals: clinical observations, body weights, food consumption, organ weights and gross necropsy findings.

Administration of triethoxy(2,4,4-trimethylpentyl)silane at 1000 mg/kg bw/day in F0 females resulted in the premature euthanasia of 1 female on lactation day 19 due to adverse clinical observations including erect fur, prominent backbone, low carriage, abnormal gait and abnormal distension. At microscopic evaluation the findings observed were the same as those observed in the terminal kill animals (minimal to mild degeneration of the skeletal muscle and minimal to mild axonal degeneration). Therefore, the poor clinical condition of this animal was considered to be associated with test substance administration.

For surviving F0 females at 1000 mg/kg bw/day, adverse clinical observations included hunched posture, erect fur, backbone prominent, decreased activity, limited use of hindlimbs, low carriage and abnormal gait.  The observations related to the locomotor function of the animals (decreased activity, limited use of hindlimbs, low carriage and abnormal gait) correlated with microscopic findings of the skeletal muscle (minimal to mild degeneration) and the sciatic and tibial nerves (axonal degeneration).  

In F0 females, there were no test item-related effects on estrous cycles at dose levels up to and including 1000 mg/kg bw/day. In F0 females, administration of triethoxy(2,4,4-trimethylpentyl)silane at 100, 300 or 1000 mg/kg bw/day had no effect on mating performance including mean pre-coital interval, female fertility index, duration of gestation and gestation index.  

Lower body weight gains and lower food consumption were observed during lactation only and at necropsy, higher liver and kidney weights were evident. The F1 litter mean pup weights of the females dosed at 1000 mg/kg bw/day were lower than the control litters from PND 4.  This difference in F1 body weights remained consistent throughout the F1 dosing period from PND 21 to at least 5 weeks of age along with correlating lower food consumption and adverse clinical observations (including erect fur, decreased activity, abnormal gait, abnormal breathing and eyes closed).  

Administration at 100 or 300 mg/kg bw/day in F0 females and at 300 mg/kg bw/day only in F1 animals was associated with non-adverse clinical observations only (salivation and ploughing behaviour). There were no test item-related effects noted at 100 mg/kg bw/day in the F1 animals.  

The available Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with the structural analogue trimethoxy(2,4,4-trimethylpentyl)silane (CAS 34396-03-7) has been included to support the read-across approach used for the registered substance, triethoxy(2,4,4-trimethylpentyl)silane (CAS 35435-21-3). Similar findings were observed, both qualitatively and quantitatively, in this study and in the EOGRT range-finder described above.

In this study, conducted according to OECD Test Guideline 422 and in compliance with GLP, 50, 150 and 300 mg/kg bw/day of trimethoxy(2,4,4-trimethylpentyl)silane (CAS 34396-03-7) in corn oil were administered daily by oral gavage to male and female rats for 28 and 63 days, respectively. The female rats were treated during pre-mating period, mating period, throughout gestation and up until post-natal day 13. In order to allow a detection of possible delayed occurrence or persistence of or recovery from toxic effects, additional animals in recovery groups (12 males and 12 females) were observed for a period of 14 days following the last administration. Animals in the recovery groups were not mated and dosed for 28 days (males) or until the first scheduled kill of dams (females) (BSL BIOSERVICE, 2020).

During the period of administration, the animals were observed each day for signs of toxicity. At the conclusion of the test, all animals were sacrificed and observed macroscopically. Body weight and food consumption were measured weekly. 

After 14 days of treatment of both male and female, animals were mated (1:1) for a maximum of 14 days. The subsequent morning onwards, the vaginal smears of females were checked to confirm the evidence of mating. After the confirmation of the mating, females were separated and housed individually. Females were allowed to give birth and each litter was examined as soon as possible after delivery of the dam to establish the number and sex of pups, stillbirths, live births, runts and the presence of gross abnormalities. Live pups were counted, sexed and litters weighed within 24 hours of parturition, on day 4 and day 13 post-partum. The anogenital distance (AGD) of each pup was measured on PND 0. The number of nipples/areolae in male pups was counted on PND 12. Blood samples from the day 13 pups and the adult males were assessed for serum levels for thyroid hormones (T4). The males were sacrificed after completion of the mating period on treatment days 29 and 30 and the females, along with their pups, were sacrificed on post-natal day 13. Non-pregnant females were sacrificed on day 26. The number of implantation sites and corpora lutea was recorded for each parental female at necropsy. Pups sacrificed on post-natal day 4 or 13 and those found dead were carefully examined for gross external abnormalities. A full histopathological evaluation of preserved tissues designated for microscopic evaluation was performed on high dose and control animals, in non-pregnant female animals and male mating partners of the LD and MD animals. For the testes, a detailed qualitative examination was made, taking into account the tubular stages of the spermatogenic cycle. Thyroid/parathyroid glands from pups and adult animals were examined. All gross lesions macroscopically identified were examined microscopically in all animals.

No mortality occurred during the treatment period or recovery period of this study. No consistent clinical signs of toxicity were seen in this study. The test item had no effect on body weight and food consumption in this study. Oestrous cycle was not affected by treatment with the test item. In each group 10/10 animals were pregnant, pre-coital interval and duration of gestation showed no test item-related or statistically significant effect. Maternal behaviour was normal in all groups. There were no effects on total number of pups born, number of male pups, number of female pups, sex ratio, number of live pups, still birth, runts on PND 0 as well as number of live pups, number of male and female pups and sex ratio on PND 4 and PND 13 when compared with the controls. Litter weight was not notably different between dose groups and control group.

Lower mean pup weight in the HD groups is assumed to be related to the slightly lower body weight observed in females of this group, compared to controls, during the lactation period. There were no test item-related effects on the number of corpora lutea or implantation sites, percent pre-implantation loss and post-implantation loss in any of the dose groups. There were no test item-related effects on the reproductive indices (copulation, fertility, viability and delivery indices) in the dose groups. The mortality of pups between PND 0 and PND 4 and between PND 4-13 was not considerably different between the dose groups and the control group. Very slight differences in anogenital distance in male (slightly shorter) and females (slightly longer) are not considered toxicologically relevant. No relevant test item effect was observed in nipple retention on PND 13. Serum T4 levels of males and of male and female PND 13 pups were not affected by treatment with trimethoxy(2,4,4-trimethylpentyl)silane. Few dead or missing pups were noted in dose groups and control group, independent of treatment.

The systemic NOAEL was determined to be 50 mg/kg bw/day for male and female rats based on adverse polyneuropathy (at 300 mg/kg bw/day) and urinary damage (at >= 150 mg/kg bw/day) (see Section 7.5). Reproductive and developmental parameters were not affected. Therefore, the NOAELs for reproductive toxicity and developmental toxicity were considered to be 300 mg/kg bw/day (BSL BIOSERVICE, 2020).

Effects on developmental toxicity

Description of key information

In the key prenatal developmental toxicity study in rats with triethoxy (2,4,4-trimethylpentyl)silane, conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for maternal and developmental effects was concluded to be greater than 1000 mg/kg bw/day based on no adverse systemic or developmental effects. An increased incidence of supernumerary rudimentary ribs and long or interrupted costal cartilages observed at the dose levels of 300 and 1000 mg/kg bw/day indicate a treatment-related minor disturbance in the development of the axial skeleton at these dose levels. Both types of variations belong to the most common seen in the control groups. They are of minor nature and not likely to affect further development and postnatal live of the animal. Therefore the increase of their incidence was considered not to be adverse (Harlan Laboratories, 2009a).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
other: Japanese Guidelines (Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, 12 Nohsan No. 8147, Teratology (2-1-18), Agricultural Production Bureau, dated November 24, 2000)
Principles of method if other than guideline:
The purpose of this study was to detect effects on the pregnant rat and development of the embryo and fetus consequent to exposure of the female to the test item from day 6 post coitum (implantation) to day 20 post coitum (the day prior to Caesarean section).
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: HanRcc: WIST(SPF)
Details on test animals or test system and environmental conditions:
Animals: Rat, HanRcc: WIST(SPF)
Breeder: Harlan Laboratories Ltd., Laboratory Animal Services, Wölferstrasse 4, 4414 Füllinsdorf / Switzerland
Number of Animals: 88 mated females (In order to complete mating within a reasonable time period, 98 female rats were obtained from the breeder. The surplus females were sacrificed after commencement of treatment for the last mated females); 22 mated females per group
Age (Day 0 Post Coitum): 11 weeks
Body Weight Range (Day 0 Post Coitum): 181 to 223 g
Identification: Cage card and individual animal number (ear tattoo).
Randomization: Computer-generated random algorithm.
Acclimatization: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

Husbandry:
Room Number, Füllinsdorf: 08A
Conditions: Standard laboratory conditions. Air-conditioned with 10 - 15 air changes per hour, continuously monitored environmental conditions (temp. range: 22 ± 3 °C; relative humidity range: 30 - 70%). There was 12-hour fluorescent light / 12-hour dark cycle with music during the light period.
Accommodation: Individually in Makrolon type-3 cages with wire mesh tops and sterilized standard softwood bedding (‘Lignocel’ Schill AG, 4132 Muttenz/Switzerland).
Diet: Pelleted standard Kliba Nafag 3433 rodent maintenance diet (Provimi Kliba SA, 4303 Kaiseraugst/Switzerland) was available ad libitum (batch no. 61/08).
Water: Community tap-water from Füllinsdorf was available ad libitum in water bottles.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Four groups of females were treated by oral gavage with SILRES® BS 1701once daily at dose levels of 0 (control), 100, 300 or 1000 mg/kg body weight/day on days 6-20 post coitum. The dose levels were selected based on a previous dose range finding toxicity study in Han Wistar rats, Harlan Laboratories Study C16981, using dose levels of 0, 100, 300 and 1000 mg/kg/day, resulting in no clinical findings or adverse effects on dams or embryo-fetal development up to and including 1000 mg/kg body weight/day. A standard dose volume of 5 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (corn oil).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose Formulations:
The dose formulations were prepared weekly using the test item as supplied by the Sponsor. SILRES® BS 1701 was weighed into a glass beaker on a tared precision balance and the vehicle was added (w/v). Using an appropriate homogenizer, a homogeneous solution was prepared. Separate formulations were prepared for each concentration. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

Storage of Dose Formulations:
Dose formulations were stored at room temperature (20 ± 5 °C) in glass beakers. Based upon the results of stability analyses performed within the (non GLP) Harlan Laboratories study C16981 (Dose Range-Finding Prenatal Developmental Toxicity Study in the Han Wistar Rat), dose formulations were stable for at least 7 days.

Analysis of Dose Formulations:
On the first treatment day samples from the control group as well as three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of concentration and homogeneity. During the last week of the treatment, samples were taken from the middle to confirm concentration. The aliquots for analysis of dose formulations were frozen (-20 ± 5 °C) and delivered on dry ice to Dr. D. Flade (Harlan Laboratories Ltd., Itingen / Switzerland) and stored there at -20 ± 5 °C until analysis. The samples were analyzed by GC coupled to a flame ionisation detector following an analytical procedure provided by the Sponsor and adapted at Harlan Laboratories. The test item was used as the analytical standard. Analysed samples were not discarded without written consent from the study director.

SILRES® BS 1701 application formulations investigated during the study were found to comprise the test item in the range of 97.8% to 102.2%. All samples met the required content limit of ±20% with reference to the nominal concentration. The proper preparation of dose formulations was confirmed by the analysis of samples collected during the last week of the treatment (recovery estimated in these samples confirm concentration of the test item in the range between 96.7% and 102.0% of the nominal concentration). The homogeneous distribution of SILRES® BS 1701 in the application formulations was approved because single results did not deviate more than 1.9% (<15%) from the corresponding mean.
Details on mating procedure:
After acclimatization, females were housed with sexually mature males (1:1) in special automatic mating cages i.e. with synchronized timing to initiate the nightly mating period, until evidence of copulation was observed. This system reduced the variation in the copulation times of the different females. The females were removed and housed individually if:
- the daily vaginal smear was sperm positive, or
- a copulation plug was observed.
The day of mating was designated day 0 post coitum. Male rats of the same source and strain were used only for mating. These male rats are in the possession of Harlan Laboratories and were not considered part of the test system. The fertility of these males had been proven and was continuously monitored.
Duration of treatment / exposure:
On days 6-20 post coitum
Frequency of treatment:
daily
Duration of test:
Up to day 21 post coitum
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
22 mated females/dose group
Control animals:
yes, concurrent vehicle
Maternal examinations:
The following observations were recorded as follows:
Viability / Mortality: Twice daily
Clinical Signs: Daily cage-side clinical observations (once daily, during acclimatization and up to day of necropsy).
Food Consumption: Recorded at 3-day intervals: days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post coitum.
Body Weights: Recorded daily from day 0 until day 21 post coitum.

At the scheduled necropsy on day 21 post coitum, females were sacrificed by CO2 asphyxiation and the fetuses removed by Caesarean section. Post mortem examination included gross macroscopic examination of all internal organs.
Ovaries and uterine content:
Post mortem examination included emphasis on the uterus, uterine contents, position of fetuses in the uterus and the number of corpora lutea was performed and the data recorded. The uteri (and contents) of all females with live fetuses were weighed during necropsy on day 21 post coitum to enable the calculation of the corrected body weight gain.
Fetal examinations:
Fetuses were removed from the uterus, sexed, weighed individually, examined for gross external abnormalities, sacrificed by a subcutaneous injection of sodium pentobarbital and allocated to one of the following procedures:
1. Microdissection technique (sectioning/dissection technique). At least one half of the fetuses from each litter was fixed in Bouin's fixative (one fetus per container). They were examined by a combination of serial sections of the head and microdissection of the thorax and abdomen. This included detailed examination of the major blood vessels and sectioning of the heart and kidneys. After examination, the tissue was preserved in a solution of glycerin/ethanol (one fetus per container). Descriptions of any abnormalities and variations were recorded.

2. The remaining fetuses were eviscerated and with the exception of over the paws, the skin was removed and discarded. Carcasses were processed through solutions of ethanol, glacial acetic acid with Alcian blue (for cartilage staining), potassium hydroxide with Alizarin red S (for clearing and staining ossified bone) and aqueous glycerin for preservation and storage. The skeletons were examined and all abnormal findings and variations were recorded. The specimens were preserved individually in plastic vials.

If no implantation sites were evident, the uterus was placed in an aqueous solution of ammonium sulfide to accentuate possible hemorrhagic areas of implantation sites.

Terminology Used in the Assessment of the Data:
Empty Implantation Site: Very early resorption or aborted implantation
Embryonic Resorption: Amorphous mass being resorbed
Fetal Resorption: Clearly defined fetal body being resorbed
Dead Fetus: Appearance of live fetus but without induced respiration or movement
Live Fetus: Breathing and/or moving fetus
Abnormality: A structural change in a fetus that would probably impair its health or development.
Variation: A fetal change that is unlikely to adversely affect survival or health. This includes a delay in growth or morphogenesis that has otherwise followed a normal pattern of development.
Statistics:
The following statistical methods were used to analyze food consumption, body weights and reproduction data:
• 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 if the variables could be dichotomized without loss of information.
Indices:
The following parameters were calculated: pre- and post-implantation losses, embryonic and fetal deaths, live and dead fetuses, abnormal fetuses, fetal sex ratios and fetal body weights.

For reproduction data, group mean values were calculated both on a litter basis and on a percentage per group basis. Mean fetal weights were calculated from the individual weights both on a per group and on a per litter basis.
Clinical signs:
no effects observed
Description (incidence and severity):
No clinical symptoms related to treatment with the test item were noted during the study at any dose level.
Mortality:
no mortality observed
Description (incidence):
All dams survived until the scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weight and mean body weight gain were not affected by treatment with the test item at any dose level. The overall differences in mean body weight gain were by +49.5%, +45.7%, +47.1 and +46.4% in order of ascending dose levels (percentages refer to the alterations within the treatment period). Mean corrected body weight gain (corrected for the weight of the gravid uterus) was similar in all dose groups: 12.4%, 10.3%, 12.8% and 10.1% in order of ascending dose levels.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects on mean food consumption were noted at any dose level. The overall differences in food consumption during the treatment period were by +0.5%, +4.2% and -0.9% in order of ascending dose levels (percentages refer to the value of the control group).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No findings were noted during macroscopic examination at any dose level.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No test item-related effects.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Incidental statistically significantly lower number of embryonic resorptions was observed at the dose level of 100 mg/kg. This effect was considered to be a result of biological variability.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
Mean number of live fetuses was similar in all groups and was 13.1, 12.2, 12.1 and 12.4 in order of ascending dose levels.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
No test item-related effects on the relevant reproduction data (post implantation loss and number of live fetuses at termination) were observed at any dose level.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed in maternal animals.
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No test item-related effects on mean weights of live fetuses were observed at any dose level. Slightly but statistically significantly higher mean body weights of live fetuses were observed at the dose levels of 100 and 1000 mg/kg bw/day. Mean fetal body weights calculated on an individual basis were 4.8 g in both groups compared to 4.7 g in the control group. Both values were in the range of historical control data (mean fetal body weight in control groups comprised values from 4.7 to 4.9 g) therefore this effect was considered not to be test item-related but a result of biological variability.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No effects on sex ratio of the fetuses were observed at any dose level. Proportions of male fetuses were 50.0%, 46.1%, 45.9% and 46.5% in order of ascending dose levels.
External malformations:
no effects observed
Description (incidence and severity):
No test item-related abnormal findings were noted during external examination of the fetuses at any dose level. A malrotaded hind limb was found in 1 fetus at the dose of 100 mg/kg bw/day and 2 fetuses at the dose of 300 mg/kg bw/day. Because of lack of the dose-correlation, this finding was considered to be incidental.

Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Bone and Cartilage Abnormalities and Variations:
During skeletal examination of fetuses, findings were noted in:
17% examined fetuses (in 55% litters) in the control group
27% examined fetuses (in 73% litters) at the dose level of 100 mg/kg bw/day
18% examined fetuses (in 68% litters) at the dose level of 300 mg/kg bw/day
20% examined fetuses (in 62% litters) at the dose level of 1000 mg/kg bw/day
The type and frequencies of the noted skeletal variations were similar in the groups receiving the test item and the control group and did not indicate any dose-dependency, therefore they were considered not to be test item-related. No test item-related abnormalities were observed. A supernumerary greater horn of hyoid arch was noted in 1 fetus in the control group. A malpositioned and/or shortened and fused costal cartilage was found in 1 fetus each at the dose levels of 100 mg/kg and 1000 mg/kg. This finding was considered to be incidental.
Bone Examination of Fetuses (Ossification Stage and Supernumerary Ribs): During bone examination of fetuses, findings were noted in:
16% examined fetuses (in 50% litters) in the control group
22% examined fetuses (in 68% litters) at the dose level of 100 mg/kg bw/day
17% examined fetuses (in 64% litters) at the dose level of 300 mg/kg bw/day
19% examined fetuses (in 57% litters) at the dose level of 1000 mg/kg bw/day
No test item-related effects on the ossification stage and supernumerary ribs were noted at the dose level of 100 mg/kg bw/day.

When compared to the control values statistically significantly lower numbers of non-ossified cervical and caudal vertebrae and incompletely ossified sternal bodies were noted at the dose level of 1000 mg/kg bw/day. Statistically significantly lower number of non-ossified digits and toes was noted in all groups treated with the test item. Most of these values were in the range of the historical control data and therefore these findings were considered not to be test item-related but a result of biological variability. Compared to the control values, a statistically significantly increased incidence of supernumerary rudimentary ribs was noted at the dose levels of 300 and 1000 mg/kg bw/day when calculated on an individual basis. This effect did not correlate with the dose levels; it was most pronounced at the dose level of 300 mg/kg bw/day. When calculated on a litter basis, statistically significant increase was noted only at the dose level of 300 mg/kg bw/day. The increased numbers of supernumerary ribs exceeded the historical control data and were considered to be test item-related. An increase of rudimentary supernumerary ribs indicate only minor and not adverse developmental disturbance as the rudimentary thoracolumbar supernumerary ribs are known to be transient, therefore this effect was considered not to be adverse.

Cartilage Examination of Fetuses (Additional Variations): During cartilage examination of fetuses, findings were noted in:
2% examined fetuses (in 14% litters) in the control group
10% examined fetuses (in 41% litters) at the dose level of 100 mg/kg bw/day
2% examined fetuses (in 14% litters) at the dose level of 300 mg/kg bw/day
4% examined fetuses (in 19% litters) at the dose level of 1000 mg/kg bw/day
No test item-related effects on the cartilage development were noted at the dose level of 100 mg/kg bw/day. At the dose level of 1000 mg/kg bw/day, statistically significantly lower number of skull cartilaginous structures with small hole was observed when compared to the control value. This value remained in the range of the historical control data and was therefore considered not to be test item-related but a result of biological variability. Compared to the control value, an increased incidence of long or interrupted costal cartilages was noted at the dose levels of 300 and 1000 mg/kg bw/day when calculated on an individual basis. This effect did not correlate with the dose levels; it was most pronounced at the dose level of 300 mg/kg bw/day. When calculated on a litter basis, statistically significant increase was noted only at the dose level of 300 mg/kg bw/day. The increased numbers of long or interrupted costal cartilages exceeded the historical control data and were considered to be test item-related. Although long or interrupted costal cartilages are considered as permanent structural changes, they are minor and most unlikely to adversely affect further development and postnatal live of the animal therefore this effect was considered not to be adverse.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
During visceral examination of fetuses, findings were noted in:
34% examined fetuses (in 100% litters) in the control group
36% examined fetuses (in 91% litters) at the dose level of 100 mg/kg bw/day
31% examined fetuses (in 86% litters) at the dose level of 300 mg/kg bw/day
35% examined fetuses (in 100% litters) at the dose level of 1000 mg/kg bw/day
The type and frequencies of the noted variations were similar in the groups receiving the test item and the control group and did not indicate any dose-dependency, therefore these findings were considered not to be test item-related. All found abnormalities (situs invertus noted in 2 fetuses/2 litters, small pituitary noted in 1 fetus and interventricular septal defect of the heart noted in 1 fetus) were noted in the control group.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse developmental effects observed.
Abnormalities:
no effects observed
Developmental effects observed:
no

No clinical signs or observations were noted up to and included dose level of 1000 mg/kg bw/day. Food consumption, body weight and corrected body weight gain (corrected for the gravid uterus weight) were not affected by treatment with the test item up to and included dose level of 1000 mg/kg. No test item-related effects on the relevant reproduction parameters were observed up to and included dose level of 1000 mg/kg bw/day. No test item-related effects on development of embryos or fetuses were observed at the dose level of 100 mg/kg bw/day. An increased incidence of supernumerary rudimentary ribs and long or interrupted costal cartilages observed at the dose levels of 300 and 1000 mg/kg bw/day indicate a treatment-related minor disturbance in the development of the axial skeleton at these dose levels. Both types of variations belong to the most common seen in the control groups. They are of minor nature and not likely to affect further development and postnatal live of the animal. Therefore the increase of their incidence was considered not to be adverse.

Conclusions:
In the prenatal developmental toxicity study in rats, conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for maternal and developmental effects was concluded to be greater than 1000 mg/kg bw/day based on no adverse systemic or developmental effects. An increased incidence of supernumerary rudimentary ribs and long or interrupted costal cartilages observed at the dose levels of 300 and 1000 mg/kg bw/day indicate a treatment-related minor disturbance in the development of the axial skeleton at these dose levels. Both types of variations belong to the most common seen in the control groups. They are of minor nature and not likely to affect further development and postnatal live of the animal. Therefore the increase of their incidence was considered not to be adverse.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In the key prenatal developmental toxicity study in rats with triethoxy(2,4,4-trimethylpentyl)silane, conducted according to OECD Test Guideline 414 and in compliance with GLP, 22 mated female rats were given daily oral gavage administration of triethoxy(2,4,4-trimethylpentyl)silane in corn oil at doses of 0, 100, 300 and 1000 mg/kg bw/day during gestation days 6 to 20 (Harlan Laboratories, 2009a). The dose levels selection was based on the findings of a preliminary prenatal developmental toxicity study (Harlan Laboratories, 2009b). The animals were observed twice daily for viability and mortality and cage-side clinical observations were performed once daily. Food Consumption was recorded on days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum. Body Weights were recorded daily from day 0 until day 21 post-coitum. At the scheduled necropsy on day 21 post-coitum, females were sacrificed and the foetuses were removed from the uterus, sexed, weighed and examined for gross external abnormalities, visceral and skeletal changes. Post-mortem examination of the dams included gross macroscopic examination of all internal organs.

No clinical signs or observations were noted up to and included dose level of 1000 mg/kg bw/day. Food consumption, body weight and corrected body weight gain (corrected for the gravid uterus weight) were not affected by treatment with the test item up to and included dose level of 1000 mg/kg. No test item-related effects on the relevant reproduction parameters were observed up to and included dose level of 1000 mg/kg bw/day. No test item-related effects on development of embryos or foetuses were observed at the dose level of 100 mg/kg bw/day. An increased incidence of supernumerary rudimentary ribs and long or interrupted costal cartilages observed at the dose levels of 300 and 1000 mg/kg bw/day indicate a treatment-related minor disturbance in the development of the axial skeleton at these dose levels. Both types of variations belong to the most common seen in the control groups. They are of minor nature and not likely to affect further development and postnatal live of the animal. Therefore the increase of their incidence was considered not to be adverse. The NOAEL for maternal and developmental effects was concluded to be greater than 1000 mg/kg bw/day based on no adverse systemic or developmental effects.

In the preliminary prenatal developmental toxicity study, no adverse systemic effects and no developmental effects were noted in maternal animals and foetuses, respectively. Based on these observations, dose levels of 100, 300 and 1000 mg/kg were considered appropriate for a main prenatal developmental toxicity study in the rat (Harlan Laboratories, 2009b).

Justification for classification or non-classification

Based on the available developmental toxicity study, triethoxy(2,4,4-trimethylpentyl)silane does not require classification for reproductive or developmental toxicity according to Regulation (EC) No. 1272/2008.

Additional information