Dimethyldioctylammonium chloride

Carcinogenicity

Description of key information

There are no studies available to assess the carcinogenic potential of the substance. However, there are two chronic studies available in rats and mice that assess the carcinogenic potential of a structurally similar substance. Dietary administration of the substance resulted in treatment-related decreases in body weight and food consumption in both male and female rats in the high dose group (1500 ppm). At 1500 ppm, hyperplasia of bile ducts in females and changes in mesenteric lymph nodes of males and females related to blood in the sinuses. There were no other treatment-related changes observed and this formed the basis for a NOAEL of 750 ppm (equivalent to 32 mg/kg bw/day in males and 41 mg/kg bw/day in females) and the substance was considered to lack oncogenic potential. No treatment-related changes, which could be considered adverse, were observed in male and female mice following dosing with the substance, when administered in powdered rodent diet for at least 78 weeks at the approximate concentrations of 100, 500 or 1000 ppm (corresponding to mean intake dose levels of 15, 76.3 and 155.5 mg/kg bw/day for the males and 18.6, 93.1 and 193.1 mg/kg bw/day for the females). The NOEL identified in this study was 500 ppm based on reduced weight and reduced weight gain in both sexes.

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:

5 July 1998 - 16 January 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Version / remarks:

May 12, 1981

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: B-1889

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: the stability of the substance was verified at before the inititation of the study and upon completion of the study.

Species:

mouse

Strain:

CD-1

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Experimental diets were analysed using a gas chromatography procedure. Homogeneity of the substance at each diet concentration was established. Prior to dosing, stability of the test substance in diets at the 100 and 1000 ppm concentrations was determined in stainless steel feeders and in the polyethylene storage containers. Diet concentrations were verified for all dose levels for the first four weeks of the study prior to administration of the diets to the animals. Thereafter, diets prepared every fourth week were analysed for concentration verification.

Duration of treatment / exposure:

18 months

Frequency of treatment:

Daily

Post exposure period:

None.

Dose / conc.:

0 ppm

Dose / conc.:

100 ppm

Dose / conc.:

500 ppm

Dose / conc.:

1 000 ppm

No. of animals per sex per dose:

60/sex/dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily, except for when detailed clinical observations were made.
- Cage side observations checked in table 2 were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for the first 14 weeks and every other week thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- How many animals:10 animals/sex from the high dose and control groups during week 52; 10 animals/sex from all dose groups during week 79.
- Parameters were examined: erythrocyte count, haemoglobin, haematocrit, erythrocyte indices, platelet count, total leukocyte count.

Sacrifice and pathology:

Following the 78-week treatment period, the terminal necropsy of all surviving animals was undertaken. A complete necropsy was performed on each animal.

Clinical signs:

effects observed, non-treatment-related

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The incidence of mortality for male mice (including those sacrificed moribund but excluding cage accidents) in the 0 (first control), 100, 500, 1000 and 0 (second control) ppm groups was 22%, 20%, 23%, 22% and 32%, respectively.
The incidence of mortality for female mice (including those sacrificed moribund but excluding cage accidents) in the 0 (first control), 100, 500, 1000 and 0 (second control) ppm groups was 28%, 20%, 25%, 20% and 17%, respectively.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean absolute body weights and body weight gains for male mice in the top dose group were decreased relative to the untreated controls during most of the treatment period. The mean absolute body weights and body weight gains for female mice in the top dose group were decreased relative to the untreated controls during from the second week of treatment thorugh to the end of the study.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Statistically significant differences in mean food consumption (incrases and decreases) were occassionally observed for males mice in the top tow dose groups, however these were considered by the authors to spurious staistical findings reflecting normal bilogical variation and not a response to treatment with the substance. No treatment-related effects were observed for females.

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Organ weight findings were statistically significantly different from both control groups in the top dose group for both sexes. This was considered by the study authors to be associated with the decreased overall body weight and not a direct effect of the treatment.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOEL

Effect level:

500 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Conclusions:

No treatment-related changes, which could be considered adverse, were observed in male and female mice following dosing with the substance, when administered in powdered rodent diet for at least 78 weeks at the approximate concentrations of 100, 500 or 1000 ppm (corresponding to mean intake dose levels of 15, 76.3 and 155.5 mg/kg bw/day for the males and 18.6, 93.1 and 193.1 mg/kg bw/day for the females). The NOEL identified in this study was 500 ppm based on reduced weight and reduced weight gain in both sexes.

Executive summary:

Male and female mice were administered the substance in powdered rodent diet for at least 78 weeks at the approximate concentrations of 100, 500 or 1000 ppm (corresponding to mean intake dose levels of 15, 76.3 and 155.5 mg/kg bw/day for the males and 18.6, 93.1 and 193.1 mg/kg bw/day for the females).No treatment-related mortality occurred and no treatment-related clinical signs were observed during the study. There was no effect observed in the haematology parameters monitored. There were treatment-related changes were observed in body weight and body weight gain, however this was not considered to be of toxicological relevance and thus not considered by the study authors to be adverse.Organ weight findings were statistically significantly different from both control groups in the top dose group for both sexes. This was considered by the study authors to be associated with the decreased overall body weight and not a direct effect of the treatment.No treatment-related findings were reported at post mortem macroscopic observations and histopathological examination. The NOEL identified in this study was 500 ppm based on reduced weight and reduced weight gain in both sexes.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13th June 1988 - 19th June 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EPA Pesticide Assessment Guidelines (Subdivision F, Section 83-5, November 1984)

Deviations:

not specified

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: B-1889

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: samples of the test material was found to be stable for the duration of the study as evidenced by analytical verification

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation:
- Housing: stainless steel cages with wire mesh floors
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66 - 75°F
- Humidity (%): 40 - 70%
- Air changes (per hr): 8/hour
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): substance was added direct to ground rodent feed
- Storage temperature of food: room temperature

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Periodic analyses were conducted for the samples taken before the initiation and after the completion of the study to verify the stability of the substance over the course of the study. Prior to administration of the diets to the animals, diet concentrations were verified for all dose levels for the first four weeks of the study. Thereafter, all diets prepared every fourth week were analysed for concentration verification.

Duration of treatment / exposure:

24 months

Frequency of treatment:

Weekly

Post exposure period:

None.

Dose / conc.:

300 ppm

Dose / conc.:

750 ppm

Dose / conc.:

1 500 ppm

No. of animals per sex per dose:

60 animals/sex/dose

Control animals:

yes, plain diet

Positive control:

None.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

None of the clinincal effects observed were considered to be related to the treatment of any dose group.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The mortality rates for male rats (including those sacrificed moribund but excluding procedural deaths) in the 0 (first control), 300, 750, 1500 and 0 (second control) ppm groups were 35%, 55%, 55%, 43% and 47%, respectively. The mortality rates for female rats (including those sacrificed moribund but excluding cage accidents) in the 0 (first control), 300, 750, 1500 and 0 (second control) ppm groups were 50%, 40%, 33%, 37% and 50%, respectively.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weight for the 1500 ppm group of males was decreased approximately 2 to 4% during the first 10 weeks of the study and remained slightly decreased throughout the remainder of the study. Decreases in mean body weight were statistically significantly different from both control groups during weeks 4 through 8, 10, 18 and 20. Mean body weight gain for the 1500 ppm group of males was decreased approximately 5 to 12% throughout the study. Decreases in mean body weight gain were statistically significantly decreased from the start of the study to 12 and during weeks 18, 20 and 22. There were no treatment-related effects on body weight or body weight gain for males in the 300 or 750 dose groups.
Mean body weight for the 1500 ppm group of females was decreased approximately 2 to 8% during the first 74 weeks of the study and 5 to 15% thereafter. Decreases in mean body weight were statistically significantly different from both control groups during weeks 5 through 7 and statistically significantly different from the first control group for the majority of the measurement periods during the study. Mean body weight gain for the 1500 ppm group of females was generally decreased 6 to 13% during the initial 74 weeks of the study and 8 to 22% thereafter. These decreases were statistically significantly different from both control groups at most measrement periods from weeks 4 to 24. There were no treatment-related effects on body weight or body weight gain for females in the 300 or 750 dose groups.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Mean food consumption was slightly decreased for the 1500 ppm group of males (2 to 10%) for most of the study. The decreases in mean food consumption were statistically significant during study weeks 3 through 11.
Mean food consumption was statistically decreased for the 1500 ppm group of females from the start of the study to week 7 (with an exception in week 2). The decreases in mean food consumption during that period were approximately 2 to 8%. Thereafter, food cosumption in the 1500 ppm group for both sexes was comparable with the controls, however, inconsistent statistically significant differences were occassionally observed.
Occasional, statistically significant differences observed in the 300 or 750 ppm group were not considered to be related to the treatment.
The approximate mean substance intake over the entire study was 13, 32 and 64 mg/kg bw/day for the males and 16, 41 and 83 mg/kg bw/day for the females of the 300, 750 and 1500 ppm groups, respectively.

Food efficiency:

not examined

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

not specified

Ophthalmological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Relatively high incidence of corneal crystals which is common among the strain of rats used in this study. The distribution of these corneal crystals was approximately equal across the dosage groups. A relatively high incidence of cataracts also occurred at the presacrifice examination. No dose-related effect was reflected by the distribution of the cataracts. All ophthalmic findings noted in the rats in this study are, therefore, considered to represent incidental findings.

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic lesions were limited to changes in mesenteric lymph nodes of males and females in the 1500 ppm group and hyperplasia of the bile ducts of females in the 1500 ppm group. Specifically, an increase in the number of males and females with red blood cells, hemosiderin and hystiocytosis in the mesenteric lymph nodes was observed in the high dose group. These lesions were considered by the study author to be of minimal toxicological significance based on the lack of microscopic evidence of hemorrhage or inflammation in the gastrointestinal tract and the small amount of blood observed. There was an increase in the incidence of animals with bile duct hyperplasia for females in the high dose group sacrificed at study week 104 (79% of the females sacrificed) compared to the control groups (53% and 63% of the animals sacrificed). This increase in the high dose group was not apparent for females that died or were sacrificed prior to study week 104. This lesion is considered to be of minimal toxicological significance based on its low degree of severity in all treatment groups and the lack of other changes in the liver to indicate hepatotoxicity. Bile duct hyperplasia occurs commonly as rats grow old. Indeed, the majority of the incidences of bile duct hyperplasia occurred in the oldest animals, that is, those which were sacrificed at the end of the study.

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

750 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Conclusions:

Dietary administration of the substance resulted in treatment-related decreases in body weight and food consumption in both male and female rats in the high dose group (1500 ppm). At 1500 ppm, hyperplasia of bile ducts in females and changes in mesenteric lymph nodes of males and females related to blood in the sinuses. There were no other treatment-related changes observed and this formed the basis for a NOAEL of 750 ppm (equivalent to 32 mg/kg bw/day in males and 41 mg/kg bw/day in females) and the substance was considered to lack oncogenic potential.

Executive summary:

The substance was administered to Sprague-Dawley CD rats (60/sex/group) in the diet at concentrations of 0, 300, 750 or 1500 ppm (equivalent to approximate intake levels of 13, 32 and 64 mg/kg bw/day for males and 16, 41 and 83 mg/kg bw/day for females) for at least 104 weeks. Two control groups were included in this study. Detailed clninical observations, including examinations for palpable masses, were conducted weekly throughout the study. Body weights and food consumption were measured weekly for the first 14 weeks of the study and every other week thereafter. Haematology and clinical chemistry evaluations were conducted on 15 animals/sex/group at 26, 52, 78 and 104 weeks of study. Urinalysis was conducted on 15 animals/sex/group at 25, 51, 77 and 103 weeks of study. Complete necropsies were performed for all animals in the study and selected organs from all surviving animals were weighed at terminal necropsy. Histopathology was conducted on a full set of tissues and organs from all animals in the control and high dose groups as well as on selected organs from animals in the low and mid dose groups. All surviving animals were given an ophthalmologic examination prior to study termination. Dietary administration of the substance resulted in treatment-related decreases in body weight and food consumption in both male and female rats in the high dose group (1500 ppm). The body weight effects at 1500 ppm were reflected in both the mean absolute body weights and the mean body weight gains. No treatment-related effects were observed in the type or incidence of clinical signs, survival, the type or incidence of palpable masses, clinical pathology, organ weights, gross anatomic pathology or ophthalmology. At 1500 ppm, hyperplasia of bile ducts in females and changes in mesenteric lymph nodes of males and females related to blood in the sinuses were the only microscopic changes of potential, but undetermined, toxicological significance. No other treatment-related microscopic changes were observed for males and females. The NOAEL is considered by the study authors to be 750 ppm.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

32 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Sufficient to address requirements.

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

Based on the findings of two reliable chronic oral carcinogenicity studies conducted on rats and mice for a structurally similar substance, classification of the substance is not justified.