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Effects on fertility

Description of key information

Oral: OECD 422 draft, rats: NOAEL (systemic) and (fertility) are not available yet. As soon as the final report is available the results will be included in the dossier.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10. January to 4. April 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
July 2016
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Bayerisches Landesamt für Gesundheit- und Lebensmittelsicherheit
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
Crl: WI (Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 13-15 weeks
- Weight at study initiation: males: 324 - 378 g, females: 203 - 250 g
- Fasting period before study: no
- Housing: 5 animals per sex per cage during pre-mating and post-mating period. During mating period males and females were housed together in ratio 1:1 (male to female).
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was prepared at least once every 10 days which is with the stability frame.

VEHICLE
- Justification for use and choice of vehicle: The vehicle was selected in consultation with the sponsor based on the test item’s characteristics and testing guideline.
- Concentration in vehicle: 0, 12.5, 37.5, 75 mg/mL
- Amount of vehicle: 4 mL/kg bw/day
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: not reported
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): 5 per cage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The determination of formulation concentrations of the test substance was based on a GC-FID method. Nominal concentrations were confirmed for all dose groups, as measured concentrations were within acceptance criterion of 10%.
Duration of treatment / exposure:
males: 28 days
females: up to 63 days
Frequency of treatment:
daily
Details on study schedule:
- Age at mating of the mated animals in the study: 17 - 19 weeks
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
main study: 10 animals per sex per dose
recovery group: 12 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The highest dose level of 300 mg/kg bw/day was chosen on the basis of a dose range finding study, where mortality was observed after repeated oral administration at a dose of 1000 mg/kg bw/day (later reduced to 600 mg/kg bw/day). Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dose-related response and a NOAEL.
- Fasting period before blood sampling for clinical biochemistry: no
Positive control:
no
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day
- Cage side observations: health condition, morbidity, moratility

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the first exposure and at least once a week thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: once before the assignment to the experimental groups, on the first day of dosing and weekly thereafter as well as at the end of the study. During pregnancy, females were weighed on gestation days (GD) 0, 7, 14 and 20 and within 24 hours of parturition (day 0 post-partum), on PND 4, 9 and 13 along with pups. All animals were weighed directly before termination.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE: No

OTHER: From 2 female pups/litter on day 4 after birth, from all dams and 2 pups/litter at termination on day 13, and from all adult males at termination, blood samples were collected. Blood samples from the day 13 pups and the adult males were assessed for serum levels for thyroid hormones (T4). Further assessment of T4 in blood samples from the dams and day 4 pups was not deemed necessary, based on the fact that no major histopathological finding was observed in thyroid/ parathyroid gland of selected male and female adult animals and no effect was observed on hormone levels of males and day 13 pups.
Oestrous cyclicity (parental animals):
Oestrous cycles were monitored using vaginal smears for 14 days before start of treatment to select the study females with regular cyclicity. Further on, vaginal smears were also examined daily from the beginning of the treatment period until evidence of mating. A vaginal smear was also examined on the day of necropsy.
Sperm parameters (parental animals):
Parameters examined in 5 randomly selected male parental generations: testis weight, epididymis weight
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups.

GROSS EXAMINATION OF DEAD PUPS: yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals of the main group were sacrificed any time after the completion of the mating period (after a minimum dosing period of 28 days).
- Maternal animals: All surviving animals were sacrificed on their respective PND 13.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY
The tissues indicated in Table 1 were prepared for microscopic examination.

ORGAN WEIGHTS
- testes (paired weight), uterus with cervix, epididymides (paired weight), ovaries (paired weight), prostate, seminal vesicles and coagulating glands (complete weight), thymus, thyroid/parathyroid glands (from 1 pup/sex/litter/group and from all adult males and females) - were weighed after fixation (complete weight), liver, kidneys (paired weight), spleen, adrenal (paired weight), brain, pituitary gland, heart
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 13 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination) as follows: carefully examined externally for gross abnormalities
Statistics:
A statistical assessment of the results of body weight, food consumption and litter data was performed for each gender by comparing values of dosed with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Results of absolute and relative organ weights, parameters of haematology, blood coagulation and clinical biochemistry was statistically analysed by comparing values of dosed with control animals using either a parametric one-way ANOVA and a post-hoc Dunnett Test or a non-parametric Kruskal-Wallis Test and a post-hoc Dunn’s Test, based on the results of homogeneity and normality tests. Statistical comparisons of data acquired during the recovery period were performed with a Dunn’s Test, Dunnett’s Test or Student’s T-Test. These statistics were performed with GraphPad Prism V.6.01 software or Ascentos 1.3.4 software (p<0.05 was considered as statistically significant).
Reproductive indices:
gestation length, pre-coital interval, number of live births, post-implanation loss, the number of implantations, corpora lutea
Offspring viability indices:
number and sex of pups, stillbirths, live births, runts
Dose descriptor:
NOAEL
Remarks on result:
other: no final report available yet
Critical effects observed:
not specified
Dose descriptor:
NOAEL
Remarks on result:
other: no final report available yet
Critical effects observed:
not specified
Key result
Reproductive effects observed:
no
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was according an apropriate OECD test guideline, and in compliance with GLP.
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 combined repeated dose oral toxicity and reproduction/developmental toxicity screening test according to OECD 422 and GLP is available with trimethoxy(2, 4, 4-trimethylpentyl)silane in male and female Wistar rats with dose levels of 50, 150, and 300 mg/kg bw/day (BSL, 2019).

However, the final study report is not available yet and discussions on the NOAEL are still ongoing. As soon as the final study report is available, the results will be included in the dossier.



Effects on developmental toxicity

Description of key information

OECD 422, rats: NOAEL (systemic) and NOAEL (development) are not available yet.

No information about developmental toxicity is available for the registered substance, however, reliable data are available for the closely related substance, triethoxy(2,4,4-trimethylpentyl)silane (CAS 35435-21-3).

Developmental/teratogenicity, oral, rat (OECD 414 with CAS 35435 -21 -3 ):
NOAEL (dev/teratogen) = 1000 mg/kg bw
NOAEL (maternal toxicity) = 1000 mg/kg bw

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to the attached justification.
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- No test item-related abnormal findings were noted during external examination of the fetuses at any dose level (see table 4). A malrotaded hind limb was found in 1 fetus at the dose of 100 mg/kg and 2 fetuses at the dose of 300 mg/kg. Because of lack of the dose-correlation, this finding was considered to be incidental.

- 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.

- 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. 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.

- 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
31% examined fetuses (in 86% litters) at the dose level of 300 mg/kg
35% examined fetuses (in 100% litters) at the dose level of 1000 mg/kg
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.

- 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
18% examined fetuses (in 68% litters) at the dose level of 300 mg/kg
20% examined fetuses (in 62% litters) at the dose level of 1000 mg/kg
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.

- 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
17% examined fetuses (in 64% litters) at the dose level of 300 mg/kg
19% examined fetuses (in 57% litters) at the dose level of 1000 mg/kg
No test item-related effects on the ossification stage and supernumerary ribs were noted at the dose level of 100 mg/kg. 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. 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 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. When calculated on a litter basis, statistically significant increase was noted only at the dose level of 300 mg/kg. The increased numbers of supernumerary ribs exceeded the historical control data and were considered to be test itemrelated. 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 [see References (N. Chernoff, J. M. Rogers: Supernumerary Ribs in Developmental Toxicity Bioassays and in Human Populations: Incidence and Biological Significance, J. Toxicol. Environ. Health. Part B, 7, pp. 437- 449 (2004))] therefore this effect was considered not to be adverse.

- 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
2% examined fetuses (in 14% litters) at the dose level of 300 mg/kg
4% examined fetuses (in 19% litters) at the dose level of 1000 mg/kg
No test item-related effects on the cartilage development were noted at the dose level of 100 mg/kg. At the dose level of 1000 mg/kg, 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 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. When calculated on a litter basis, statistically significant increase was noted only at the dose level of 300 mg/kg. 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.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
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
Quality of whole database:
The study was conducted according to an/the appropriate OECD test guideline/EU test method/national standard method, and in compliance with GLP. Read-across to the registered substane is considered scientifically justified.
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

A combined repeated dose oral toxicity and reproduction/developmental toxicity screening test according to OECD 422 and GLP is available with trimethoxy(2, 4, 4-trimethylpentyl)silane in male and female Wistar rats with dose levels of 50, 150, and 300 mg/kg bw/day (BSL, 2019).

However, the final study report is not available yet and discussions on the NOAEL are still ongoing. As soon as the final study report is available, the results will be included in the dossier.

No information about developmental toxicity is available for the registered substance, however, reliable data are available for the closely related substance, triethoxy(2,4,4-trimethylpentyl)silane (CAS 35435-21-3).

In a developmental toxicity study according to OECD 414 and in compliance with GLP regulations (Harlan, 2009b) 22 pregnant Wistar rats per dose were treated by oral gavage with triethoxy(2,4,4 -trimethylpentyl)silane (CAS 35435-21-3) from gestation day 6 until day 20 at doses of 100, 300, 1000 mg/kg/day. Animals were observed for clinical signs and mortality; and in addition body weights, food consumption and necropsy findings were recorded. The sacrifice was performed on gestation day 21. Ovaries and uterine content were recorded and foetal examinations were performed including external examinations, soft tissue examinations, and skeletal examinations. No test item-related findings were observed. Minor effects in the foetuses were within the normal range of biological variability. Thus, the NOAEL for maternal and developmental toxicity is 1000 mg/kg bw.

Justification for classification or non-classification

Based on the available data on developmental toxicity, classification according to 67/584/EEC and EC/1272/2008 is not warranted.

A final conclusion on classification for reproductive toxicity after repeated exposure will be made as soon as the final report data is available for the OECD 422.

Additional information

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