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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19th June 2018 to 05th September 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / De velopmental Toxicity Screening Test
Version / remarks:
2016
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EPA OPPTS 870.3650, Combined Repeated Dose Toxicity Study with the Reproduction/Developm ental Toxicity Screening Test
Version / remarks:
2000
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Commission Regulations (EC)
Version / remarks:
440/2008, L 142, Annex Part B, May 30, 2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazine-2,4,6(1H,3H,5H)-trione
EC Number:
247-465-8
EC Name:
1,3,5-tris[3-(trimethoxysilyl)propyl]-1,3,5-triazine-2,4,6(1H,3H,5H)-trione
Cas Number:
26115-70-8
Molecular formula:
C21H45N3O12Si3
IUPAC Name:
tris[3-(trimethoxysilyl)propyl]-1,3,5-triazinane-2,4,6-trione
Test material form:
liquid
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Solubility and stability of the test substance in the solvent/vehicle: homogenous and stability was demonstrated for 10 days at room temperature
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item formulations were prepared with dried corn oil and thereafter administered within the stability time frame of 10 days. The test item was weighed into a tared plastic vial on a suitable precision balance and the vehicle was added to give the appropriate final concentration of the test item further vortexing it for 2-3 minutes and/or stirring until visual homogeneity was achieved.
- Preliminary purification step (if any): n/a
- Final dilution of a dissolved solid, stock liquid or gel: n/a
- Final preparation of a solid: n/a

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
Crl: WI(Han)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test item formulations were prepared with dried corn oil and thereafter administered within the stability time frame of 10 days. The test item was weighed into a tared plastic vial on a suitable precision balance and the vehicle was added to give the appropriate final concentration of the test item further vortexing it for 2-3 minutes and/or stirring until visual homogeneity was achieved.

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item formulation was prepared with dried corn oil. The vehicle was selected as suggested by the sponsor based on the test item’s characteristics and testing guideline.
- Concentration in vehicle: 25, 75 and 250 mg/mL
- Amount of vehicle (if gavage): not specified
- Lot/batch no. (if required): MKCC9871, MKCF8882
- - Purity: not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For verification of dose concentrations samples were taken of formulation samples in study week 1 (p re-mating period), 3 (first week of mating), 5 (gestation) and in the last week of the study (gestation / lactation) from all groups (16 samples).
Details on mating procedure:
- M/F ratio per cage: ratio of 1:1 (male to female)
- Length of cohabitation: 14 days of mating
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Due to unsuccessful mating pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: not specified
- After successful mating each pregnant female was caged (how): After the confirmation of mating, females were kept individually during gestation/lactation period
- Any other deviations from standard protocol: none
Duration of treatment / exposure:
The test item was administered for a treatment period of up to 63 days, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during the gestation period and up to post-natal day 12 in females. The males of the recovery groups were treated for 28 days and were subjected to necropsy 15 days after the last administration (end of recovery period). The females of the recovery groups were treated up to the first scheduled necropsy of dam and were subjected to necropsy 15 days thereafter (end of recovery period).
Frequency of treatment:
A single dose was given daily.
Duration of test:
Up to 63 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
low dose (LD)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
mid dose (MD)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
high dose (HD)
No. of animals per sex per dose:
10 males and 10 females per test group plus additional 10 recovery group males and 10 recovery group females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The selected dose levels were based on findings of a dose range-finding study conducted with the registered substance and in consultation with the sponsor.
- Rationale for animal assignment (if not random): random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once per day for general health condition and twice daily for mortality and morbidity
- Cage side observations checked included: mortality, morbidity and general health condition of the animals

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure, and at least once a week thereafter, detailed clinical observations were made in all animals of the main groups and the recovery groups outside the home cage in a standard arena. Clinical observations included spontaneous activity, lethargy, rectum bent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in the skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size. Changes in gait, posture, response to handling as well as the presence of clonic or tonic movements, stereotypes, difficult or prolonged parturition or bizarre behaviour were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: The animals were weighed 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, PND 9 and PND 13 along with pups. All animals were weighed directly before termination. Any animal prematurely sacrificed was weighed pr ior to the sacrifice.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Food consumption was measured on the corresponding days of the body weight measurements after the beginning of the dose administration. Food consumption was not measured during the mating period in males and females and the post-mating period in males.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on post-natal day 13
- Organs examined: See table No 1

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
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, 5 blood coagulation and clinical biochemistry were 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 homogenei ty and normality tests. Statistical comparisons of data acquired during the recovery period werewill be performed with a 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).
Indices:
viabiliyt, copulation, fertility, viability and delivery indices

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
Females of LD, MD and HD group showed clinical signs like moving the bedding and slight to mode rate salivation immediately after administration during the treatment period. All these findings indicate local reactions to the oral gavage and are not assumed to be a sign of systemic toxicity.
No clinical signs were observed in C and HD recovery groups during the recovery period. Clinical signs like scratch, broken left incisor, cut on tongue, hairless area, regurgitation of the test material, sunken flanks and crust (ear) were observed mostly transiently or on single days and were within the normal background frequency.
During the weekly detailed clinical observation, no significant changes or differences between the groups were found during the treatment or recovery periods.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
Mortality was observed in 5/15 male animals at 1000 mg/kg bw/day. No mortality occurred among female test animals.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Test item had no effect on body weight development in females of the HD group during premating, gestation and lactation period. However, slight and statistically significant lower body weight was observed in HD recovery females (day 7-14) during the recovery period. The test item had no effect on body weight development in this study up to the MD level
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Slight, but statistically significant lower food consumption was observed in females of the HD group towards end of gestation/lactation and. A slight decrease in food consumption was observed on day 1-14 during the recovery period in HD recovery females. The test item had no effect on food consumption up to the MD level.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In the HD group moderate, statistically significantly higher reticulocytes were observed at the end of the treatment period (females 60% above control). This was not associated with changes in red blood cell parameters. In HD females monocytes were moderately statistically significant elevated (119 % above controls) at the end of the recovery period. Slightly but statistically significant higher platelet count in the HD group at the end of the treatment period in females (25 % above controls) are not considered toxicologically relevant as values were within the range of historical control data. Coagulation was not affected by the test item.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
ALAT and ASAT were moderately but statistically non-significiant increased in female animals of the HD group (>4-fold and >2-fold of controls, respectively) at the end of the recovery period. This was accompanied by a slight, non-significant increase in TBA (>2-fold of controls). All above-mentioned findings are assumed to be related to hepatotoxicity observed histopathologically. Slight and statistically significant increases in TP and Alb were observed in female animals of the HD group at the end of the recovery period (9 and 13 % above controls, respectively). These slight changes are not considered toxicologically relevant as there were no corresponding changes in globulin fraction or creatinine levels and they were not associated with histopathological findings.
Urinalysis findings:
no effects observed
Description (incidence and severity):
The test item had no toxicologically relevant effect on urinary parameters analysed at the end of the treatment period and recovery period.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
In females, no test item-related effects were observed in any of the parameters of the functional observation battery before and at the end of the treatment period and also at the end of recovery period.
Immunological findings:
not examined
Description (incidence and severity):
The study method may give a basic indication of immunological effects, however, no particular investigation were performed for this purpose
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A slightly to moderately increased kidney weight (relative and absolute) was observed in female animals of the HD group at the end of the treatment (13 % and 17 % above controls, respectively) and was statistically significant also at the end of the recovery period (8 % and 15 % above controls, respectively). A slight, statistically significant decreased liver weight (relative) was observed in female animals of the MD group (9 % below controls) at the end of treatment
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test item-related macroscopic findings correlating with histopathology changes were observed in kidney and livers of the HD group males at the end of treatment and recovery period. Ureters were dilated in 1/10 female animals of the LD group (animal no. 61) and in 2/10 female animals (animal nos. 81, 82) of the HD group. A fluid-filled dilated uterus (both horns) was observed in control recovery female no. 91; white spotted adrenal glands were observed in MD female no. 74; a red spotted thymus was observed in control female no. 57.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver: Test item-related changes were observed in decedent and surviving animals from the HD group only. In all moribund and decedent animals minimal to marked microvesicular fatty change was observed. Additionally, slight hepatocellular necrosis was noticed in the decedent Animal No. 33. In surviving animals from the HD group (treatment and recovery periods), minimal microvesicular fatty change was observed. Minimal hepatocellular necrosis (single cell necrosis) was also observed in Animal No. 39.
Further, in Animal No. 14 (LD group), hepatocellular necrosis was observed. The above-mentioned hepatic change was associated with severe congestion and moderate hemorrhage and was not considered to be a test item-related finding, but rather an incidental finding.
Kidney: Test item-related changes were observed in decedent and surviving animals from the HD group only. In decedent animals from the HD group, slight to moderate tubular dilatation and minimal tubular necrosis were observed. Furthermore, severe tubular dilatation, minimal to slight tubular necrosis, slight tubular basophilia and slight multifocal mineralization (dystrophic change) were observed.
In surviving males from the HD group (end of treatment period), moderate to severe tubular dilatation, minimal to moderate mononuclear and mixed cell infiltrates in the tubular lumen and renal interstitium, slight to moderate interstitial fibrosis, slight tubular necrosis, slight tubular basophilia and minimal to slight mineralization were observed. Additionally, moderate mixed cell infiltrates and minimal tubular dilatation were noticed in females from the same group,. In recovery males from the HD group, minimal to slight tubular dilatation, slight to moderate mixed cell infiltrates, minimal to slight mononuclear cell infiltrates, slight to moderate fibrosis, slight tubular necrosis and slight to moderate tubular basophilia were observed, whereas in females no histopathological changes were noticed.

Heart: Cardiac lesions that could be attributed to the treatment with the test item were observed in decedent recovery animals from the HD group only. These cardiac changes consisted of moderate myocardial mineralization, slight vascular mineralization (e.g. tunica media of aorta and few coronary vessels), slight cardiomyocytes necrosis and slight mononuclear infiltrates.
All other recorded findings were considered incidental or were within the range of spontaneous background alterations that may be recorded in Wistar rats at these ages. No histological evidence of toxicity in the reproductive organs and tissues including testes, epididymides, prostate gland, seminal vesicles, coagulating glands, ovaries, uterus and cervix, and vagina could be detected. The tubular stages of the spermatogenic cycle were checked for completeness of cell populations, completeness of stages and degenerative changes. No treatment-related effects on the testicular histomorphology were observed. Moreover, no treatment-related effect on interstitial cell structure was noticed.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no test item treatment-related effects observed on the number of pre-implantation loss and post implantation loss in LD, MD and HD groups when compared with the control group.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There were no test item-related effects on the reproductive indices (copulation, fertility, viability and delivery indices) in the dose groups when compared to the control group.
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no test item-related effects on the reproductive indices (copulation, fertility, viability and delivery indices) in the dose groups when compared to the control group.
Dead fetuses:
no effects observed
Description (incidence and severity):
No test item-related effect on mean mortality of pups between PND 0 and PND 4 and during PND 4-13 in LD and HD groups. However, a slightly and statistically significant higher mean mortality of pups on PND 0-4 was observed in the MD group (5.41 %). As this effect was not dose-dependent, it is not considered to be an adverse effect of the test item.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
There was no test item-related or statistically significant effect observed on the duration of precoital interval and the duration of gestation in the LD, MD and HD groups when compared to the control group.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There were no test item-related effects on the reproductive indices (copulation, fertility, viability and delivery indices) in the dose groups when compared to the control group.
Other effects:
no effects observed

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive effects
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse reproductive effects were observed in maternal animals
Key result
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
ca. 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: Based on histopathological changes in liver and kidneys.

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There was no test item-related or statistically significant effect on pup mean weight, total litter weight, male litter weight, or female litter weight on PND 0, PND 4 and PND 13 observed in LD, MD and HD groups when compared with the controls.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were no test item-related or statistically significant effects observed in LD, MD and HD groups on litter data parameters like group mean total number of pups born number of live pups, still birth, runt on PND 0 as well as number of live pups on PND 4 and PND 13 when compared with the controls.. No test item-related effect on mean mortality of pups between PND 0 and PND 4 and during PND 4-13 in LD and HD groups. However, a slightly and statistically significant higher mean mortality of pups on PND 0-4 was observed in the MD group (5.41 %). As this effect was not dose-dependent, it is not considered to be an adverse effect of the test item.
Changes in sex ratio:
not examined
Description (incidence and severity):
There were no test item-related or statistically significant effects observed in LD, MD and HD groups on litter data parameters like number of male pups, number of female pups, sex ratio, as well as number of male and female pups and sex ratio on PND 4 and PND 13 when compared with the controls.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There was no test item-related or statistically significant effect on pup mean weight, total litter weight, male litter weight, or female litter weight on PND 0, PND 4 and PND 13 observed in LD, MD and HD groups when compared with the controls.
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
No test item-related effect on mean mortality of pups between PND 0 and PND 4 and during PND 4-13 in LD and HD groups. However, a slightly and statistically significant higher mean mortality of pups on PND 0-4 was observed in the MD group (5.41 %). As this effect was not dose-dependent, it is not considered to be an adverse effect of the test item.
External malformations:
no effects observed
Description (incidence and severity):
No test item-related gross external abnormalities of toxicological relevance on PND 0-12 were observed in the pups of any of the groups.
A few specific findings like flattened abdomen (pup no. 13 from dam no. 56) and missing tail tip (pup no. 1 from dam no. 60) of control group were observed. No indication of suckling on PND4 for the pups 1-15 from dam no. 68 of LD was observed. No indication of suckling on PND0 for pup 10 and dark head for the pup 4 from dam no. 73 of MD were observed. All these findings were considered to be spontaneous and not related to test item treatment.
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
In male and female pups, no test item-related effects in absolute and relative anogenital distance were observed in the dose groups when compared to the controls.
No statistically significant effect or toxicological relevance was observed on nipple retention in the male pups of any of the groups when compared with the controls.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed in F1

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Summary result rables and individual animal data result tables will be added at a later date when they are available.

Applicant's summary and conclusion

Conclusions:
In the Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with 2,4,6-tris[3-(trimethoxysilyl)propyl] isocyanurate, conducted according to OECD Test Guideline 422 and in compliance with GLP, concluded a NOAEL of 1000 mg/kg bw/day for developmental toxicity based on no effects observed in F1 at the highest dose tested.