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Description of key information

In a study conducted according to OECD Test Guideline 408 and in compliance with GLP (Charles River Laboratories, 2021a, reliability score 1), Wistar Han rats were administered 3-(triethoxysilyl)propanethiol (CAS No. 14814-09-6, EC No. 238-883-1) at 0, 100, 300, and 900 mg/kg bw/day via oral gavage (corn oil vehicle) for 7 days/week over 13 weeks. The systemic NOAEL for 3-(triethoxysilyl)propanethiol was <100 mg/kg bw/day, based on degenerative renal effects in females at 100 mg/kg bw/day (tubular degeneration and inflammatory cell infiltrates). For males, the systemic NOAEL was 100 mg/kg bw/day, based on renal effects starting at 300 mg/kg bw/day (above findings plus granular casts and papillary necrosis at 900 mg/kg bw/day). For local effects in the stomach (glandular and/or non-glandular), the NOAELs for females and males were 100 and 300 mg/kg bw/day, respectively.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2020/08/04 - 2022/04/2022
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Han
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 7-8 weeks
- Weight at study initiation: Males weighed between 178 and 219 g and females between 136 and 177 g
- Fasting period before study: No, except during designated procedures. During motor activity measurements, animals had no access to food for a maximum of 2 hours.
- Housing: Up to 5 animals of the same sex and same dosing group housed together in polycarbonate cages (Makrolon type 2000P )
- Diet: SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany, ad libitum
- Water: Municipal tap water, ad libitum
- Acclimation period: 14 days

DETAILS OF FOOD AND WATER QUALITY:
Results of analysis for nutritional components and environmental contaminants were provided by the supplier and are on file at the Test Facility. Periodic analysis of the water was performed, and results of these analyses are also on file. It is considered that there were no known contaminants in the feed or water that would interfere with the objectives of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22
- Humidity (%): 47 to 77
- Air changes (per hr): 10 or more
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2020/09/02 To: 2021/01/14
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
dried and deacidified
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared weekly. Dose formulations were homogenized to visually acceptable levels, and divided into aliquots where required to allow dispensation on each dosing occasion. Weekly preparations stored at 2-8C. An adjustment was made for specific gravity of the test item. No correction was made for the purity/composition of the test item.

VEHICLE
- Justification for use and choice of vehicle: Trial preparations were performed (separate from this study) to select the suitable vehicle
- Concentration in vehicle: 0, 25, 75, 225 mg/ml
- Amount of vehicle (if gavage): 4 ml/kg bw dose volume
- Lot/batch no.: MKCK6411, MKCM3364
- Purity: Not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulation samples were obtained for weeks 1, 6 and 13, and analyzed for concentration (all groups) and homogeneity (groups 2 and 4) using a validated analytical procedure
Duration of treatment / exposure:
7 days a week for a minimum of 13 weeks
Frequency of treatment:
Once daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
900 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10M/10F main, 5M/5F 28 day recovery
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on the results of a 14-day oral range finding study, and in attempt to produce graded responses to the test item
- Rationale for animal assignment: Random
- Fasting period before blood sampling for clinical biochemistry: Overnight with maximum of 24 hours
- Rationale for selecting satellite groups: To assess recovery from or delayed toxicity
- Post-exposure recovery period in satellite groups: 28 days
- Section schedule rationale (if not random): Not specified
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- All main and recovery animals: At least once daily from treatment day 1, during dosing

DETAILED CLINICAL OBSERVATIONS: Yes
- All main and recovery animals: Once pre-treatment, weekly during treatment and recovery, and on the day of necropsy

BODY WEIGHT: Yes
- All main and recovery animals: Weekly from at least day 1 and throughout the study. Fasted weight on the day of necropsy.

FOOD CONSUMPTION: Yes
- All main and recovery animals: Weekly from at least day 1 and throughout the study. Quantitatively measured per cage.

FOOD EFFICIENCY: No

WATER CONSUMPTION: Yes
- All main and recovery animals: Regular basis throughout the study. Monitored by visual inspection of the water bottles.

OPHTHALMOSCOPIC EXAMINATION: Yes
- All main and recovery animals: Once
- All group 1 (control) and group 4 (900 mg/kg bw/day) main study animals: During week 13
- Using ophthalmoscope after application tropicamide 5 mg/ml solution

HAEMATOLOGY: Yes
- All main and recovery animals: At the end treatment / recovery. After fasting (24 hour maximum) and under isoflurane anesthesia.
- See Table 1 below

COAGULATION PARAMETERS: Yes
- All main and recovery animals: At the end treatment / recovery. After fasting (24 hour maximum) and under isoflurane anesthesia.
- For prothrombin time (PT) and activated partial thromboplastin time (APTT)

CLINICAL CHEMISTRY: Yes
- All main and recovery animals: At the end treatment / recovery. After fasting (24 hour maximum) and under isoflurane anesthesia.
- See Table 2 below

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- The first 5 animals per sex per group during week 12-13 of dosing. These tests were performed after clinical observations.
- Endpoints evaluated: Hearing ability, pupillary reflex, static righting reflex, fore- and hind-limb grip strength, locomotor activity (total movements and ambulations)

IMMUNOLOGY: No

OESTROUS CYCLE DETERMINATION: Yes
- All main and recovery animals: At the end of treatment / recovery, on the day of necropsy, via vaginal smear to determine the stage of estrus
Sacrifice and pathology:
SACRIFICE
- All main and recovery animals: All animals survived until scheduled euthanasia, were weighed, and euthanized using isoflurane, followed by exsanguination. Animals were fasted (maximum of 24 hours) before their scheduled necropsy.
- The terminal procedures are summarized in Table 3 below

ORGAN WEIGHT: Yes
- All main animals and group 0 (control) and group 4 (900 mg/kg bw/day) recovery animals: Organs in Table 4 were weighed, with organ weights relative to body weight calculated

GROSS PATHOLOGY: Yes
- All main animals and group 0 (control) and group 4 (900 mg/kg bw/day) recovery animals: Subjected to a complete necropsy examination of carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues.

HISTOPATHOLOGY: Yes
A microscopic examination was performed on:
- Group 1 (control) and group 4 (900 mg/kg bw/day) main animals: Full list of tissues in Table 5 except for nasal body cavity, femur bone clitoral gland, harderian gland, lacrimal gland, preputial gland, parotid salivary gland, larynx, tibial nerve and tongue
- Group 2 (100 mg/kg bw/day) and group 3 (300 mg/kg bw/day) main animals: Gross lesions plus targeted tissues (kidney, urinary bladder, liver, lung, stomach and mesenteric lymph node in males and females and thymus, testes, epididymides and ureter in males)
- Group 0 (control) and group 4 (900 mg/kg bw/day) recovery animals: Gross lesions plus targeted tissues (same targeted as group 2 and 3 main animals)
Statistics:
Varied by endpoint / dataset evaluated and included:
- Descriptive analysis: Means, standard deviations (or % coefficient of variation or standard error, when deemed appropriate), ratio, percentages, numbers, and/or incidences, reported as appropriate by dataset
- Parametric / non-parametric methods: Collectively, Levene’s test, one-way ANOVA F-test, Kruskal-Wallis test, Dunnett’s or Dunn’s test, analysis of covariance (ANCOVA), and Fisher’s exact test
- All statistical tests were conducted at the 5% significance level
- All pairwise comparisons were conducted using two sided tests and were reported at the 1% or 5% levels. Pairwise comparisons were made for: group 2 (100 mg/kg bw/day), group 3 (300 mg/kg bw/day), and group 4 (900 mg/kg bw/day), each versus group 1 (control).
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Up to 300 mg/kg bw/day, no toxicologically relevant clinical signs were observed in males or females

At 900 mg/kg bw/day (^ considered adverse):
- Erect fur and hunched posture were observed in all animals from day 17 and 31 onwards, respectively ^
- Urogenital staining was noted in 11/15 females from day 34 onwards ^
- Hypersensitivity was noted in 3/15 females on one or more days from day 87 onwards
- Transient tremors, convulsions and increased activity were noted in one female on day 92, which transitioned into decreased activity and prostate posture
- Shallow breathing or decreased activity were incidentally noted in two males

During the first days of the recovery period, erect fur, hunched posture and/or urogenital staining were still noted. Thereafter, no relevant clinical signs were noted.

Any other clinical signs were considered not related to the test item, or not toxicologically relevant.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 100 mg/kg bw/day in males and up to 900 mg/kg bw/day in females, no toxicologically relevant effect on body weight.

At 300 mg/kg bw/day in males, not specified as adverse (not statistically significant):
- Lower body weight (down to 7.8% on Day 91) compared to the control from Day 57 onwards
- Lower body weight gain between days 36 and 43

At 900 mg/kg bw/day in males (^ considered adverse):
- Lower body weight (down to 22.3% on day 91) compared to the control from Day 15 onwards ^
- Lower body weight gain throughout the dosing period ^
- During recovery, higher body weight gain compared to the control group in the first three weeks (up to 11.4x higher), followed by similar body weight gains in the final week, suggesting a full recovery
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 100 mg/kg bw/day in males and up to 900 mg/kg bw/day in females, no toxicologically relevant effect on food consumption.

At 300 mg/kg bw/day in males, not specified as adverse:
- Lower food consumption (down to 11.6% between days 85-91) compared to the control group from day 50 onwards

At 900 mg/kg bw/day in males (^ considered adverse):
- Lower food consumption (down to 23.1% between days 78-85) throughout the dosing period ^
- During recovery, higher food consumption was seen in the males compared to the control in the first three weeks (up to 13.4% between days 92-99), followed by a lower food consumption (-18.6% between days 113-120) in the last week, suggesting a partial recovery
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Description (incidence and severity):
Water consumption was monitored by visual inspection of the water bottles, results not reported
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No ophthalmology findings were considered related to treatment with the test item. The nature and incidence of ophthalmology findings during the pre-treatment period and in week 13 occurred within the range considered normal for rats of this age and strain.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Up to 300 mg/kg bw/day in males and at 100 mg/kg bw/day in females, no toxicologically relevant changes were noted in haematological parameters. None of the findings were considered adverse.

At 300 and/or 900 mg/kg bw/day in females, not considered adverse:
- At both doses, increase in white blood cell, lymphocyte and large unstained cell counts
- Additionally at 900 mg/kg bw/day, increase in neutrophil, monocyte and eosinophil counts
- At end of recovery, all findings showed an opposite effect compared to end of treatment

At 900 mg/kg bw/day in males, not considered adverse:
- Increased concentrations of neutrophils, monocytes, large unstained cells (LUCs) and platelets
- At end of recovery, neutrophils, monocytes and platelets concentrations normalized, but LUCs showed an opposite effect compared to end of treatment

See summary findings in Table 6 below.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At 100 mg/kg bw/day in females, no toxicologically relevant changes were noted in clinical chemistry parameters. Except for urea (both sexes) and total protein (males) at 900 mg/kg bw/day which correlated with renal histopathology, none of the findings were considered adverse.

At 100, 300, and/or 900 mg/kg bw/day in males (^ considered adverse):
- At all three doses, increased alanine aminotransferase (ALT) activity.
- Additionally at 300 and 900 mg/kg bw/day, increased concentrations of albumin and potassium, and decreased thyroxine (T4) concentrations
- Additionally at 900 mg/kg bw/day, increased total protein ^, urea ^, calcium and phospholipids concentration and decreased concentrations of cholesterol and HDL cholesterol. The urea and total protein findings correlated with the renal histopathology
- At end of recovery, all changes normalized except ALT activity, which showed an opposite effect compared to end of treatment

At 300 and/or 900 mg/kg bw/day in females (^ considered adverse):
- At both doses, increased concentrations of cholesterol, HDL cholesterol and calcium, and decreased concentrations of total bilirubin, T3 and T4
- Additionally at 900 mg/kg bw/day, increased ALT activity, and increased concentrations of urea ^, phospholipids and TSH
- At end of recovery, all changes normalized except ALT activity, total bilirubin and TSH at 900 mg/kg bw/day, which showed an opposite effect compared to end of treatment

See summary findings in Table 7 below.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Hearing ability, pupillary reflex and static righting reflex were normal in all examined animals and grip strength was similar between control and high dose (900 mg/kg bw/day) animals. None of the neurobehavioural findings were considered adverse.

Up to 900 mg/kg bw/day in males and up to 300 mg/kg bw/day in females, motor activity was similar between treated and control groups.

At 900 mg/kg bw/day in females, a decrease in motor activity (total movements and ambulations) was observed compared to the control, but at the severity observed, this finding was considered not toxicologically relevant or adverse.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were test item-related organ weight changes in adrenal glands, kidney, liver and thymus of males and females. Except for increased kidney weights (females from 100 mg/kg bw/day and males from 300 mg/kg bw/day) which correlated with renal histopathology, none of the findings were considered adverse.

Adrenal gland weight, not considered adverse:
- At 900 mg/kg bw/day, statistically significant increase in males (relative to body weight) and females (absolute and relative)
- No microscopic correlate identified

Kidney weight, considered adverse:
- At 100 to 900 mg/kg bw/day in females, statistically significant increase (absolute and relative), remained higher in recovery (900 mg/kg bw/day) females
- At 900 mg/kg bw/day in males, statistically significant increase (absolute)
- At 300 and 900 mg/kg bw/day in males, statistically significant increase (relative), remained higher in recovery (900 mg/kg bw/day) males
- Correlated with microscopic findings in both sexes (tubular degeneration, inflammatory cell infiltrates, tubular basophilia, tubular dilatation)

Liver weight, not considered adverse:
- At 300 and 900 mg/kg bw/day in females, statistically significant increase (absolute and relative), absolute remained higher in recovery (900 mg/kg bw/day) females
- At 300 and 900 mg/kg bw/day in males, statistically significant increase (relative)
- Correlated with microscopic findings in both sexes (centrilobular hypertrophy)

Thymus weight, not considered adverse:
- At 900 mg/kg bw/day in males and females, statistically significant decrease (absolute and relative)
- In males, correlated with microscopic findings (lymphoid depletion), no correlate identified for females

All other statistically significant effects on organ weight were considered not related to the test item or considered a result of the test item impact on final body weight in males (25% body weight loss).

See summary findings in Table 8 below.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test item-related macroscopic findings were present in males in the epididymides, thymus, ureter and urinary bladder, and locally in males and females in the stomach. Except for urinary bladder / ureter (males) and local stomach findings (both sexes) at 900 mg/kg bw/day which correlated with histopathology, none of the findings were considered adverse.

Locally in the stomach, considered adverse:
- At 900 mg/kg bw/day in males, glandular, thick; non-glandular, discolouration and/or irregular surface; discoloration also noted in one recovery male at 900 mg/kg bw/day
- At 900 mg/kg bw/day in females, non-glandular, discolouration, no effects at recovery
- Correlated with microscopic findings (ulceration/erosion and/or edema and/or inflammatory cell infiltrates (glandular), and hyperplasia/hyperkeratosis (non-glandular)

In the thymus, not considered adverse:
- At 100 to 900 mg/kg bw/day in males, small size, also noted in one recovery male at 900 mg/kg bw/day
- Correlated with microscopic findings (lymphoid depletion)

In the urinary bladder / ureter, considered adverse:
- At 900 mg/kg bw/day in males, thick wall or nodule (bladder), dilatation (ureter)
- Correlated with microscopic findings (bladder: diffuse epithelial hyperplasia, presence of crystals; ureter: luminal dilatation)

In the epididymides, not considered adverse:
- At 900 mg/kg bw/day in males, nodule
- Correlated with microscopic findings (sperm granuloma)

The remaining macroscopic findings were within the range of background for rats of this age and strain.

See summary findings in Table 9 below.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Test item-related microscopic findings were noted in the kidney, urinary bladder / ureter, liver, lung and locally in the stomach of males and females, and in the thymus, testes and epididymides of males. The kidney, urinary bladder / ureter, and local stomach findings were considered adverse.

In males, test item-related microscopic findings consisted of adverse degenerative findings in the kidney, such as granular casts and/or tubular degeneration and/or papillary necrosis and/or inflammatory cell infiltrates at a minimal to marked degree, and non-adverse regeneration-related findings such as tubular basophilia, tubular dilatation, hyperplasia of the papillary epithelium at a minimal to severe degree, starting at 300 mg/kg bw/day. In addition, mild urothelial hyperplasia and ulceration (together with the presence of crystals) were observed in the urinary bladder, and dilatation of the lumen up to a moderate degree was present in the ureters of males treated at 900 mg/kg bw/day. After the recovery period, microscopic findings including basophilia, inflammatory cell infiltrates, tubular dilatation and fibrosis remained present in the kidney, and urothelial hyperplasia and dilatation of the lumen in the urinary bladder and ureters, respectively, were still present at minimal degree, suggesting partial recovery.

Other test item-related findings in males showed full recovery, including minimal centrilobular hypertrophy and minimal to mild microvesicular vacuolation in the liver of males of all treatment groups, an increased incidence of alveolar macrophages up to a mild degree in the lung at 900 mg/kg bw/day, a minimal increased incidence of lymphoid depletion in the thymus at 900 mg/kg bw/day, an increased incidence of minimal germ cell degeneration and the presence of minimal abnormal residual bodies in the testes, with an increased incidence of minimal to marked sperm granulomas in the epididymides in males treated at 900 mg/kg bw/day and, locally in the stomach, glandular stomach ulceration and erosion together with submucosal edema and eosinophilic infiltrates up to a moderate degree and non-glandular hyperplasia and/or hyperkeratosis up to a mild degree at 900 mg/kg bw/day.

In females, test item-related microscopic findings consisted of urothelial hyperplasia up to moderate degree in the urinary bladder in all females starting at 300 mg/kg bw/day. This finding was still present up to a mild degree in all recovery females treated at 900 mg/kg bw/day, suggesting partial recovery.

Other test-item related findings in females showed a full recovery, including degenerative findings such as tubular degeneration and/or inflammatory cell infiltrates up to a moderate and mild degree, respectively, and regeneration-related findings such as tubular basophilia, tubular dilatation and hyperplasia of the papillary epithelium (up to a marked, mild and minimal degree, respectively) in the kidney starting at 100 mg/kg bw/day with a higher incidence and/or severity at 300 mg/kg bw/day compared to 900 mg/kg bw/day, minimal centrilobular hypertrophy in the liver in all test item-treated females, minimal to mild microvesicular vacuolation in females starting at 300 mg/kg bw/day, an increased incidence of alveolar macrophages up to a mild degree at 900 mg/kg bw/day and non glandular ulceration and glandular erosion together with non-glandular submucosal edema and eosinophilic infiltrates up to a mild degree in the stomach starting at 300 mg/kg bw/day.

There were no other test item-related histologic changes in males or females. The remainder of the findings were within the range of background for rats of this age and strain.

See summary findings in Table 10 below.
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
COAGULATION PARAMETERS:
Up to 300 mg/kg bw/day in males and up to 900 mg/kg bw/day in females, no toxicologically relevant changes were noted in coagulation parameters. Coagulation findings were not considered adverse.

At 900 mg/kg bw/day in males, not considered adverse:
- Prolonged prothrombin time (PT; 1.12x of control), which normalized at the end of recovery.

OESTROUS CYCLE DETERMINATION:
Results to be provided as attached background material once the final study report is available.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Remarks on result:
other: Based on kidney histopathology findings (correlating with increased kidney weight) in males at 300 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Effect level:
< 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Remarks on result:
other: Based on kidney histopathology and increased kidney weight in females at 100 mg/kg bw/day
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
no
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (nominal)
System:
urinary
Organ:
bladder
ureter
Treatment related:
yes
Dose response relationship:
yes

Table 6. Summary of test item-related haematology changes

Dose (mg/kg bw/day)

100

300

900

Sex

M

F

M

F

M

F

White Blood Cells

 

 

 

 

 

 

End of Treatment

-

-

-

1.45

-

1.64/0.611

Neutrophils

 

 

 

 

 

 

   End of Treatment

-

-

-

-

2.01/0.911

1.82/0.431

Lymphocytes

 

 

 

 

 

 

End of Treatment

-

-

-

1.50

-

1.60/0.661

Monocytes

 

 

 

 

 

 

   End of Treatment

-

-

-

-

1.77/1.001

1.96/0.621

Eosinophils

 

 

 

 

 

 

End of Treatment

-

-

-

-

-

1.65/0.631

Large Unstained Cells

 

 

 

 

 

 

End of Treatment

-

-

-

1.70

1.45/0.471

2.30/0.851

Platelets

 

 

 

 

 

 

End of Treatment

-

-

-

-

1.18/1.021

-

- : not test item-related; x-fold changes compared to concurrent control group are given; changes indicated in bold reached statistical significance;1x-fold changes compared to concurrent control group at end of recovery.

 

Table 7. Summary of test item-related clinical chemistry changes

Dose (mg/kg bw/day)

100

300

900

Sex

M

F

M

F

M

F

ALT

 

 

 

 

 

 

End of Treatment

1.24

-

1.23

-

1.28/0.771

1.48/0.701

Urea

 

 

 

 

 

 

End of Treatment

-

-

-

-

1.47/1.151

1.39/0.961

Calcium

 

 

 

 

 

 

End of Treatment

-

-

-

1.09

1.09/0.971

1.08/1.021

Phospholipids

 

 

 

 

 

 

End of Treatment

-

-

-

-

1.37/0.921

1.22/0.951

Cholesterol

 

 

 

 

 

 

End of Treatment

-

-

-

1.19

0.78/1.011

1.21/1.121

HDL Cholesterol

 

 

 

 

 

 

End of Treatment

-

-

-

1.20

0.83/0.991

1.19/1.121

Albumin

 

 

 

 

 

 

End of Treatment

-

-

1.05

-

1.13/1.021

-

Potassium (K)

 

 

 

 

 

 

End of Treatment

-

-

1.08

-

1.17/0.991

-

Total protein

 

 

 

 

 

 

End of Treatment

-

-

-

-

1.08/1.011

-

Total bilirubin

 

 

 

 

 

 

End of Treatment

-

-

-

0.81

-

0.85/0.681

T3

 

 

 

 

 

 

End of Treatment

-

-

-

0.82

-

0.73/1.111

T4

 

 

 

 

 

 

End of Treatment

-

-

0.80

0.71

0.63/1.161

0.76/1.211

TSH

 

 

 

 

 

 

End of Treatment

-

-

-

-

-

1.42/0.281

- : not applicable; x-fold changes compared to concurrent control group are given; changes indicated in bold reached statistical significance ;1x-fold changes compared to concurrent control group at the end of recovery.

 

Table 8. Mean percent organ weight differences from control groups

Males

 

Main Males

Recovery Males

Dose Level (mg/kg bw/day):

100

300

900

900

 

 

 

 

 

Adrenal glands

 

 

 

 

              Absolute

10

-8

17

9

              Relative to body weight

9

2

54**

18

 

 

 

 

 

Kidneys

 

 

 

 

              Absolute

5

5

14*

13

              Relative to body weight

5

15*

52**

22*

 

 

 

 

 

Liver

 

 

 

 

              Absolute

7

7

1

0

              Relative to body weight

7

17**

35**

9

 

 

 

 

 

Thymus

 

 

 

 

              Absolute

-8

-13

-56**

-24

              Relative to body weight

-8

-5

-42**

-18

*: P<0.05, **: P<0.01


Females

 

Main Females

Recovery Females

Dose Level (mg/kg bw/day):

100

300

900

900

 

 

 

 

 

Adrenal glands

 

 

 

 

              Absolute

11

10

26**

-4

              Relative to body weight

6

7

30**

-7

 

 

 

 

 

Kidneys

 

 

 

 

              Absolute

18*

28**

22**

19*

              Relative to body weight

12*

24**

27**

16*

 

 

 

 

 

Liver

 

 

 

 

              Absolute

11

19**

33**

21*

              Relative to body weight

5

16**

38**

17

 

 

 

 

 

Thymus

 

 

 

 

              Absolute

-8

-16

-33**

13

              Relative to body weight

-12

-18

-30**

10

*: P<0.05, **: P<0.01

 

Table 9.Summary test item-related macroscopic findings

Males

 

Main Males

Recovery Males

Dose Level (mg/kg bw/day):

0

100

300

900

0

900

 

 

 

 

 

 

 

Urinary bladdera

10

10

10

10

5

5

      Thick; wall

-

-

-

1

-

-

      Nodule; clear, firm, yellow, wall

-

-

-

1

-

-

 

 

 

 

 

 

 

Ureter

10

10

10

9

5

5

      Dilatation

-

-

-

2

-

-

 

 

 

 

 

 

 

Stomacha

10

10

10

10

5

5

      Thick; glandular

-

-

-

4

-

-

      Focus, dark; brown, glandular

-

-

-

3

-

-

      Irregular surface; non-glandular

-

-

-

2

-

-

      Focus, pale; white, non-glandular

-

-

-

1

-

-

      Focus, dark; red, non-glandular

-

-

-

-

-

1

 

 

 

 

 

 

 

Thymus

10

10

10

10

5

5

      Small

-

1

1

8

-

1

 

 

 

 

 

 

 

Epididymidesa

10

10

10

10

5

5

      Nodule; yellow, soft/firm, head/tail

-

-

-

2

-

-

a = Number of tissues examined from each group. Test item-related findings in bold.

 

Females

 

Main Females

Recovery Females

Dose Level (mg/kg bw/day):

0

100

300

900

0

900

 

 

 

 

 

 

 

Stomacha

10

10

10

10

5

5

      Focus, dark-red, non-glandular

-

-

-

1

-

-

a = Number of tissues examined from each group. Test item-related findings in bold.

 

Table 10. Summary test item-related microscopic findings

Males

 

Main Males

Recovery Males

Dose Level (mg/kg bw/day):

0

100

300

900

0

900

 

 

 

 

 

 

 

Kidneya

10

10

10

10

5

5

    Cast, granular

 

 

 

 

 

 

      Minimal

-

-

-

1

-

-

      Mild

-

-

-

1

-

-

   Degeneration, tubular  

 

 

 

 

 

 

      Minimal

-

-

6

-

-

-

      Mild

-

-

-

2

-

-

      Moderate

-

-

-

1

-

-

      Marked

-

-

-

1

-

-

   Necrosis, papillary       

 

 

 

 

 

 

      Mild

-

-

-

1

-

-

      Moderate

-

-

-

2

-

-

   Infiltration,mononuclear

 

 

 

 

 

 

      Minimal

2

1

7

1

-

1

      Mild

1

-

2

1

-

-

   Infiltration,histiocytic

 

 

 

 

 

 

      Mild

-

-

-

1

-

-

   Infiltration,mixed cell

 

 

 

 

 

 

      Mild

-

-

-

1

-

-

      Moderate

-

-

-

1

-

1

   Basophilia, tubular

 

 

 

 

 

 

      Minimal

2

7

-

2

-

2

      Mild

1

1

2

1

-

1

      Moderate

-

-

8

2

-

-

     Severe

-

-

-

1

-

-

   Dilatation, tubular        

 

 

 

 

 

 

      Minimal

-

-

2

1

-

-

      Mild

-

-

1

-

-

-

      Moderate

-

-

-

1

-

-

      Marked

-

-

-

-

-

1

   Hyperplasia, epithelial 

 

 

 

 

 

 

      Minimal

-

-

-

2

-

-

   Fibrosis

 

 

 

 

 

 

      Marked

-

-

-

-

-

1

 

 

 

 

 

 

 

Urinarybladdera

10

10

10

10

5

5

   Hyperplasia, urothelial

 

 

 

 

 

 

      Minimal

-

-

-

-

-

3

      Mild

-

-

-

6

-

-

   Ulceration (and crystal present)

 

 

 

 

 

 

      Mild

-

-

-

1

-

-

 

 

 

 

 

 

 

Ureter

10

9

10

10

5

5

   Dilatation, lumen          

 

 

 

 

 

 

      Minimal

-

-

-

-

-

1

      Mild

-

-

-

1

-

-

      Moderate

-

-

-

1

-

-

 

 

 

 

 

 

 

Livera

10

10

10

10

5

5

   Hypertrophy, centrilobular         

 

 

 

 

 

 

      Minimal

-

2

2

3

-

-

   Vacuolation, microvesicular       

 

 

 

 

 

 

      Minimal

-

1

1

2

-

-

      Mild

-

-

-

2

-

-

 

 

 

 

 

 

 

Lunga

10

10

10

10

5

5

   Macrophages, alveolar

 

 

 

 

 

 

      Minimal

-

3

1

5

-

-

      Mild

-

-

1

4

-

1

 

 

 

 

 

 

 

Stomacha

10

10

10

10

5

5

   Ulceration, glandular   

 

 

 

 

 

 

      Moderate

-

-

-

2

-

-

   Erosion, glandular       

 

 

 

 

 

 

      Mild

-

-

-

1

-

-

   Edema, submucosal, glandular  

 

 

 

 

 

 

      Minimal

-

-

-

1

-

-

      Mild

-

-

-

2

-

-

      Moderate

-

-

-

1

-

-

   Infiltration, eosinophilic, glandular

 

 

 

 

 

 

      Minimal

-

-

-

1

-

-

      Mild

-

-

-

2

-

-

   Hyperplasia and/or hyperkeratosis

 

 

 

 

 

 

      Mild

-

-

-

2

-

-

 

 

 

 

 

 

 

Thymus

10

10

10

10

5

5

   Depletion, lymphoid

 

 

 

 

 

 

      Minimal

-

1

1

4

1

-

 

 

 

 

 

 

 

Testesa

10

10

10

10

5

5

   Degeneration, germ cells

 

 

 

 

 

 

      Minimal

-

1

2

4

1

-

   Abnormal residual bodies

 

 

 

 

 

 

      Minimal

-

-

-

3

-

-

 

 

 

 

 

 

 

Epididymidesa

10

10

10

10

5

5

   Sperm granuloma

 

 

 

 

 

 

      Minimal

-

-

-

3

-

-

      Marked

-

-

-

1

-

-

a = Number of tissues examined from each group.Test item-related findings in bold.

 

Females

 

Main Females

Recovery Females

Dose Level (mg/kg bw/day):

0

100

300

900

0

900

 

 

 

 

 

 

 

Kidneya

10

10

10

10

5

5

   Degeneration, tubular  

 

 

 

 

 

 

      Minimal

-

5

1

-

-

-

      Mild

-

-

5

-

-

-

      Moderate

-

-

4

1

-

-

   Infiltration,mononuclear

 

 

 

 

 

 

      Minimal

1

4

1

-

-

-

      Mild

-

-

9

1

-

-

 

 

 

 

 

 

 

   Basophilia, tubular

 

 

 

 

 

 

      Minimal

-

2

-

-

-

1

      Mild

-

4

-

-

-

-

      Moderate

-

2

9

1

-

-

      Marked

-

-

1

-

-

-

   Dilatation, tubular        

 

 

 

 

 

 

      Minimal

-

-

1

-

-

-

      Mild

-

-

2

-

-

-

      Moderate

-

-

-

-

-

-

      Marked

-

-

-

-

-

-

   Hyperplasia, epithelial 

 

 

 

 

 

 

      Minimal

-

-

-

1

-

-

   Fibrosis

 

 

 

 

 

 

      Minimal

-

1

-

-

-

-

      Marked

-

-

-

-

-

-

 

 

 

 

 

 

 

Urinary bladdera

10

10

10

10

5

5

   Hyperplasia, urothelial

 

 

 

 

 

 

      Minimal

-

-

1

2

-

1

      Mild

-

-

-

3

-

4

      Moderate

-

-

-

5

-

-

 

 

 

 

 

 

 

Livera

10

10

10

10

5

5

   Hypertrophy, centrilobular         

 

 

 

 

 

 

      Minimal

-

1

5

5

-

-

   Vacuolation, microvesicular       

 

 

 

 

 

 

      Minimal

-

-

6

5

-

-

      Mild

-

-

-

1

-

-

 

 

 

 

 

 

 

Lunga

10

10

10

10

5

5

   Macrophages, alveolar

 

 

 

 

 

 

      Minimal

2

-

2

5

1

1

      Mild

-

-

-

3

-

-

 

 

 

 

 

 

 

Stomacha

10

10

10

10

5

5

   Ulceration, non-glandular          

 

 

 

 

 

 

      Minimal

-

-

1

-

-

-

      Mild

-

-

-

1

-

-

   Erosion, glandular       

 

 

 

 

 

 

      Mild

-

-

-

1

-

-

   Edema, subm., non-glandular     

 

 

 

 

 

 

      Mild

-

-

-

1

-

-

   Infiltration, eosinoph., non-gland.

 

 

 

 

 

 

      Mild

-

-

-

2

-

-

a = Number of tissues examined from each group. Test item-related findings in bold.

Conclusions:
In a study conducted according to OECD Test Guideline 408 and in compliance with GLP (reliability score 1), Wistar Han rats were administered 3-(triethoxysilyl)propanethiol (CAS No. 14814-09-6, EC No. 238-883-1) at 0, 100, 300, and 900 mg/kg bw/day via oral gavage (corn oil vehicle) for 7 days/week over 13 weeks. The systemic NOAEL for 3-(triethoxysilyl)propanethiol was <100 mg/kg bw/day, based on degenerative renal effects in females at 100 mg/kg bw/day (tubular degeneration and inflammatory cell infiltrates). For males, the systemic NOAEL was 100 mg/kg bw/day, based on renal effects starting at 300 mg/kg bw/day (above findings plus granular casts and papillary necrosis at 900 mg/kg bw/day). For local effects in the stomach (glandular and/or non-glandular), the NOAELs for females and males were 100 and 300 mg/kg bw/day, respectively.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Key reliability score 1 study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

3-(Triethoxysilyl)propanethiol has been evaluated in a study conducted according to OECD Test Guideline 408 and in compliance with GLP (Charles River Laboratories, 2021a, reliability score 1). Wistar Han rats were administered 3-(triethoxysilyl)propanethiol at 0, 100, 300, and 900 mg/kg bw/day via oral gavage (corn oil vehicle) for 7 days/week over 13 weeks. The main study included 10 rats per sex per dose group, with 5 rats per sex in the 28-day recovery (0 and 900 mg/kg bw/day) groups. Observations and examinations were conducted per OECD Test Guideline 408, including cage side observations, detailed clinical signs, functional observation tests, body weights, food consumption, ophthalmology, oestrous stage determination, clinical pathology parameters (haematology, coagulation, and clinical chemistry), organ weights, gross necropsy, and histopathologic examination.

 

As discussed below, the findings considered test item-related and adverse encompass: clinical signs; body weight / food consumption; gross and histopathology in the urinary bladder, ureter if present, locally in stomach; and renal-related clinical chemistry, kidney weight, and histopathology.

 

Clinical signs included hunched posture, erect fur, and urogenital staining observed at 900 mg/kg bw/day in males and/or females.

 

In males at 900 mg/kg bw/day, lower body weight (down to 22.3% on day 91) compared to the control was observed from day 15 onwards, with a lower body weight gain throughout the dosing period. Lower food consumption was also observed at 900 mg/kg bw/day in males (23.1% between days 78-85). Recovery data suggested full (body weight gain) or partial (food consumption) recovery.

 

Test item and adverse gross pathology was identified in the urinary bladder (both sexes), ureter (males) and locally in the stomach (both sexes) at 900 mg/kg bw/day, correlating with histopathology. The specific adverse findings included: urinary bladder (thick wall, nodule), ureter (dilatation, locally in the stomach (thick, irregular surface, and/or discolouration)). Except for one recovery male with a discoloured stomach, these findings were resolved at end of recovery.

Test item-related and adverse findings related to the kidney were identified based on clinical chemistry, kidney weight, and histopathology.

- Urea (both sexes) and total protein (males) were increased at 900 mg/kg bw/day which correlated with renal histopathology. The urea / total protein findings normalized at the end of recovery.

- Absolute and/or relative kidney weights were increased (females from 100 mg/kg bw/day and males from 300 mg/kg bw/day) which correlated with renal histopathology. Kidney weights remained higher at end of recovery in both sexes.

 

Upon histopathologic examination, both test item-related systemic and local findings were reported, with adverse effects noted for the kidney (both sexes, degenerative), urinary bladder (both sexes), ureter (males), and locally in the stomach (both sexes):

- Kidney (degenerative) starting at 300 mg/kg bw/day in males and 100 mg/kg bw/day in females, including up to marked tubular degeneration, papillary necrosis, granular casts, and/or inflammatory cell infiltrates, depending on sex and dose. Kidney weight correlation from 300 mg/kg bw/day in males and from 100 mg/kg bw/day in females. Clinical chemistry correlation at 900 mg/kg bw/day (both sexes).

- Urinary bladder and ureters at 900 mg/kg bw/day in males, up to mild hyperplasia and/or ulceration (with presence of crystals) in the bladder and up to moderate luminal dilatation in the ureter

- Urinary bladder at 900 mg/kg bw/day in females, minimal to moderate hyperplasia

- Stomach (glandular and non-glandular) at 900 mg/kg bw/day in males and starting at 300 mg/kg bw/day in females, including up to moderate ulceration, erosion, edema, and/or hyperplasia, depending on sex and dose.

- Recovery data suggested partial recovery from adverse effects in the male kidney, male urinary bladder / ureter, and female urinary bladder and a full recovery in the female kidney and stomach of both sexes.

 

The overall systemic NOAEL for 3 -(triethoxysilyl)propanethiol was <100 mg/kg bw/day, based on degenerative renal effects in females at 100 mg/kg bw/day (tubular degeneration and inflammatory cell infiltrates). For males, the systemic NOAEL was 100 mg/kg bw/day, based on renal effects starting at 300 mg/kg bw/day (above findings plus granular casts and papillary necrosis at 900 mg/kg bw/day). For local effects in the stomach (glandular and/or non-glandular), the NOAELs for females and males were 100 and 300 mg/kg bw/day, respectively.

 

In a 14-day range finding study conducted in compliance with GLP (Charles River Laboratories, 2021a, reliability score 2), Wistar Han rats (three per sex per dose group) were administered 3-(triethoxysilyl)propanethiol at 0, 100, 300, and 1000 mg/kg bw/day via daily oral gavage (corn oil vehicle) for 14 days. These endpoints were assessed: mortality, cage side clinical signs, body weight / food consumption, and organ weights / gross pathology (liver and kidney). Except as noted in the endpoint study record, the test system, procedures and techniques were identical to those used during the main study. The systemic NOAEL for 3-(triethoxysilyl)propanethiol was 300 mg/kg bw/day, based on effects at 1000 mg/kg bw/day in both sexes (clinical signs, decreased body weight / food consumption, increased liver weight). The findings were used for dose selection (0, 100, 300, and 900 mg/kg bw/day) for the main repeated dose study.

Justification for classification or non-classification

Based on the available OECD 408 test, 3-(triethoxysilyl)propanethiol does not require classification for specific target organ toxicity following repeated exposure in accordance with Regulation (EC) No. 1272/2008, as the observed effects in the female kidney within the classifiable range (100 mg/kg bw/day) were not indicative of ‘significant’ or ‘severe’ toxicity, i.e. not indicative of significant organ damage, multi-focal or diffuse granuloma formation, or of morphological changes that provide clear evidence of marked organ dysfunction.