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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study predated formal guideline requirements and GLP but performed according to existing scientific standards. Reliabilty check by Expert Panel (American Chemistry Council Fatty Nitrogen Derivatives) passed.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
modifications in exposure period
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): XSA-201 (Ditallowdimethylammonium chloride)
- Physical state: liquid
- Analytical purity: approximately 75%
- Impurities (identity and concentrations): not stated
- Composition of test material, percentage of components: approximately 75% active, 15% isopropanol, water as remainder
- Isomers composition: n.a.
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): n.a.
- Specific activity (if radiolabelling): n.a.
- Locations of the label (if radiolabelling): n.a.
- Expiration date of radiochemical substance (if radiolabelling): n.a.
- Stability under test conditions: no data
- Storage condition of test material: no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
other: oral gavage; oral diet
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
days 6 - 13 or 6 - 18 of gestation
Frequency of treatment:
daily
Duration of test:
days 0 - 21 of gestation
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 mg/kg body weight
Basis:
actual ingested
oral gavage
Remarks:
Doses / Concentrations:
500 mg/kg body weight
Basis:
actual ingested
oral gavage
Remarks:
Doses / Concentrations:
508 mg/kg body weight (0.65% active in diet)
Basis:
actual ingested
oral diet
No. of animals per sex per dose:
25 rats per group (10 animals sacrified after 13 days, 15 animals after 21 days of gestation)
Control animals:
yes, concurrent vehicle
yes, plain diet
Details on study design:
Two concurrent control groups: One receiving the gavage vehicle isopropanol, one receiving control feed only

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 9, 12, 15, 18 and 21 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (feeding part of study). Evaluated for days 12 and 18 of gestation

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 13 and day 21 of gestation
- Organs examined: heart, lung, stomach, liver, pancreas, spleen, mesenteric lymph nodes, jejunum, kidney, adrenal, bladder, ovary

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Statistics:
Chi-square test, F-test, Student`s t-test, Cochran`s approximation test
Indices:
number and location for each horn of resorptions, embryos and implantation sites, number of corpora lutea of pregnancy per ovary, total litter weights, mean fetal weights

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Depressed body weight gains and lower feed consumption during gestation in group having received the test compound in the diet.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Remarks:
by gavage
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No differences considered to be related to the administration of the test substance were noted in fetal size and sex, variations in degree of ossification or malformations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no effects at highest dose level

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Reliability check by ACC FND Expert Panel revealed a reliability with restriction (Klimisch 2A).

Applicant's summary and conclusion

Conclusions:
Based on the results from this study ditallowdimethylammonium chloride is not considered to be a developmental toxicant.
Executive summary:

Ditallowdimethylammonium chlorid (DTDMAC) was investigated for developmental toxicity in the rat. 25 female rats per group were administered the test substance either by oral gavage at dose levels of 100 and 500 mg active ingredient per kg body weight per day (vehicle was 15% isopropanol) or in the diet at a dose level of 0.65% active ingredient beginning on day 6 of gestation. Two control groups were run concurrently. One received the gavage vehicle and the other received control feed only.

Ten rats per group were sacrificed after the day 13 treatment and 15 rats per group were treated through day 18 and sacrificed on day 21 of gestation. Body weights were taken on days 0, 6, 9, 12, 15, 18 and 21 of gestation. Food consumption was evaluated for days 12 and 18 of gestation. Clinical observations were made daily for signs of pharmacologic or toxicologic effect and mortality. Gross necropsies were conducted on all surviving rats, moribund rats and rats that died spontaneously. At necropsy, for rats sacrificed on day 13 of gestation, the uterus (number and location for each horn of resoptions, embryos and implantation sites) and ovaries (number of corpora lutea of pregnancy per ovary) were observed. At necropsy for rats sacrificed on day 21 of gestation, the uterus (number and location for each horn of live fetuses, dead fetuses, early and late resorptions and impantation sites) and ovaries ( number of corpora lutea of pregnancy per ovary) were observed. The necropsy for all maternal rats also included observations for obvious abnormalities and the following tissues were examined: heart, lung, stomach, liver, pancreas, spleen, mesenteric lymph nodes, jejunum, kidney, adrenal, bladder and ovary.

With regard to maternal data, no adverse effects attributable to DTDMAC administration were noted in comparison of pregnancy and mortality rates. Depressed body weight gains during gestation were noted in the group that received the test substance in the diet together with less food consumption values compared to the group that received control feed. Early deliveries and abortions, necropsy findings, and reproduction data were considered not to be affected by treatment with the test substance. An increase in resorptions was observed for the 100 mg/kg/day gavage group compared to the isopropanol control group (7.1% vs 2.1%). This difference was not considered a treatment-related effect due to the lack of dose response and a low value for the control group compared to historical data from the laboratory.

With regard to fetal data, no differences considered to be related to the adminsitration of ditallowdimethylammonium chloride were noted in fetal size and sex, variations in degree of ossification or malformations.

Based on the results of this study, the NOAEL for maternal toxicity was considered to be greater 500 mg/kg body weight per day by gavage. No NOAEL for maternal toxicity was established for dietary treatment because of the slight effects on body weight gain. With regard to developmental toxicity the NOAEL was established to be greater 500 mg/kg body weight per day by gavage and greater 508 mg/kg body weight per day via the diet.