Quaternary ammonium compounds, C20-22-alkyltrimethyl, chlorides

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:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

batch number is not presented for the vehicle (purified water) in the study report; autolysed foetuses were not sexed at the time of hysterectomy and head sections were archived in the same way as brain sections.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Quaternary ammonium compounds, benzyl C12-C16 (even numbered) -alkyldimethyl chlorides

Molecular formula:

C12-14H25-29-(CH3)2-C6H5-N.CL

IUPAC Name:

Quaternary ammonium compounds, benzyl C12-C16 (even numbered) -alkyldimethyl chlorides

Constituent 2

Reference substance name:

Quaternary ammonium compounds, benzyl-C12-C16-alkyldimethyl, chloride (i.e., benzyl C12-16 alkyl dimethyl ammonium chloride)

IUPAC Name:

Quaternary ammonium compounds, benzyl-C12-C16-alkyldimethyl, chloride (i.e., benzyl C12-16 alkyl dimethyl ammonium chloride)

Details on test material:

containing ca. 50% C12-16-benzyldimethylammonium chloride (CAS no.: 68424-85-1) in water only.
Specification: C12-16 BKC (C12: 72.0%; C14: 27.7%; C16: 0.3%)

Test animals

Species:

rabbit

Strain:

New Zealand White

Administration / exposure

Route of administration:

oral: gavage

Duration of treatment / exposure:

Day 6 to 28 post coitum

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

3 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

10 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

30 mg/kg bw/day

No. of animals per sex per dose:

22 mated females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

Sex: female
Duration of test: GD 6-28

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

3 mg/kg bw/day

Basis for effect level:

body weight and weight gain

gross pathology

mortality

Results (fetuses)

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day

Basis for effect level:

other: no treatment related effect up to the highest dose

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Result: The test substance is not teratogenic in rabbits.

Maternal effects:
At 30 mg/kg bw/d:
- three females died and two females were prematurely sacrificed for ethical reasons or abortion,
- the relevant clinical signs concerned the deceased females and two prematurely sacrificed females. No other clinical signs were noted in females from this group.
- body weight gain was transiently reduced (GD 9-12, -70% below the control, p<0.05) but returned to normal values thereafter,
- the necropsies revealed in 8/22 females: accentuated lobular pattern in the liver, pale liver, whitish areas and/or blackish deposits and/or edema in the stomach mucosa, reddish or brownish foci on the lungs, blackish contents in
the intestines, dilated intestines and dilated gall bladder,

At 10 mg/kg bw/d:
- there were no deaths. Reduction of maternal body weight gain and food consumption did not reach statistical significance,

- There were no relevant clinical signs except for two females with blood in the bedding on Days 22 and 23 post-coitum or absence of feces from Day 26 post-coitum
- the necropsies revealed in 5/22 females: dilated gall bladder, accentuated lobular pattern, 

- pale liver, brownish or reddish foci on the lungs, blackish deposit on the stomach mucosa,

At 3 mg/kg bw/d:
no signs of maternal toxicity,

Teratogenic / embryotoxic effects:
There were no effects on litter data parameters and no treatment-related findings upon external, visceral or skeletal observation in any of the dose groups.

Litter and foetal evaluation:
The fluctuations noted in the mean number of corpora lutea, implantation sites and post-implantation were slight and not
dose-related, they were consequently considered not to be treatment-related.
The fluctuations recorded for the mean number of resorptions (early or late) and the mean number of dead foetuses and
consequently for the percentages of post-implantation loss were also not considered to be treatment-related, as they
were minimal and not dose-related. The percentage of male foetuses was considered similar among the groups and the fetal body weight was unaffected by treatment.

External, soft tissue and skeletal observations in foetuses and final fetal assessment:
The occurrence of some external and soft tissue malformations throughout all treated groups, including the
controls, did not suggest any substance-related origin because of their low incidence, absence of dose-relationship
and/or statistical significance.
Concerning the skeletal observations, no relevant malformations was noted but the presence of a full supernumerary 13th pair of ribs (as a foetal variation), was markedly increased at 10 and 30 mg/kg bw/day. These differences
in foetal or litter incidence, which were within background data, were most probably due to a low control value. The
incidence of one other skeletal variation (unossified 5th sternebra) was significantly greater but in the low dose-group only.

Conclusion: Test substance is not teratogenic in rabbits.

LO(A)EL maternal toxic effects:
10 mg/kg bw/d, based on necropsy findings in 5/22 animals.
Incidence was increased to 8/22 at 30 mg/kg bw/d (dilated gallbladder 3/22, accentuated lobular pattern liver 3/22).
Foci (reddish/brownish) in the lung was also observed in 2 females, but also in view of findings in range finding study and
parallel study with comparable compound, this can be caused by inadvertent presence of substance into the airways and
not attributable to systemic toxicity. Incidence was not increased in the top-dose group. There is an indication of
lower body weight gain, correlating to a lower food consumption, but that was not statistical significant and in
the high-dose goup not different from the mid-dose group.
Blackish content in stomack and intestines is indicative of local corrosive effects of test substance.

NO(A)EL maternal toxic effects:
3 mg/kg bw/d. There seems to be a dose-response related increase in necropsy findings in stomach, intestine and liver.
Dilated gallbladder incidence was not increased in highest dose group compared to mid-dose.
LO(A)EL embryotoxic / teratogenic effects:
Based on the number of foetuses presenting malformations or variations and in the absence of a treatment-related
increase of such observation, the embryo-fetal development was not considered to be affected by treatment.
NO(A)EL embryotoxic / teratogenic effects:
30 mg/kg bw/d, being the highest tested dose.

Applicant's summary and conclusion

Conclusions:

The developmental toxicity of C12-16 ADBAC was investigated in accordance with OECD 414 in rabbits . The maternal NOAEL was 3 mg/kg/d and the developmental NOAEL was 30 mg/kg/d. No indication of developmental toxicity was found.

Executive summary:

A guideline equivalent developmental toxicity study was conducted in rabbits. C12-16 ADBAC was administered to pregnant rabbits by gavage from Day 6 to 28 post-coitum at the dose-levels of 3, 10 or 30 mg/kg bw/day of active substance. The dose of 30 mg/kg bw/day caused the death of three females, severe clinical condition or abortion in two other females and transient, lower maternal body weight gain. Necropsies revealed in 8/22 females accentuated lobular patterns in the liver, whitish areas and/or blackish deposits in the stomach mucosa and dilated intestines. At 10 mg/kg bw/day, relevant necropsy findings were noted in 5/22 females (dilated gall bladder, accentuated lobular pattern, pale liver, brownish or reddish foci on the lungs, blackish deposit on the stomach mucosa). No maternal toxicity or effects on litter data parameters or embryo-foetal development were noted at 3 mg/kg bw/day. Under the condition of the study, the NOAEL for maternal toxicity was 3 mg/kg bw/day while the NOAEL for embryo-foetal development was 30 mg/kg bw/day.