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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
125 mg/kg bw/day
Additional information

One study is recorded for this endpoint and was chosen as a key study.

In a reproductive/developmental toxicity screening study according to OECD Guideline 421 following the principles of Good Laboratory practices, groups of 10 males and 10 females rats received daily doses of 0, 62.5, 125 and 500 mg/kg bw/day by gavage. Males were treated daily from two weeks before mating, during mating and until a dosing period of a total of 28 days had been completed. Females were treated daily from two weeks before mating until the 4 th day of lactation.

At daily doses of 500 mg/kg bw one male and one female died after 12 and 10 treatments respectively. Clinical observations revealed dyspnea, soft stools in all females and almost all males. Half of the females also showed slight to moderate dilation of the abdomen. Body weight loss was observed in both sexes during the first week of treatment. Further, statistically significantly lower mean daily food consumption was observed in the males during the premating period and in the dams during the first week of pregnancy. Statistically significantly lower mean dam body weights were observed after 14 and 20 days of gestation and at the day of birth after delivery.

No toxicologically relevant effects were observed at dosages of 125 and 62.5 mg/kg bw/day.

At sacrifice of the parental animals, no significant differences were found in the organ weights of uterus, ovaries, testes and epididymides. Histopathology of testes, epididymides and of the ovaries of the animals of the 500 mg/kg dose groups did not show any compound related changes. No substance related changes were reported for the evaluation of testicular stages of spermatogenesis performed in the PAS-hematoxylin stained sections.

At the dosages of 62.5 and 125 mg/kg/day all of the 10 paired females revealed to be sperm positive after mating, all revealed to be pregnant and all delivered live litters. The numbers of corpora lutea had not been evaluated during this study.

At 500 mg/kg/day, from the 9 paired females 7 revealed to be sperm positive (77 %) after mating, 6 out of 9 (67 %) revealed to be pregnant, and 5 out of 6 (83 %) delivered live litters. One animal revealed to have fully resorbed. Mean pre-coital time was longer in this group (about 6.1 days) when compared to the controls and the lower dosage groups (1.5 to 2.1 days).

After birth, for the animals treated with 62.5 or 125 mg/kg/day there were no substance related biological differences in their pregnancy outcome in comparison to the control group. At 500 mg/kg/day, the percentage of post implantation losses was increased by 19% per litter in comparison to about 6% per litter in the controls and in the lower treatment groups, thus resulting in a statistically significantly lower rate of live borns of 83% in comparison to 94% in the controls and in the lower treatment groups. However, the viability index on postnatal day 4 was in the range of the controls and the lower treatment groups.

For all dose groups under investigation no statistically significant differences were found for the body weights of male and female pups at birth and on postnatal day 4. External abnormalities have not been reported.

The No-observed-adverse-effect level (NOAEL) regarding reproductive toxicity was established at 125 mg/kg bw/day and adopted for an existing EU risk assessment on this compound as well. Additionally, from oral repeated dose toxicity studies performed with dioctadecyldimethylammonium chloride or dihydrogenatedtallowdimethylammonium chloride, no indications with regard to histopathological changes of reproductive organs exist.


Short description of key information:
There are only limited experimental data available on quaternary ammonium compound, di-C16-18-alkyldimethyl, chloride with regard to reproductive toxicity. However, based on data for dialkyldimethylammonium chlorides in general, a concern with regard to reproductive toxicity is not deducible for this class of compounds. For assessment purposes of quaternary ammonium compound, di-C16-18-alkyldimethyl, chloride, a reproduction/developmental toxicity screening test according to OECD 421 on pure dioctadecyldimethylammonium chloride is used which has not revealed any indication of significant reproductive concern. The NOAEL from this study with regard to reproductive effects was established at 125 mg/kg body weight per day via gavage and was adopted for an existing EU risk assessment on this compound as well. Additionally, from repeated dose toxicity studies available, also no indications of effects on reproductive organs exist.

Effects on developmental toxicity

Description of key information
There are no adequate data available on quaternary ammonium compound, di-C16-18-alkyldimethyl, chloride with regard to developmental toxicity and teratogenicity. However, read-across can be made to experimental results from the structural closely related ditallowdimethylammonium chloride. In this study no indications of developmental toxicity were observed neither by oral administration via gavage nor by oral uptake of the test compound via the diet. The NOAEL for developmental toxicity was established to be greater than 500 mg/kg body weight per day via gavage and greater than 508 mg/kg body weight per day via the diet. Although the study predates formal guidelines and GLP, a reliabilty check by an expert panel of the American Chemistry Council concluded that the study was reliable with restrictions (Klimisch 2A). 
Moreover, two evaluation reports on the structural closely related DidecylDimethylAmmonium Chloride (DDAC) have been recently published by the European Competent Authorities and conclude that the substance was of no concern for developmental toxicity (Document I- Draft Evaluation reports in the frame of the directive 98/8/EC concerning the placing of biocidal products on the market - DDAC CAS 7173 -51 -5- Product type 8 - RMS Italy, July 2007 and April 2010)
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
500 mg/kg bw/day
Additional information

The endpoint developmental toxicity / teratogenicity is covered by read across from a respective study conducted with the structurally closely related substance 'ditallowdimethylammonium chloride' as test item instead of the substance 'quaternary ammonium compound, di-C16 -18 -alkyldimethyl, chloride'. The former is produced by the reaction of the ditallowalkylmethylamine with methylhalide while the latter is produced by reaction of the di-C16 -C18 alkylmethylamine with the same methylhalide. Therefore the reaction products are structurally closely related and the result concerning developmental toxicity / teratogenicity for 'ditallowdimethylammonium chloride' can be extrapolated to 'quaternary ammonium compounds, di-C16 -18-alkyldimethylammonium chloride'.

Although the study of Killeen (1975) predates formal guidelines and GLP, a reliabilty check by an expert panel of the American Chemistry Council concluded that the study was reliable with restrictions (Klimisch 2A).

In this study, 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.

The study of Palmer (1983) is disregarded. Due to the well known very poor dermal absorption of quaternary ammonium compounds, the topical route of application is considered not to be suited for the evaluation of an inherent potential for developmental toxicity. This view is in line with the conclusions from the existing EU risk assessment on DODMAC.

Justification for classification or non-classification

Based on the results available on dioctadecyldimethylammonium chloride, no reproductive toxicity or effects on fertility of quaternary ammonium compound, di-C16-18-alkyldimethyl, chloride are anticipated. From the study performed in rat with the structural analogue ditallowdimethylammonium chloride, it is concluded that quaternary ammonium compound, di-C16-18-alkyldimethyl, chloride should not be toxic to the embryo and the fetus and shoud not be teratogenic No classification is required according to regulation 67/548/ EEC and CLP regulation(EC) N° 1272/2008.