Dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

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 peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Quaternary Silsesquioxane: A Developmental Toxicity Study in Rats

Author:

Waheed H. Siddiqui And Raymond G. York

Year:

1993

Bibliographic source:

Fundamental And Applied Toxicology 21, 66 - 70 (1993)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

The developmental toxicity of an antimicrobial organosilicon quaternary ammonium chloride (Quaternary Silsesquioxane) was evaluated in rats.
Study was conducted according to The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)

GLP compliance:

no

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:

dimethyl(octadecyl)[3-(trimethoxysilyl)propyl]azanium 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 (as cited in study report):Quaternary Silsesquioxane
- Molecular formula (if other than submission substance):C26H58CL1N1O3Si1
- Molecular weight (if other than submission substance):496.30g/mol
- Substance type:Organic
- Physical state:Liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
-Sex: Female
- Source: Charles River Breeding Laboratories, Inc. (Portage, MI).
- Age at study initiation: 13 weeks
- Weight at study initiation: 206 to 275 g at gestation day 0
- Fasting period before study: No data available
- Housing: Animal were housed individually, except during mating, in suspended stainless steel wire mesh cages from receipt until sacrifice.
- Use of restrainers for preventing ingestion (if dermal): No data available
- Diet (e.g. ad libitum): basal laboratory diet of 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): 17 -20°C
- Humidity (%):Relative humidity: 30-70%
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): 12 hrs

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

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

corn oil

Details on exposure:

Details on oral exposure
PREPARATION OF DOSING SOLUTIONS: Quat-Silsesquioxane was suspended fresh daily in corn oil

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- 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 mating procedure:

- M/F ratio per cage: 1:1
- Proof of pregnancy: Copulatory plug was designated Day 0 of gestation

Duration of treatment / exposure:

10 days

Frequency of treatment:

Single daily dose

Duration of test:

20 days of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 300, and 1000 mg/kg/day
Basis:
no data

No. of animals per sex per dose:

Total: 100
0 mg/kg/day: 25 female
100 mg/kg/day: 25 female
300 mg/kg/day: 25 female
10000 mg/kg/day: 25 female

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 maternalnor 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
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups:No data available
- Section schedule rationale (if not random):No data available

Examinations

Maternal examinations:

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

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
- 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

other:
organ weight: liver and gravid uterine weight was recorded

Ovaries and uterine content:

Nongravid Uteri were examined for Corpora lutea, Total implantation and Postimplantation loss.

Fetal examinations:

viable fetuses, crown-rump length, fetal body weight and sex ratio, gross pathology and histopathology were examined.

Statistics:

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 t test for equal and unequal variance (Steel and Torrie, 1960) using Dunnett's multiple comparison(Dunnett, 1964). The proportions of resorbed and dead fetuses and postimplantation losses were compared by the Mann-Whitney t/test (Siegel,1956). Male to female fetal sex ratios and the proportions of litters with malformations and developmental variations were compared using the x1 test criterion with Yate's correction for 2 X 2 contingency tables and/or
Fisher's exact probability test (Siegel, 1956; Weil, 1970). All statistical analyses compared the mean values of the treated groups with those of the
control, with the levels of significance at p < 0.05 and p < 0.01.

Indices:

Viability, Fertility and gestation were examined

Historical control data:

No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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):

no effects observed

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Mortality – No effect on survival of treated female rats were observed as compared to control.

Clinical signs- No clinical signs or behavioral changes were observed in treated female rats as compared to control.

Body weights – No body weight changes were observed in treated female rats as compared to control.

Feed consumption - No feed consumption changes were observed in treated female rats as compared to control.

Organ weight - Slight but significant increase in relative liver weight of treated female rats was observed as compared to control.

Maternal developmental toxicity

Number of abortions:

not specified

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Reproductive function: estrous cycle:
No adverse effects on mean number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length.

Reproductive performance:
Ratio of male and female pups at the 1000 mg/ kg/day dose level was significantly different from the control group but was not considered treatment related.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Abnormalities:

not specified

Localisation:

not specified

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

not specified

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

No developmental parameter such as viability, fetal body weight and external malformations were observed in treated fetuses as compared to control. One fetus with bent limb bones, two fetuses from different mothers with microphthalmia and two other fetuses with omphalocele were observed at 1000 mg/kg/day and single fetus with multiple malformations were observed at 300 mg/kg/day in treated fetuses as compared to control. The incidence of developmental variations in the treated litters was not significantly increased over the control incidence.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

changes in sex ratio

fetal/pup body weight changes

external malformations

Fetal abnormalities

1

Abnormalities:

not specified

2

Abnormalities:

not specified

Localisation:

other: not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

TABLE 1

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

		Dose levels (mg/kg/day)
Gestation day		0	100	300	1000
		Mean body weight change (g)
0-6		26 ± 7^a	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^b		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(20 days of gestation)
Absolute (g)	15.4 + 2.9		15.3 ±2.9	16.1 ±2.6	16.5 ±2.5
Relative (%)	4.4 ± 0.4		4.4 ± 0.3	4.5 ±0.3	4.6 ± 0.2*

^aMean ± SD.

^bDam body weight minus the uterus and its contents.

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

          

TABLE 2

Summary of Observations at Time of Cesarean Sections

	Dose levels (mg/kg/day)
	0	100	300	1000
Animals examined at cesarean sections	25	25	25	25
Nongravid	7	7	5	4
Gravid	18	18	20	21
Dams with resorptions only	0	0	0	0
Dams with viable fetuses	18	18	20	21
Viable fetuses/dam^a	13.3 ±2.7	13.3 ± 3.3	13.2 ± 4.2	12.4 ± 4.0
Postimplantation loss/dam^a	1.1 ±0.8	0.6 ± 0.61	1 5 ± 2.31	0.8 + 0.8
Total implantation/dam^a	14.4 ±2.5	13.9 ± 3.5	14.7 ± 3.4	13.2 ± 4.4
Corpora lutea/dam^a	17.8 ±3.3	15.8 ± 2.6	17.7 ± 2.9	16.2 ± 3.2
Mean crown-rump length (cm)	3.5 ±0.1	3.5 ± 0.2	3.5 ± 0 1	3.5 ± 0 1
Group mean uterine weights (g)	70.1 ±14.1	71.3 ±17.7	70.3 ±21.2	66.5 ± 18.2
Group mean preimplantation loss (%)	18.8	12.0	17.2	18.2
Group mean postimplantation loss (%)	7.7	4.4	9.9	6.1
Mean fetal body weight (g)	3.4 ±0.2	3.5 ± 0.5	3.4 ± 0.2	3.4 + 0.3
Fetal sex ratio—m:f (%)	44:56	49:51	50:50	55:45*

^aMean ± SD.

* Significantly different; x2. P * 0.05.

TABLE 3

Summary of the Incidence of Fetal Malformations*

	Dose levels (mg/kg/day)
	No. examined
Litters	18	18	20	21
Fetuses externally	240	238	263	260
Fetuses viscerally	119	118	132	129
Fetuses skeletally	121	121	132	132
	No.of fetuses (No. Of litters) affected
Malformations observed
Anophthalmia	1 (1)
Microphthalmia				2(2)
Gastroschisis			1(1)
Omphalocele				2(2)
Tail agenesis			1(1)
Tarsal flexure			1(1)
Edema			1(1)
Malformed skull bones			1(1)
Bent clavicle			1(1)
Bent scapula			1(1)
Amelia			1(1)
Micromelia			1(1)
Bent limb bones	1(1)			1(1)
Vertebral agenesis			1(1)
Pelvic malformation			1(1)
Total fetuses (litters) with malformations	2(2)	0(0)	1(1)	5(4)

* No statistical significance was observed.

TABLE 4

Summary of the Incidence of Fetal Variations*

	Summary of the Incidence of Fetal Variations*
	Dose levels (mg/kg/day)
	0	100	300	1000
	No. examined
Litters	18	18	20	21
Fetuses externally	240	238	263	260
Fetuses viscerally	119	118	132	129
Fetuses skeletally	121	121	132	132
	No.of fetuses (No. Of litters) affected
Developmental variations observed
Renal papillae not developed		1(1)	1(1)
Distended ureter		1(1)	1(1)
Skull reduced in ossification	2(1)	3(2)	2(2)
Hyoid unossified	1(1)		1(1)	1(1)
25 presacral vertebrae			1(1)	2(2)
Greater than 13 pairs of full ribs			2(2)
14th rudimentary rib(s)	6(3)	7(4)	12(5)	6(5)
Bent ribs		1(1)		2(1)
7th cervical rib	3(3)		2(2)
Vertebrae reduced in ossification	1(1)		1(1)
Misaligned sternebra(e)	8(6)	6(5)	8(6)	4(3)
Sternebra 5 and/or 6 unossified	3(5)	7(6)	4(4)	8(6)
Other sternebra(e) unossified	1(1)		1(1)	1(1)
Ischia reduced in ossification	1(1)			2(1)
Total fetuses (litters) with developmental variations	22(12)	24(11)	30(14)	22(12)

* No statistical significance was observed.

Applicant's summary and conclusion

Conclusions:

NOAEL was considered to be 300 mg/kg bw for P generation and 1000 mg/kg for F1 generation when Sprague-Dawleyd female rats were treated with Quat-Silsesquioxane orally by gavage from day 6 to 15 of gestation.

Executive summary:

In a developmental toxicity reproductive toxicity was evaluated in Sprague-Dawley female rats by using Quat-Silsesquioxane in the concentration of 0, 100, 300, or 1000 mg/kg/day orally by gavage in corn oil.No maternal mortality and clinical signs or behavioral changes were observed in treated female rats as compared to control. No effect on body weight and feed consumption changes were observed in treated female rats as compared to control. Similarly, no effect number of corpora lutea, number of live fetuses per litter, litter size, mean fetal body weight, or mean crown-rump length was observed in treated rats. Ratio of male and female pups at the 1000 mg/ kg/day dose level was significantly different from the control group but was not considered treatment related. Slight but significant increase in relative liver weight of treated female rats was observed as compared to control. In addition, No developmental parameter such as viability, fetal body weight and external malformations were observed in treated fetuses as compared to control. One fetus with bent limb bones, two fetuses from different mothers with microphthalmia and two other fetuses with omphalocele were observed at 1000 mg/kg/day and single fetus with multiple malformations were observed at 300 mg/kg/day in treated fetuses as compared to control. The incidence of developmental variations in the treated litters was not significantly increased over the control incidence. They occurred in low frequency and were distributed randomly across the Quat-Silsesquioxane treated and control groups. Therefore,NOAEL was considered to be 300 mg/kg bw for P generation and 1000 mg/kg for F1 generation when Sprague-Dawley female rats were treated with Quat-Silsesquioxane orally by gavage from day 6 to 15 of gestation.