N-benzyl-N-C16-18 (even numbered)-alkyl-N-methyl-C16-18 (even numbered)-alkyl-1-aminium chloride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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:

secondary source

Title:

Unnamed

Year:

1975

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

modifications in exposure period

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ditallowdimethylammonium chloride

IUPAC Name:

Ditallowdimethylammonium chloride

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 or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
100 mg/kg body weight
Basis:
actual ingested
oral gavage

Doses / concentrations 2

Remarks:

Doses / Concentrations:
500 mg/kg body weight
Basis:
actual ingested
oral gavage

Doses / concentrations 3

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)

1

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

2

Dose descriptor:

NOAEL

Remarks:

by gavage

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

3

Dose descriptor:

NOAEL

Remarks:

via diet

Effect level:

508 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental 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.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

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:

Justification for cross reading of Benzyl-dihydrogenated-methyl ammonium chloride (BDHTMAC) to dihydrogenated-dimethyl-ammonium chloride (DHTDMAC):

An overview of available data existing on common toxicological endpoints for the two substances demonstrates their similar toxicological behaviour: Both substances have a low acute toxicity but strong skin and eye corrosive properties. They are not sensitising and not mutagenic. The 28-day repeated dose toxicity studies performed by oral route in rats conclude to the same NOAEL of 100 mg/kg bw /day. The same biochemical changes (increase in ALAT enzyme) and the same target organ (adrenals) have been identified by these studies. Based on these results, the two substances display a similar toxic profile and it is scientifically appropriate to use cross-reading. Concerning

thedevelopmental toxicity and teratogenicity assessment, there are no adequate data available on quaternary ammonium compound, benzyl di-C16-18-alkylmethyl, chlorides. However, read-across can be made to experimental results from the structural closely related ditallowdimethylammonium chloride (DTDMAC).

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.

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 2).