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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was performed accoding to the OECD guideline 414, in compliance with GLP with few deviations that were not considered to have compromised the validity or integrity of the study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005

Materials and methods

Test guideline
Qualifier:
according to
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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
Remarks:
Doses / Concentrations:
0, 3, 10 or 30 mg/kg bw/d
Basis:

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)

Dose descriptor:
NOAEL
Effect level:
3 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

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:
Under the condition of the study, the NOAEL for maternal toxicity was 3 mg a.i./kg bw/d while NOAEL embryo-foetal development was considered as 30 mg a.i./kg bw/d.
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 (Gaoua W, 2005).