Didecyldimethylammonium chloride

Carcinogenicity

Description of key information

Based on the study results, the test substance was not found to be carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 Nov, 2003 - 13 Mar, 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was performed in accordance with the OECD and OPPTS protocols, although there were few subsequent amendments, with the following deviations from the agreed Study plan: - the temperature and relative humidity recorded in the animal room were sometimes out of the target ranges specified in the Study plan, - on day 47, animals were checked for mortality or signs of morbidity only once, instead of at least twice as stated in the Study plan, - in order to decrease cross-contamination risks, the racks were no longer rotated around the room from day 280, - I. Gaou took on the responsibility of this study from 19 October 2004, instead of 18 November 2003 as specified by error in her statement, - further to the receipt of a new certificate of analysis, the test substance contained 39.6% DDAC instead of 40.5%, - the concentration of preparations was additionally checked in week 104. These deviations were not considered to have compromised the validity or integrity of the study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: US EPA guideline OPPTS 870.3700, August, 1998

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

Administration/ Exposure: Oral (dietary admixture)
Duration of treatment: 52 (chronic part) or 104 weeks (carcinogenicity part)
Interim sacrifice(s): After 52 weeks (chronic part)
Final sacrifice: After 104 weeks
Freqency of exposure: Daily by feed admixture
Postexposure period : None
Concentration: 0, 700, 1500 and 3000 ppm of the test substance (corresponding to 280, 600 or 1200 ppm of DDAC) for groups 1, 2, 3 and 4, respectively, in dietary admixtures supplied ad libitum.
Vehicle: The test item was given by dietary admixture in A04 C P2.5 powdered maintenance diet (SAFE, Villemoisson, Epinay-sur-Orge, France).
Controls: Vehicle (untreated diet)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analysis of mean achieved dose levels were performed at regular intervals.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

daily

Post exposure period:

none

Remarks:

Doses / Concentrations:
700, 1500 and 3000 ppm of test substance i.e., 40% active DDAC (i.e., corresponding to 277.2, 594 or 1188 ppm of DDAC)
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
12.6, 27.3 and 55.4 mg a.i./kg bw/day for males and 15.7, 33.8 and 69.5 mg a.i./kg bw/day for females
Basis:
nominal in diet

No. of animals per sex per dose:

Fifty males and 50 females in each group were used to investigate the carcinogenic potential.

Control animals:

yes, concurrent vehicle

Details on study design:

Rats were treated with the test substance (Batch No. WIR03048) containing 39.6% of the active substance DDAC (Didecyldimethylammonium chloride) by daily oral administration (dietary admixtures) at the constant concentrations of 700, 1500 or 3000 ppm (corresponding to 277.2, 594 or 1188 ppm of DDAC).

Positive control:

Not applicable

Observations and examinations performed and frequency:

The animals were checked at least once a day for mortality and twice daily for clinical signs. In addition, detailed clinical examinations were made once a week. After 6 months of treatment, all animals were palpated every 2 weeks in order to record the time of onset, location, size, appearance and progression of palpable masses. Body weights were recorded once during the pre-treatment period, on the first day of treatment, once a week during the first 13 weeks of the treatment period and then once every 4 weeks until the end of the study. Food consumption was recorded once a week during the first 13 weeks of the study, once every 3 months between weeks 14 and 26, once a month between weeks 27 and 39 and then every 4 weeks until the end of the study. The differential white cell count was determined for all surviving control animals and those treated at 3000 ppm in weeks 52, 78 and 104.

Sacrifice and pathology:

Carcinogenicity sub-group animals were killed at the end of the 104-week treatment period. A full macroscopic post-mortem examination was performed on all the animals. Designated organs were weighed and selected tissue specimens preserved. A microscopic examination was performed on all masses, and on designated tissues from control animals and those treated at 3000 ppm of the test substance sacrificed at the end of the 52 or 104-week treatment periods, and from animals that died prematurely.

Other examinations:

None

Statistics:

Analysis of survival data - Kaplan Meier technique and Peto's method.
Analysis of tumor incidence: Peto's method, one-tailed exact test and Armitage's test.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

In the carcinogenicity sub-groups:
. survival rate in animals treated with DDACwas not statistically different from to controls. Further, mortality was comparable in terms of time of occurrence and cause,
. no test item-related clinical signs were observed in any treated group,
. in comparison to controls, mean body weight and body weight gain were slightly lower in males and females (respectively -6 and -16% for the mean body weight gain over the 13 first weeks) at 1200 ppm DDAC, and food consumption was slightly lower during the first 13 weeks for the females in this group,
. there were no differences in the number and localization of palpable masses in test-treated animals and controls,
. there were no significant differences in the differential white blood cell parameters of males and females treated at 1200 ppm,when compared with controls.

Histopathological examinations were summarized as follows:
. treatment with DDAC for up to 2 years had no effect on organ weights,
. no treatment-related necropsy findings of toxicological significance,
. changes in the mesenteric lymph node consisted of hemorrhage (high dose males at 52 weeks), histiocytosis (high dose females at 104 weeks), and mastocytosis (high dose males and females at 104 weeks),
. changes in Peyer’s patches consisted of a decrease in germinal centres in high dose females at 52 weeks ands in high dose males and females at 104 weeks.
. the administration of the test item did not induce neoplastic changes under the conditions of this study.

Relevance of carcinogenic effects / potential:

The study was relevant in evaluating the carcinogenic potential of the test substance.

Key result

Dose descriptor:

dose level:

Effect level:

ca. 55.4 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: No carcinogenic lesions observed

Key result

Dose descriptor:

dose level:

Effect level:

ca. 69.5 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

female

Basis for effect level:

other: No carcinogenic lesions were observed at this dose

Mean achieved dosages expressed in mg/kg/day of DDAC for 700 - 1500 - 3000 ppm test substance (280, 600, 1200 ppm DDAC):
Male: 12.5 - 27.0 - 54.9
Female: 15.9 - 34.3 - 70.5

Conclusions:

The test substance was not considered to be carcinogenic under the conditions of this study

Executive summary:

The carcinogenic potential of the test substance was evaluated in a 104 week study in rats according to OECD Guideline 453 and OPPTS Guideline 870.3700. The test substance (40% active DDAC) was administered daily to Sprague-Dawley rats by dietary admixture at the concentrations of 700, 1500, and 3000 ppm of for 52 weeks (toxicology sub-group) (equivalent to 15.6, 32.6 and 66.1 mg a.i./kg bw/day for males and to 18.2, 39.2 and 77.2 mg a.i./kg bw/day for females) or for 104 weeks (carcinogenicity sub-groups) (corresponding to dose levels of 12.6, 27.3 and 55.4 mg a.i./kg bw/day for males and 15.7, 33.8 and 69.5 mg a.i./kg bw/day for females). There was no treatment-related mortality or clinical signs. At 3000 ppm, the mean body weight and body weight gain of the treated animals were slightly lower than controls, correlating in females with slightly lower mean food consumption during the first 13 weeks. There were no significant differences in hematological, biochemical and/or urinalysis parameters and no macroscopic findings attributable to the test substance. Non-neoplastic histopathological findings were confined to the mesenteric lymph nodes and Peyer's patches and were consistent with the continued action of a mild irritant. These were therefore considered to be of limited toxicological significance. In conclusion, the test substance was not considered to be carcinogenic under the conditions of this study.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Qualifier:

no guideline followed

Conclusions:

DDAC was not considered to be oncogenic / carcinogenic under the conditions of this study.

Executive summary:

In a two year feeding study, Sprague-Dawley rats received 0, 300, 750 and 1500 ppm of DDAC in the diet (13, 32 and 64 mg/kg bw/day males; 16, 41 and 83 mg/kg bw/day females). DDAC was not considered to be oncogenic under the conditions of this study. In another study, CD-1 mice received 0, 100, 500 or 1000 ppm of DDAC in the diet for at least 78 weeks. Approximate mean intake levels were 15, 76.3 and 155.5 mg/kg bw/day for males, and 18.6, 93.1 and 193.1 mg/kg bw/day for females. Again, DDAC was not considered to be carcinogenic under the conditions of this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

55.4 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Guideline compliant GLP study. No treatment related neoplastic findings up to highest tested dose of 3000 ppm (55.4 mg a.i./kg bw/day in males and 69.5 mg a.i./kg bw/day in females).

Organ:

other: Carcinogenicity assessment overall

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The available studies in rat and mouse demonstrated no carcinogenic effects of the test substance. Hence, no classification for this endpoint is required according to EU CLP (Regulation EC/1272/2008) criteria. 

Additional information

The carcinogenic potential of the test substance was evaluated in a 104 week study in rats according to OECD Guideline 453 and OPPTS Guideline 870.3700, in compliance with GLP. The test substance (40% a.i.) was administered daily to Sprague-Dawley rats by dietary admixture at the concentrations of 700, 1500, and 3000 ppm of for 52 weeks (toxicology sub-group) (equivalent to 15.6, 32.6 and 66.1 mg a.i./kg bw/day for males and to 18.2, 39.2 and 77.2 mg a.i./kg bw/day for females) or for 104 weeks (carcinogenicity sub-groups) (corresponding to dose levels of 12.6, 27.3 and 55.4 mg a.i./kg bw/day for males and 15.7, 33.8 and 69.5 mg a.i./kg bw/day for females). There was no treatment-related mortality or clinical signs. At 3000 ppm, the mean body weight and body weight gain of the treated animals were slightly lower than controls, correlating in females with slightly lower mean food consumption during the first 13 weeks. There were no significant differences in hematological, biochemical and/or urinalysis parameters and no macroscopic findings attributable to the test substance. Non-neoplastic histopathological findings were confined to the mesenteric lymph nodes and Peyer's patches and were consistent with the continued action of a mild irritant. These were therefore considered to be of limited toxicological significance. In conclusion, the test substance was not considered to be carcinogenic under the conditions of the study (CIT, 2008).

In a two year feeding study, Sprague-Dawley rats received 0, 300, 750 and 1500 ppm of test substance in the diet (13, 32 and 64 mg/kg bw/day males; 16, 41 and 83 mg/kg bw/day females). The substance was not considered to be oncogenic under the conditions of the study. In another study, CD-1 mice received 0, 100, 500 or 1000 ppm of test substance in the diet for at least 78 weeks. Approximate mean intake levels were 15, 76.3 and 155.5 mg/kg bw/day for males, and 18.6, 93.1 and 193.1 mg/kg bw/day for females. Again, the test substance was not considered to be carcinogenic under the conditions of the study (Henderson, 1992).