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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: Limited reporting, method similar to OECD 414. US EPA evaluated: Reliable without restriction; guideline study.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Identity: Varisoft 475 (75%)
CAS RN: 68122-86-1;
Chemical name: Imidazolium compounds, 4,5-dihydro-1-methyl-2-nortallow alkyl-1-(2-tallow amidoethyl) Me sulfate)
Purity: 76.6% in isopropyl alcohol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Timed-pregnant rats

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
copulation plug-positive females
Duration of treatment / exposure:
gestation days (gd) 6 through 15.
Frequency of treatment:
Daily
Duration of test:
until gd 21
Doses / concentrations
Remarks:
Doses / Concentrations:
o, 100, 300 and 1000 mg a.i./kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
Twentyfive females per group
Control animals:
yes
Details on study design:
control group received Milli-Q water at a dose volume equivalent to that used in the high dose group.

Examinations

Maternal examinations:
Clinical observations were made daily (twice daily during dosing), and maternal body weights were measured on gd 0, 6, 9, 12, 15, 18 and 21. At scheduled sacrifice on gd 21, the dams were evaluated for liver and gravid uterine weights.
Ovaries and uterine content:
gravid uterine weights, number of corpora lutea and number and status of implantation sites (including early and late resorptions, dead fetuses and live fetuses).
Fetal examinations:
Approximately one-half of the live fetuses in each litter were examined for visceral and craniofacial malformations and variations. The remaining one-half of the fetuses were stained with alizarin red S and were examined for skeletal malformations and variations.
Statistics:
The unit of comparison was the pregnant dam or the litter.
ANOVA, t-tests, Kruskal-Wallis Test, Mann-Whitney U Test and Fisher’s Exact Test were used where appropriate.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL (maternal and developmental) >1000 mg/kg-day (highest dose tested)
Executive summary:

The objective of this study was to evaluate the potential of the test substance to produce developmental toxicity when administered by a gavage to pregnant CD® rats during organogenesis. Maternal toxicity was also evaluated. Timed-pregnant rats were administered the test substance by gavage on gestation days (gd) 6 through 15. Twentyfive copulation plug-positive females per group were dosed with undiluted test substance at dose levels corresponding to 100, 300 and 1000 mg active ingredient/kg/day. An additional 25 females, assigned to the control group, received Milli-Q water at a dose volume equivalent to that used in the high dose group. Clinical observations were made daily (twice daily during dosing), and maternal body weights were measured on gd 0, 6, 9, 12, 15, 18 and 21. At scheduled sacrifice on gd 21, the dams were evaluated for liver and gravid uterine weights, number of corpora lutea and number and status of implantation sites (including early and late resorptions, dead fetuses and live fetuses). Approximately one-half of the live fetuses in each litter were examined for visceral and craniofacial malformations and variations. The remaining one-half of the fetuses were stained with alizarin red S and were examined for skeletal malformations and variations.

 

Maternal: The pregnancy rate was equivalent across groups and ranged from 88 - 100%. No females aborted or delivered early. At scheduled sacrifice, three females in the control group, two females in the 100 mg/kg/day group and one female in the 300 mg/kg/day group were found to be nonpregnant. One female from the control group and one female from the 300 mg/kg/day group contained no viable fetuses at scheduled sacrifice. Twenty-one to 25 live litters were available for evaluation from each group. One female in the 300 mg/kg/day treatment group became moribund and was sacrificed on gd 10. Two to three dams in the 300 and 1000 mg/kg/day treatment groups exhibited audible respiration during or subsequent to the treatment period. None of these observations were considered to be test substance related. There were no treatment-related effects on food consumption, gestational body weight and body weight gain, corrected body weight, corrected body weight gain, and gravid uterine weight. No treatmentrelated differences in gestational parameters including total number of implantations, number of viable implants, and number of nonviable implants, were observed in any dose group.

 

Fetal: Fetal body weights per litter were not affected by treatment.

No treatment-related malformations or variations were observed in this study.

 

Maternal toxicity NOEL: > 1000 mg/kg/day

Developmental toxicity NOEL: > 1000 mg/kg/day