Phosphorodithioic acid, O,O-di-C1-14-alkyl esters, zinc salts

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Data is from publication

Data source

Reference

Reference Type:

publication

Title:

A Developmental Toxicity Study in Rats.

Author:

WAHEED H. SIDDIQUI et. al.

Year:

1993

Bibliographic source:

FUNDAMENTAL AND APPLIED TOXICOLOGY,1993

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Repeated dose oral toxicity study was performed to determine the toxic nature of Quaternary Silsesquioxane according to The Federal Insecticide,
Fungicide, and Rodenticide Act (F1FRA) Good Laboratory Practice Standards (U.S. EPA, 1989).

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride

EC Number:

248-595-8

EC Name:

Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride

Cas Number:

27668-52-6

Molecular formula:

C26H58NO3Si.Cl

IUPAC Name:

N,N-dimethyl-N-[3-(trimethoxysilyl)propyl]octadecan-1-aminium chloride

Constituent 2

Reference substance name:

Quaternary Silsesquioxane

IUPAC Name:

Quaternary Silsesquioxane

Test material form:

other: Liquid

Details on test material:

- Name of test material:Quaternary Silsesquioxane
- Molecular formula : C26H58NO3Si.Cl
- Molecular weight:496.287 g/mol
- Substance type: Organic
- Physical state: Liquid

Specific details on test material used for the study:

- Name of test material:Quaternary Silsesquioxane
- Molecular formula : C26H58NO3Si.Cl
- Molecular weight:496.287 g/mol
- Substance type: Organic
- Physical state: Liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc. (Portage, MI)
- Age at study initiation: Adult virgin, 13 weeks of age when paired for mating
- Weight at study initiation: 206 to 275 g at gestation day 0
- Fasting period before study: No data available
- Housing: The females rats were housed individually in suspended stainless steel wire mesh cages from receipt until sacrifice except during the period of mating
- Diet (e.g. ad libitum): Certified Rodent Chow 5002 (Ralston Purina Co., St. Louis, MO) ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 64-69°F (17.8 - 20.5 °C)
- Humidity (%):Relative humidity: 30-70%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): Light cycle of 12 hrs

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test article was suspended fresh daily in corn oil to give a dose range of 0, 100, 300, and 1000 mg/kg/day

DIET PREPARATION
- Rate of preparation of diet (frequency): Daily
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 100, 300, and 1000 mg/kg/day
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

10 days (From gestation days 6 to 15)

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

0, 100, 300, and 1000 mg/kg/day

No. of animals per sex per dose:

Total: 100
0 mg/Kg/day: 25 females rats
100 mg/Kg/day: 25 females rats
300 mg/Kg/day: 25 females rats
1000 mg/Kg/day: 25 females rats

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dosage levels were selected from the results obtained in a range-finding developmental toxicity study. In that study neither maternal nor developmental toxicity was seen at dosage levels of up to 1000 mg/kg/ day.
- Rationale for animal assignment (if not random): Mated females were assigned consecutively, in the order the mating was detected, to one control and three treatment groups consisting of 25 rats
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked in table [No.?] were included. For mortality and overt changes in appearance and behavior.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily on Gd 6 to 20

BODY WEIGHT: Yes
- Time schedule for examinations: daily on Gestation Days 0,6,9, 12, 16, and 20

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, daily on Gestation Days 0,6,9, 12, 16, and 20
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time weighted averages from the consumption and body weight gain data: No data available

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 data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY:
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined.: No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, Immediately following sacrifice on Day 20 of gestation, the uterus was excised, gravid uterine weight was recorded, the fetuses were removed, and pertinent developmental endpoints were recorded. Maternal liver weights and postmortem body weights were recorded. Individual fetuses were weighed, measured (crown-rump length), sexed, and examined for external malformations and developmental variations.

HISTOPATHOLOGY: Yes, Uteri from females that appeared nongravid were opened and placed in 10% ammonium sulfide solution for detection of implantations. One-half of the fetuses were placed in Bouin's solution for subsequent soft tissue examination using the Wilson razor blade technique, and the remaining half of the fetuses were fixed in alcohol, macerated in potassium hydroxide, stained with Alizarin Red-S, and cleared with glycerin for subsequent skeletal examination.

Other examinations:

No data

Statistics:

1)Mean maternal body weights and liver weights, maternal feed consumption, numbers of corpora lutea, total implantations, live fetuses, gravid uterine weight, and mean fetal body weights were compared by one-way analysis of variance (ANOVA), Bartlett's test for homogeneity of variance, and the appropriate test for equal and unequal variance (Steel and Torrie, 1960) using Dunnett's multiple comparison.
2) The proportions of resorbed and dead fetuses and postimplantation losses were compared by the Mann-Whitney t/test.
3) Male to female fetal sex ratios and the proportions of litters with malformations and developmental variations were compared using the x2 test criterion with Yate's correction for 2 X 2 contingency tables and/or Fisher's exact probability test.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

Clinical signs: No clinical sign was observed in dams.

Mortality:

no mortality observed

Description (incidence):

No maternal mortality was observed during the study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight and weight gain:
Mean body weight was not affected during study.
Mean corrected body weights (terminal body weight minus gravid uterine weight) were increase as liver to body weight ratio at highest dose when compare to control.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Feed consumption was not affected during study.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Maternal Liver weight and postmortem body weights were recorded.
Slight increase in liver-to-body-weight ratio was observed in 1000 mg/kg/day concentrations.

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

At uterotomy no adverse effects were observed number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length. The pre- and postimplantation losses did not differ statistically between the control and the Quat-Silsesquioxane-treated groups.

Effect levels

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No significant change were observed on clinical signs; mortality; body weight; food consumption

Remarks on result:

other: No toxic effect observed.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table: Summary of Maternal Body Weight Gain, Food Consumption, and Liver Weights

Dose level Mg/kg/day	0	100	300	1000
Gestation day
	Mean Body weight change
0-6	26 ± 7*	25 ±7	27 ± 7	29 ±8
6-9	3 ± 8	3 ± 8	7±7	6 ± 8
9-12	16 ± 10	19 ±6	15 ± 4	15 ± 9
12-16	27 + 7	26 ± 12	22 ± 8	22 ± 11
16-20	59 ± 11	61 ± 17	62 ± 13	60 ± 15
0-20	131 ± 19	133 ±25	132 ± 19	132 ±25
0-20 adjusted	61 + 13	62 ± 14	62+13	66 ± 13
	Mean food consumption (g/dam/day)
0-6	21.5 + 2	21.5 ±2	22.3 ±2	22.0 ± 4
6-9	17.8 ± 4	15.2 ±3*	17.9 ± 3	19.9 ± 8
9-12	17.9 ± 2	17.9 ± 2	19.9 ±3*	21.2 ± 8
12-16	19.8 ± 2	21.1 ± 5	20.4 ± 3	20.2 ± 4
16-20	27.3 ± 2	27.4 ± 3	26.2 ± 6	28.0 ± 2
0-20	21.3±1	21.2 ± 2	21.7 ± 2	22.5 ± 3
	Mean maternal liver weight
Absolute (g)	15.4 + 2.9	15.3 ±2.9	16.1 ±2.6	16.5 ±2.5
Relative (g)	4.4 ± 0.4	4.4 ± 0.3	4.5 ±0.3	4.6 ± 0.2*

* Significantly different from controls; ANOVA, Welch Test, P < 0.05.

Applicant's summary and conclusion

Conclusions:

Based on the result observed for maternal rats on mortality, clinical signs and organ weight, Quaternary Silsesquioxane (27668-52-6) has a No Observed Adverse Effect Level (NOAEL) of 300 mg /kg/day concentration.

Executive summary:

Repeated oral toxicity test was performed in virgin female Sprague-Dawley derived Charles River CD rats using different concentrations of Quaternary Silsequioxane as 0,100,300 or 1000 mg/kg/day. Adult virgin female Sprague-Dawley rats were taken, mated with male and evidence of mating was detected and designated as Day 0 of gestation. Including control in all groups 25 rats were taken for treatment at each dose level. Doses were given orally from Days 6 through 15 at a constant volume of 10 ml/kg. Mortality, clinical signs, organ weight and fetuses were observed in maternal rats. No mortality was observed in study, no changes in clinical signs and behavior were observed. Mean body weight gains and feed consumption in treated animals were not affected during the study when compared to those of the control group. A slight but significant increase in relative liver-to- body- weight ratio was observed at the 1000 mg/kg/day dose level. Based on the result observed for maternal rats on mortality, clinical signs and organ weight, the Quaternary Silsesquioxane (27668-52-6) has a No Observed Adverse Effect Level (NOAEL) of 300 mg /kg/day concentration.