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Toxicological information

Toxicity to reproduction

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Administrative data

fertility, other
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic information given
Justification for type of information:
Since in the stomach the gastic juice is acidic, made up of acids and enzymes, it is suggested that in this evironment it is highly unlikely that the quaternary ammonium compounds, di-C12-18-alkyldimethyl, nitrites substance (s) will remain ionically bound to each other and thus are prone to dissociation in which case the released cation(s) will associate with other anions and the released anion will associate with cations. Thererfore, it is suggested that read-across data from sodium nitrite is considered appropriate in order to arrive at a conclusion in terms of any health effects that may be incurred from exposure to "nitrite" whichever cation it may be associated with.

In addition, in 1988, the US EPA, Office of Pesticides and Toxic Substances issued a Notice to producers, Formulators, Distributors and Registrants regarding quaternary ammonium compounds with regard to "Clustering" of such quaternary ammonium compounds.

Prior to this, EPA had required each quat compound to be individually coded and registered as a new chemical, even when the chemical structure of individual compounds differed only slightly in alkyl distribution and chain lengths. This procedure was continued with the new generations of quats having two, three, and four chains. As a result, EPA records showed that some 211 registered technical grade active ingredient products containing varying concentrations of quats, each coded separately on the basis of alkyl chain length and percentage carbon distribution within the chain. At this time, there are approximately eight to ten thousands (8-10,000) registered end-use formulations.

However, questions were raised regarding whether the EPA could cluster or group the quats and pick one or more representative members of each cluster to be used in toxicity studies, instead of requiring separate studies on each quat. These same questions were raised when the EPA issued its March 4, 1987 Data Call-In Notice requiring all registrants of antimicrobial active ingredients to submit subchronic and chronic toxicological data to support the continued registration of their products.

In response to these questions, EPA solicited information from industry, the public, academia, industry cooperative work groups, the state of California, and Canada. EPA then reviewed all of the assembled information along with the chemical structure of most of the quats. Based on the results of this review, EPA developed the following four groupings of currently registered quat compounds:

Group I. The alkyl or hydroxyalkyl (straight chain) substituted Quats
Group II. The non-halogenated benzyl substituted Quats (includes hydroxybenzyl, ethylbenzyl, hydroxyethybenzyl, napthylmethyl, dodecylbenzyl, and alkyl benzyl)
Group III. The di-and tri-chlorobenzyl substituted
Group IV. Quats with unusual substituents (charged heterocyclic ammonium compounds).

Fundamental to this discussion EPA determined that "X-" in all of these structures would be attributed to "any anionic species". Therefore, this would mean in terms of toxicological evaluation the coutner anion in such quaternary ammonium compounds could be regarded as; e.g halogen (Cl-, Br-, I-,), saccharinate or cyclohexylsulphamate. It is therefore suggested here that nitrite (NO2-) could also be regarded as a pertinent anion.

Since the US EPA deem that such a clustering of structures for toxicological evaluation is well founded and that the counter anion could be regarded as "any anionic species" then it would seem that to consider available toxicological data on sodium nitrite, in order to evaluate any health effects that may be incurred from exposure to the nitrite anion (NO2-), is justifiable.

Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference Type:
Effects of imipramine, nitrite and dimethylnitrosamine on reproduction in mice
Anderson, L.M., Goner-Sorolla, A., Ebeling, D.
Bibliographic source:
Research Communications in Chemical Pathology and Pharmacology Vo. 19 (2), 311 ff

Materials and methods

Test guideline
no guideline available
Principles of method if other than guideline:
Determination of effects on reproductive parameters, including rates of fertility and perinatal survival, litter sizes, and weanling weights
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
Didecyldimethylammonium chloride
EC Number:
EC Name:
Didecyldimethylammonium chloride
Cas Number:
Molecular formula:
Didecyldimethylammonium chloride
Test material form:
Specific details on test material used for the study:
Sodium nitrite

Test animals

Details on test animals or test system and environmental conditions:
CD-1 female mice (5-6 weeks old, Charles River Breeding Farms) were housed in groups of 10 and treated as follows. Group 1 received imipramine (Bio-Craft Laboratories) thoroughly mixed (100 mg/kg) with powdered Purina Laboratory Chow. Group 2 received 1 g/l NaNO2 in their drinking water. Group 3 received both imipramine and nitrite. Group 4 received in their water 0.1 ppm DMN diluted twice weekly from a stock solution kept cold and dark and prepared fresh monthly . All mice were housed in plastic cages with hardwood shavings and filter bonnets, in a room at 24 ± 2°C, 40% relativehumidity and a 14/10 hr light/dark cycle.

Administration / exposure

Route of administration:
oral: drinking water
Details on mating procedure:
After 10 wk males were added. The females were separated to individual cages when a vaginal plug was found and treatment was continued. Near term they were inspected for births once daily, except weekends . Females showing no signs of pregnancy were returned to the males for a second fertilization.The reproductive success of each group was measured by the number of females with surviving litters and the total number of offspring at weaning. Only in the control group did each of the 10 females have surviving offspring. Fewer offspring were weaned in the DMN-, imipramine-, and nitrite-treatment groups, compared with the controls. This effect was of statistical significance for the imipramine group and the nitrite group. However, imipramine and nitrite administered together did not have an additive adverse effect of reproduction; indeed the progeny yield in this group was not significantly differentfrom that in the control group, even though 1 female had no litter.After Exp . 1 indicated potentially interesting effects of the chemicals on reproductive success, Exp. 2 was carried out to study these effects in more detail.
Duration of treatment / exposure:
Exposure period: During mating and pregnancyPremating exposure period (males): no dataPremating exposure period (females): 20 weanling female mice were given tap water for 1 week and then drinking water with NaNO2 at a concentration of 1000 mg/l for the next 75 days (pretreatment period).Duration of test: about 100 days
Frequency of treatment:
Doses / concentrations
Dose / conc.:
190 mg/kg bw/day (nominal)
Basis : nominal in water
No. of animals per sex per dose:
Control animals:
yes, concurrent no treatment


Parental animals: Observations and examinations:
Preconception water consumption and weight gain, conception time, litter size, rates of stillbirth and neonatal death, histopathology of the major organs of dead pups
Litter observations:
Histopathology of the major organs of dead pups, weaning weights and sex ratios of the offspring

Results and discussion

Results: P0 (first parental generation)

Reproductive function / performance (P0)

Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
Compared to control values, average conception time was 5 days longer, and more females littered more than 30 days after the males were added. Litters were on the average slightly smaller than control.

Details on results (P0)

Perinatal death was more common than among the controls; most of the dead young were stillborn. At weaning the offspring were somewhat smaller than controls, a difference which was statistically significant for males.

Effect levels (P0)

Key result
Dose descriptor:
Basis for effect level:
reproductive performance
Remarks on result:
not determinable
no NOAEL identified. Generation not specified (migrated information)

Overall reproductive toxicity

Key result
Reproductive effects observed:
not specified

Applicant's summary and conclusion

No NOAEL could be determined.
Executive summary:

In a publication entitled "Effects of imipramine, nitrite and dimethylnitrosamine on reproduction in mice" (Anderson, L.M., Goner-Sorolla, A., Ebeling, D., Research Communications in Chemical Pathology and Pharmacology Vo. 19 (2), 311 ff, 1978), the fertility of CD-1 mice (females) upon exposure to sodium nitrite was investigated.

This study is assigned a reliability score of 2 in accordance with the criteria for assessing data quality set forth by Klimisch et al (1997).

Under the conditions of the study no NOAEL could be determined.

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