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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1971
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was conducted by Industrial Bio-Test Laboratories Inc.(IBT) and no information is available as to whether this study has been audited in the EPA/ FDA post-hoc programme. The interpretation of the study must take into account that the rats were not the same age at the start of the study and there were large differences in the starting weights and subsequent weights.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1971
Report Date:
1971

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The main part of the study is comparable to OECD 408, however there is an additional reproductive element to the study.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Dimethyl di "hydrogenated tallow" ammonium chloride (DHTA.Cl), also known as Arquad 2HT, obtained from Armour Industrial Chemical Company.

Test animals

Species:
rat
Strain:
other: Charles River albino
Sex:
male/female
Details on test animals and environmental conditions:
Charles River albino rats, obtained from Charles River Breeding Laboratories, Massachusettes. Animals were approximately 7 days old at the start of the test. Rats were fed ad libitum. They were housed individually (except during mating) in standard wire-bottomed steel cages.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test substance was provided in the diet at 3 levels. The appropriate amount of test substance was mixed with the standard rat diet ration in a Hobart mixer. Fresh diets were prepared each week, and each rat was offered an amount of diet sufficient for 1 week's ad libitum feeding.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Parental animals: approximately 4 weeks (it is not known if test substance administration was continued through gestation).
Offspring: 90 days.
Frequency of treatment:
Daily in diet.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 7, 140, 2800 ppm.
Basis:
nominal in diet
No. of animals per sex per dose:
Parental animals: 2 males/dose and 5 females/dose.
Offspring: 15 rats/sex/dose.
Control animals:
yes, plain diet
Details on study design:
Phase 1 (parental animals):
8 males and 20 females were fed the test material for approximately 4 weeks (between the ages of 70 and 100 days). When the rats reached 100 days of age, each male was randomly mated with 2 or 3 females from the same group.

Phase 2 (offspring):
15 males and 15 females were selected from the litters of each group of Phase 1 for the 90 day feeding study. Following the 90 day study, some of the rats were maintained on the respective diets to facilitate the collection of urine and faeces for residue analysis. This additional feeding period appears to be 24 hours. Rats were weighed on the day of sacrifice for determination of organ to body weight ratios.
Only results relating to the 90 day feeding study (offpsring) are presented in the report.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
Offspring (90 day feeding study):
- Each rat was weighed on the first day of the study and at weekly intervals thereafter. Food consumption data were collected individually for 5 rats of each sex in every group weekly during the study.
- Rats were observed for clinical signs and mortality on a daily basis.
- Blood and urine samples were collected individually from 10 rats of each sex from both the control and high dose groups after 45 and 84 days (see below).
Sacrifice and pathology:
All surviving rats were sacrificed at the end of the study and subject to gross necropsy. Animals that died during the study were also necropsied unless examination was precluded by postmortem autolysis. A complete set of organs and other tissues were removed from each rat and preserved in formalin solution. Organ weights were recorded for the liver, kidneys, spleen, gonads, heart and brain.
Tissues from the control and high dose groups were stained with haematoxylin-eosin and examined microscopically (see below).
Other examinations:
None reported.
Statistics:
ANOVA and t-tests.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
mortality was not related to treatment
Mortality:
mortality observed, treatment-related
Description (incidence):
mortality was not related to treatment
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
- Mortality:
Five rats died during the study. Two of the deaths were attributed to an acute respiratory infection, whilst the other 3 resulted from trauma incurred during the collection of blood samples. No abnormal behavioural reactions were noted during the study.

- Body weight and food consumption:
There was a slight depression in weight gain recorded for all of the treated groups, however there was no dose-related relationship. The only statistically significant reductions in weight gain (compared to controls) were the males fed 2800 ppm and the females fed 7 ppm. The authors report that variations in initial body weights were the result of different aged animals in each of the groups. At the start of the 90 day feeding study, the mean male rat body weight ranged from 69 to 127 g (with the high dose group have lower body weights than all other groups), and the mean female rat body weight ranged from 62 to 100 g (again the high dose groups had lower body weights than all other groups).
Food consumption was slightly lower in all treated groups compared to controls. As food consumption data were not corrected for body weight therefore this may explain the result observed here.

- Haematology , clinical chemistry and urinalysis:
There were no differences between high dose rats and control rats in the haematology, clinical chemistry and urinalysis parameters.

-Macroscopic examinations and histopathology:
No abnormalities were noted at necropsy. Whilst there was some variation in organ weights and organ weight ratios, there was no evidence of a dose-response relationship therefore these findings were considered incidental and not related to treatment.
Lesions noted at histopathological examination were those of spontaneous disease and not unusual for rats. The most frequent findings were lesions in the trachea and lungs, indicating chronic murine pneumonia. Lesions occurred in both treated and control rats.



Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
2 800 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects at highest dose-level of the study
Dose descriptor:
NOAEL
Effect level:
ca. 140 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects at highest dose-level of the study

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There were no significant effects of treatment, therefore the 90 day NOAEL derived from this study is 2800 ppm.
Executive summary:

Dihydrogenatedtallowdimethylammonium chloride (purity unknown) was administered to rats in the diet for approximately 4 weeks at dietary levels of 0, 7, 140 and 2800 ppm. These rats were then mated, and a 90-day oral toxicity study was conducted with the offspring at the same dietary levels. No data were presented regarding the parental animals, however it is reported in a letter appended to the report that mating and reproductive performance were normal and all of the offspring were normal. The following data are concerning the offspring in the 90 day feeding study only.

There was a slight depression in weight gain of the treated rats compared to controls, however there was no dose-response relationship. Food consumption was lower for all treated groups compared to controls. It appears that the rats were not the same age at the start of the study and there were large differences in the starting weights (and subsequent weights) because of this, age at study initiation are not included in the report. This may explain the differences in weight gain, and the differences in food consumption as food consumption data were not corrected for body weight.

There were not treatment related mortalities. There were no differences in haematology, clinical chemistry or urinalysis between 2800 ppm rats and controls. Lesions noted at histopathological examination were those of spontaneous disease and not unusual for rats. The most frequent findings were lesions in the trachea and lungs, indicating chronic murine pneumonia. Lesions occurred in both treated and control rats.

Whilst it appears that the 90 day dietary NOAEL is 2800 ppm, the results should be interpreted with caution.