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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
07.02.2000 to 26.07.2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: partial revision of 'Test method of new chemical substances' in Kanpogyo No. 700, Yakuhatsu No. 1039 and 61 kikyoku No. 1014 dated 5th Dec 1986
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of 4,4,15,15-tetraethoxy-3,16-dioxa-8,9,10,11-tetrathia-4,15-disilaoctadecane and 4,4,14,14-tetraethoxy-3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane and 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
EC Number:
915-673-4
Cas Number:
211519-85-6
Molecular formula:
C18H42O6SxSi2
IUPAC Name:
Reaction mass of 4,4,15,15-tetraethoxy-3,16-dioxa-8,9,10,11-tetrathia-4,15-disilaoctadecane and 4,4,14,14-tetraethoxy-3,15-dioxa-8,9,10-trithia-4,14-disilaheptadecane and 4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
Constituent 2
Reference substance name:
Polysulfides
IUPAC Name:
Polysulfides

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan Inc.
- Age at study initiation: Five weeks
- Weight at study initiation: Males: 126.7-142.5 g; Females: 113.4-125.5 g
- Fasting period before study: No data
- Housing: Individually in stainless steel cages with wire floors
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Yes, but period not specified


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ±2
- Humidity (%): 55 ±10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 07.02.2000 to 26.07.2000

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Test substance was accurately weighed and dissolved in olive oil. The mixture of 0.08, 0.4 and 2 % w/v were made from 10% w/v mixture by dilution. The 10% mixture was prepared once per week and dilutions were conducted later.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Olive oil used as TS not stable in water
- Concentration in vehicle: 10, 2, 0.4 and 0.08% w/v
- Amount of vehicle (if gavage): Total volume doses: 10 ml/kg
- Lot/batch no. (if required): 011OOA
- Purity: No data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily (7 days/week)
Doses / concentrationsopen allclose all
Dose / conc.:
8 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Six
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A repeated dose 14-day pretest was conducted using doses of 50, 250 and 1000 mg/kg bw/day. Adverse effects were observed at all doses. Therefore the doses were adjusted for the current 28-day study to try and determine a NOAEL.
- Rationale for selecting satellite groups: To investigate reversibility of effects
- Post-exposure recovery period in satellite groups: 14 day post-exposure group for control and 1000 mg/kg bw/day groups
Positive control:
No positive control

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least one per day for general clinical observations. At least twice per day for mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before start of exposure and then once per week (all groups, except recovery groups)

BODY WEIGHT: Yes
- Time schedule for examinations: Day prior to start of exposure, then on day 1 (at 1st administration), 3, 8, 12, 17, 21, 26, 28 during the administration period, and on day 1, 5, 10 and 14 during the recovery period.

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of treatment and recovery periods
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: All
- Parameters checked in table No.1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of treatment and recovery periods
- Animals fasted: Yes
- How many animals: All
- Parameters checked in table No.1 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: On the last day of of administration and recovery periods (16 hour collection prior to scheduled sacrifice)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table No.1 were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Fourth week of exposure period and second week of recovery period
- Dose groups that were examined: All
- Battery of functions tested: Sensory activity to different types of stimulation, grip strength and locomotor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Other examinations:
None reported.
Statistics:
All data were evaluated with Bartlett's test for an equal variance and if the equality of variance was valid at 5% confidence limit, ONE-way ANOVA was used. If significant differences were obtained with ANOVA, data from control and treatment groups were compared by Dunnett test. If the equality of variance was no established, Kruskal-Wallis test was used. If significant differences were obtained, data from control and treatment groups were compared by nonparametric Dunnett test. Furthermore, FOB data were analysed with Kruskal-Wallis test, and if significant difference was obtained, data were further analysed with nonparametric Dunnett test.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no deaths related to treatment. Clinical signs were salivation and staining around the nose and mouth. Salivation was observed in all dose groups, and is generally associated with gavage dosing.

BODY WEIGHT AND WEIGHT GAIN: No adverse effects.

FOOD CONSUMPTION: No adverse effects.

HAEMATOLOGY: Haematological examinations revealed an increase in prothrombin time and activated partial thromboplastin time in the males of the 1000 mg/kg bw/day group at the end of the treatment period. Changes were thought to be secondary to effects on the liver.

CLINICAL CHEMISTRY: Blood chemistry tests revealed an increase in total proteins and albumin in males and females, an increase in calcium in males, an increase in gamma-GPT, GPT, total cholesterol and a decrease in alkaline phosphatase in females, in groups dosed with 1000 mg/kg bw/day. Changes were thought to be secondary to effects on the liver.

URINALYSIS: No adverse effects.

NEUROBEHAVIOUR: No adverse effect on sensory activity and locomotor activity.

ORGAN WEIGHTS: At the end of the treatment period there was an increase in liver weights in males and females, and an increase in kidney weights in males in groups dosed with 1000 mg/kg bw/day.

GROSS PATHOLOGY: An increase in liver weights was also observed in females of the 1000 mg/kg bw/day group. During necropsy, enlarged liver was also observed at the end of the recovery period in males and females dosed with 1000 mg/kg bw/day.

HISTOPATHOLOGY: Centrilobular hepatocyte hypertrophy in males and females, and basophilic renal tubules in males at the end of the administration period in the 1000 mg/kg bw/day group. There was also an increase in acidophilic bodies and hyaline droplets observed in males in the 200 mg/kg bw/day group. The basophilic renal tubules in males, and increased relative liver weight in females in the highest dose group were still present at the end of the recovery period. However, the effects in the liver appeared to be reversible, as weights were reducing and histopathological changes were not apparent by the end of the recovery period.

Effect levels

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on liver hypertrophy at 1000 mg/kg bw/day. Kidney effects assumed not relevant to humans.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a 28-day repeated dose oral gavage study, conducted to a national standard method and GLP (reliability score 1), the NOAEL for TESPPS was 200 mg/kg bw/day, based on adverse effects in the liver (enlarged liver accompanied by finding of centrilobular hypertrophy) at the higher dose of 1000 mg/kg bw/day. There were also adverse effects in the kidneys of male rats at 200 and 1000 mg/kg bw/day; however, these appeared to be alpha 2u-globulin-type effects, and have been discounted as not relevant to humans by the author of this EPSR.