Dimethyldioctylammonium chloride

Endpoint summary

Description of key information

No studies are available to assess the repeated dose toxicity of the substance following oral administration. However, there is one reliable sub-chronic oral study in rats and two chronic studies in rats and mice available for a structurally similar substance. Treatment of rats with the substance at a concentration of 1000 ppm or less for 13-weeks in a dietary study resulted in a no treatment-related difference in any measurements and thus the NOEL for the substance for this strain of rats is considered to be 1000 ppm. 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). 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.

In a subacute toxicity study the substance was administered to male and female (2/sex/dose) rabbits (strain unspecified) by dermal application levels of 0.00025, 0.001 and 0.002% of a 100% active solution. At no time during the study were there any aberrations in food or fluid intake, excretions, appearance or behaviour noted. All blood and urine findings were within normal limits. Gross and histopathological examinations of significant organs and tissues were all unremarkable. The NOEL is identified to 0.002%. However, this study cannot be used for deriving DNELs because it is rated as Klimisch 4 (unreliable).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: 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:

other: OECD 451 - Carcinogenicity Studies

Version / remarks:

May 12, 1981

Deviations:

no

GLP compliance:

yes

Limit test:

no

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:

Eighteen months.

Frequency of treatment:

Daily.

Dose / conc.:

0 ppm

Dose / conc.:

100 ppm

Dose / conc.:

500 ppm

Dose / conc.:

1 000 ppm

No. of animals per sex per dose:

Sixty/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

Critical effects observed:

no

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 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:

chronic toxicity: 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

Limit test:

no

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 oral 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:

yes

Details on analytical verification of doses or concentrations:

Experimental diets were analysed using a gas chromattography procedure.

Duration of treatment / exposure:

Twenty four months

Frequency of treatment:

Daily

Dose / conc.:

300 ppm

Dose / conc.:

750 ppm

Dose / conc.:

1 500 ppm

No. of animals per sex per dose:

60/sex/dose

Control animals:

yes, plain diet

Positive control:

None.

Observations and examinations performed and frequency:

Observations for mortality was made twice daily (am and pm) during the treatment period.
Detailed clinical observations, including palpitations, were performed once each week.
Observations for overt clinical signs were made once daily during the treatment period except on days that detailed clinical observations were made.
Body weight and food consumption data were collected for all animals weekly for the first 14 weeks and every other week thereafter.
Ophthalmic examinations were performed for all animals, using an indirect ophthalmoscope, prior to the start of the study and prior to final sacrifice.

Sacrifice and pathology:

Haematology and clinical chemistry evaluations were conducted on 15 animals/sex/group at 26, 52, 78 and 104 weeks of study. At 26, 52, 78 and 104 weeks, the animals identified for clinical investigations were fasted overnight prior to the bleeding procedures. At 104 weeks, all animals were fasted overnight prior to bleeding and/or sacrifice.
Urinalysis was conducted on the same 15 animals/sex/group during study weeks 25, 51, 77 and 103 except in the case of animal replacement.

Statistics:

Data for continuous, parametric variables were compared between the treatment and control groups by use of Levene's test for homogeneity of variances, by analysis of variance, and by pooled variance t-tests. The t-tets were used, if the analysis of variance was significant, to delineate which treatment groups differed from the control group. If Levene's test indicated heterogeneous variances, the groups were compared by an analysis of variance for unequal variances followed, when appropriate, by separate variance t-tests. Non-parametric data were alaysed by the Kruskal-Wallis test or by the Wilcoxon rank sum test as modified by Mann-Whitney. Mortality and the mean days to first palpable mass were analysed using the life-table analyses. Frequency data were compared using Fisher's exact tests where appropriate.

Clinical signs:

no effects observed

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 specified

Histopathological findings: non-neoplastic:

effects observed, 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

Other effects:

not specified

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

Critical effects observed:

no

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).

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 clinical 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 (equivalent to approximate intake levels of 32 mg/kg bw/day for males and 41 mg/kg bw/day for females).

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16th September 1987 - 18th December 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Batch number B-1889.
- Expiration date of the lot/batch:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: stable.

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 32 days (approximately)
- Housing: stainless steel cages with solid sides and wire mesh floors.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66 - 75 °F
- Humidity (%): 40 - 70%
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh diet was prepared and offered to the animals each week.
- Mixing appropriate amounts with (Type of food): Test diets were prepared by the direct addition of the substance to ground rodent feed. A concentrated premix was perpared to ensure maximal loss of the ethanol (approximately 10% by weight) from the test material during the original mixing time of 1 hour.
- Storage temperature of food: Diets were stored in polyethylene containers at room temperature.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Experimental diets were analysed using a gas chromatographic procedure. Homogeneity of the substance at each diet concentration was established prior to start of the study.

Duration of treatment / exposure:

13 weeks.

Frequency of treatment:

Daily.

Dose / conc.:

100 ppm

Dose / conc.:

300 ppm

Dose / conc.:

600 ppm

Dose / conc.:

1 000 ppm

Dose / conc.:

3 000 ppm

No. of animals per sex per dose:

15 animals/sex/dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: AM and PM

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once each week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified

Statistics:

Data for continuous, parametric variables were intercompared for the dose and control groups by use of Levene's test for homogeneity of variances, by analysis of variance, and by pooled variance t-tests.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Treatment-related clinical signs were observed in both sexes from the high dose group only.In general, the signs indicated general cachexia (emaciation, unkempt appearance, pallor, hunched posture) and were observed in animals that died or were sacrificed in a moribund condition and, to a lesser extent, in the 3 animals/sex that survived to sacrifice. In addition, loose faeces was observed in all animals from the high dose group and associated perianal redness was observed in all animals that survived. All other clinical signs recorded during the study for all groups were sporadic and not related to treatment with the substance.

Mortality:

mortality observed, treatment-related

Description (incidence):

Treatment-related deathsTwelve male rats from the 3000 ppm group were found dead or sacrificed in a moribund condition from day 8 to day 17, and twelve of the 15 females from this group died from day 5 to day 16. One female from the 300 ppm died on day 81 of the study. Death was preceded by observattions related to general cachexia and the death was not considered to be treatment related.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

No effect on body weight or weight gain was observed for either sex in any group other than in the high dose (3000 ppm) group. Animals of both sexes from the high dose group showed marked weight loss during the initial stages of the study, and the weights and weight gains for the surviving rats in this study remained reduced from the controls throughout the study.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was markedly reduced in males and females from the 3000 ppm dose group in the first three weeks of the study. The food consumption for the three males and three females that survived through the study was also reduced but to a lesser extent than observed in the first three weeks. No effects on food consumption were observed in either sex from any other dose group.
The mean substance intake over the entire study was 6.2, 18.5, 36..8 and 60.7 mg/kg bw/day for the males and 7.5, 22.3, 44.4 and 74.3 mg/kg bw/day for the females from the 100, 300, 600 and 1000 ppm, respectively. An accurate daily doage could not be calculated for the 3000 ppm dose group due to the extensive mortality and food spillage.

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):

Approximately 90% of the animals in the prestduy evaluation and approximately 85% in teh terminal examination (distributed across both sexes and all groups including control) were observed to have corneal crystals. Corneal crystals consisted of fine granular deposits of calcium phosphate, located along with corneal epithelium basement membrane. The deposits were found within the epithelium and beneath it in the superficial stroma. The cause of the condition is not known to the authors of the study report. Other lesions were infrequent, occurred in all groups including controls and were not considered related to treatment with the substance.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In the 3000 ppm group decreased albumin and globulin concentration in females and increased erythrocyte count, haemoglobin concentration and hematocrit concentration in males was observed.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the 3000 ppm group decreased glucose and protein concentrations was observed in both sexes.

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At 3000 ppm intestinal ileus consisting of distended fluid and gas filled viscera affecting the caecum and colon was observed. These lesions tended to be more extensive in the animals that were found dead or sacrificed moribund than in those that survived to final sacrifice.

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Contracted spleens were observed in those animals that died or sacrificed moribund, this was indicative of terminal dehydration and shock.Another effect was glycogen depletion of the liver assumed to be secondary to inanition. Stomach irritation may have been evident in some animals that died although this finding was difficult to confirm due to autolysis. Typhlitis, as seen as a minimal to mild lymphoplasmacytic infiltrate in the caecal lamina propria, was observed in all animals from the 3000 ppm dose group that survived the 13-week exposure period.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOEL

Effect level:

1 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

Critical effects observed:

no

Conclusions:

Treatment of rats with the substance at a concentration of 1000 ppm or less for 13-weeks in a dietary study resulted in a no treatment-related difference in any measurements and thus the NOEL for the substance for this strain of rats is considered to be 1000 ppm.

Executive summary:

In a subchronic toxicity study the substance was administered in the rodent diet for 13 consecutive weeks at the approximate concentrations of 100, 300, 600, 1000 or 3000 ppm. At concentrations of 1000 ppm or less there was no treatment-related effects observed with regards to mortality, clinical signs, neurotoxic effects, ophthalmology, organ weight changes, body weight changes, histopathology and food consumption. At the top concentration of 3000 ppm there was 80% mortality. Animals from this group that survived to the end of treatment were observed to have markedly reduced body weights compared to the controls, fluid- or gas-filled intestines at necropsy and typhlitis. Clinical pathological changes were considered to be related to the debilitated condition of the animals and/or the gastro-intestinal lesions. Gross pathological findings and microscopic lesions in the animals that died or were sacrificed in a moribund condition supported ileus and shock as the probable cause of death or the morbidity. In addition, 3000 ppm concentration of the substance may have been irritating to the gastric mucosa. Treatment of rats with the substance at a concentration of 1000 ppm or less for 13-weeks in a dietary study resulted in a no treatment-related difference in any measurements and thus the NOEL for the substance for this strain of rats is considered to be 1000 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.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not spcified.

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Qualifier:

no guideline available

Principles of method if other than guideline:

According to 'Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics' published by the Association of Food and Drugs Officials of the United States.

GLP compliance:

not specified

Specific details on test material used for the study:

Quat LF-50
50% active, but the test concentrations employed were based on 100% actives.

Species:

rabbit

Strain:

not specified

Sex:

male/female

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on exposure:

The substance (4 ml) was applied daily to the skin to cover 10% of the body surface for 20 consecutive days.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Twenty days of repeated daily applications.

Frequency of treatment:

Daily.

Dose / conc.:

0.002 other: based on 100% actives

Dose / conc.:

0.001 other: based on 100% actives

Dose / conc.:

0 other: based on 100% actives

No. of animals per sex per dose:

Two/sex/dose

Control animals:

yes, concurrent no treatment

Positive control:

None.

Observations and examinations performed and frequency:

Food, bodyweight, fluid intake, excretions and behaviour and appearance were oberved. Blood and urine studies were performed at the begining of the test, at the 20 day interval and prior to autopsy.

Sacrifice and pathology:

Following sacrifice tissues were collected for gross and histological examinations. The tissues collected were skin, thyroid, lungs, heart, liver, spleen, adrenal, kidney, ovary, uterus and testes. Histopathology was examined in skin, thyroid, liver, lung, spleen, heart, adrenal, testes, ovary and fallopian tubes.

Clinical signs:

no effects observed

Dermal irritation:

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 specified

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

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:

0.002 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical signs

dermal irritation

gross pathology

haematology

histopathology: non-neoplastic

mortality

urinalysis

Remarks on result:

not determinable due to absence of adverse toxic effects

Conclusions:

The substance caused no significant toxicity or pathology in rabbits following daily dermal exposure to concentrations of 0.002, 0.001 and 0.00025%.

Executive summary:

In a subacute toxicity study the substance was administered to male and female (2/sex/dose) rabbits (strain unspecified) by dermal application levels of 0.00025, 0.001 and 0.002% of a 100% active solution. At no time during the study were there any aberrations in food or fluid intake, excretions, appearance or behaviour noted. All blood and urine findings were within normal limits. Gross and histopathological examinations of significant organs and tissues were all unremarkable. The NOEL is identified to 0.002%.

Endpoint conclusion

Endpoint conclusion:

no study available

Study duration:

subacute

Species:

rabbit

Quality of whole database:

The available study is assessed to be unreliable (Klimisch 4)

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not spcified.

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Qualifier:

no guideline available

Principles of method if other than guideline:

According to 'Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics' published by the Association of Food and Drugs Officials of the United States.

GLP compliance:

not specified

Specific details on test material used for the study:

Quat LF-50
50% active, but the test concentrations employed were based on 100% actives.

Species:

rabbit

Strain:

not specified

Sex:

male/female

Type of coverage:

not specified

Vehicle:

unchanged (no vehicle)

Details on exposure:

The substance (4 ml) was applied daily to the skin to cover 10% of the body surface for 20 consecutive days.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Twenty days of repeated daily applications.

Frequency of treatment:

Daily.

Dose / conc.:

0.002 other: based on 100% actives

Dose / conc.:

0.001 other: based on 100% actives

Dose / conc.:

0 other: based on 100% actives

No. of animals per sex per dose:

Two/sex/dose

Control animals:

yes, concurrent no treatment

Positive control:

None.

Observations and examinations performed and frequency:

Food, bodyweight, fluid intake, excretions and behaviour and appearance were oberved. Blood and urine studies were performed at the begining of the test, at the 20 day interval and prior to autopsy.

Sacrifice and pathology:

Following sacrifice tissues were collected for gross and histological examinations. The tissues collected were skin, thyroid, lungs, heart, liver, spleen, adrenal, kidney, ovary, uterus and testes. Histopathology was examined in skin, thyroid, liver, lung, spleen, heart, adrenal, testes, ovary and fallopian tubes.

Clinical signs:

no effects observed

Dermal irritation:

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 specified

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

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:

0.002 other: %

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical signs

dermal irritation

gross pathology

haematology

histopathology: non-neoplastic

mortality

urinalysis

Remarks on result:

not determinable due to absence of adverse toxic effects

Conclusions:

The substance caused no significant toxicity or pathology in rabbits following daily dermal exposure to concentrations of 0.002, 0.001 and 0.00025%.

Executive summary:

In a subacute toxicity study the substance was administered to male and female (2/sex/dose) rabbits (strain unspecified) by dermal application levels of 0.00025, 0.001 and 0.002% of a 100% active solution. At no time during the study were there any aberrations in food or fluid intake, excretions, appearance or behaviour noted. All blood and urine findings were within normal limits. Gross and histopathological examinations of significant organs and tissues were all unremarkable. The NOEL is identified to 0.002%.

Endpoint conclusion

Endpoint conclusion:

no study available

Study duration:

subacute

Species:

rabbit

Quality of whole database:

The available study is assessed to be unreliable (Klimisch 4)

Justification for classification or non-classification

Based on the findings of a reliable 90-day sub chronic oral toxicity study in rats and two chronic oral toxicity studies in rats and mice conducted on a structurally similar substance, classification of the substance is not justified.