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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
1981
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(ethyl-3-oxobutanoato-O'1,O'3)(2-dimethylaminoethanolato)(1-methoxypropan-2-olato)aluminium(III), dimerised
EC Number:
402-370-2
EC Name:
(ethyl-3-oxobutanoato-O'1,O'3)(2-dimethylaminoethanolato)(1-methoxypropan-2-olato)aluminium(III), dimerised
Cas Number:
149057-70-5
Molecular formula:
C14H28AlNO6
IUPAC Name:
octaaluminium(3+) octakis((2Z)-4-ethoxy-4-oxobut-2-en-2-olate) octakis(1-methoxypropan-2-olate) octakis(2-(dimethylamino)ethan-1-olate)
impurity 1
Chemical structure
Reference substance name:
1-methoxypropan-2-ol
EC Number:
203-539-1
EC Name:
1-methoxypropan-2-ol
Cas Number:
107-98-2
Molecular formula:
C4H10O2
IUPAC Name:
1-methoxypropan-2-ol
Test material form:
liquid
Details on test material:
purified with vacum distillation, analyzed by Gel permeation chromatography as stated in one of the study reports

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Sprague-Dawley CFY rats, selected for this study as it is a readily available rodent species, historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.
Sex:
male/female
Details on test animals or test system and environmental conditions:
At the start of the treatment the males weighed 119 to 162g, and the females weighed 117 to 150g, and were approximately six to eight weeks old.
The animals were housed in groups of five by sex in polypropylene grid-floor cages suspended over trays lined with absorbent paper. The animals were allowed free access to food, except before blood collection and urinalysis when food was withdrawn overnight.
A pelleted diet (SQC Rat and Mouse Diet No. 1 Expanded, Special Diet Services Limited, Witham, Essex. U.K.} was used. A certificate of analysis of the batch of diet is given in Appendix VIII. The animals were allowed free access to mains water from polycarbonate bottles attached to the cage. The diet and .drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.
The animals were housed in a single air-conditioned room maintained at a tem-perature of 19 -25°C and relative humidity of 50 -75%. The rate of air ex-change was approximately 15 changes per hour and the fluorescent lighting was automatically controlled to give 12 hours light and 12 hours 'darkness. Environmental conditions were monitored and recorded daily.
The animals were randomly allocated to groups of five by sex and the treatment groups allocated to each cage using random letter tables. The group mean bodyweights were then determined to ensure similarity between the dose groups.
The animals were uniquely identified within the study, by an ear punching system routinely used in these laboratories. Colour coded cage labels were used to assist recognition of dose groups according to the following schedule.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see study report appendix X
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
The test material was administered by gavage using a metal cannula attached to a disposable plastic syringe.
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Remarks:
The test material was administered by gavage using a metal cannula attached to a disposable plastic syringe.
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
The test material was administered by gavage using a metal cannula attached to a disposable plastic syringe.
Dose / conc.:
400 mg/kg bw/day (actual dose received)
Remarks:
The test material was administered by gavage using a metal cannula attached to a disposable plastic syringe.
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
A control group of five males and five females was dosed with vehicle alone (arachis oil B.P.). ·
Positive control:
no

Examinations

Observations and examinations performed and frequency:
Clinical Observations (in particular respiratory effects including noisy and gasping respiration), Bodyweight, Food Consumption, Water Consumption, Haematology, Blood chemistry, necropsy, organ weights, histopathology
Sacrifice and pathology:
all animals were subjected to a gross necropsy examination and a limited histo-pathological evaluation of tissues from high dose and control animals was performed.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
signs were sporadic in nature and generally became less severe during the second half of the study. Noisy respiration was conrnon and was occasionally accompanied. in males by gasping respiration. Hunched posture, pilo-erection and red/brown staining around the snout and decreased respiratory rate were occasionally noted and some males showed additional signs of toxicity inclu-ding: lethargy, increased salivation, diuresis and pallor of the extremities. The decedent male showed signs of noisy and gasping respiration. red/brown staining around the snout and diarrhoea, during the survival period. Signs of toxicity were not apparent in all animals and one male and two females from this group remained unaffected throughout the study period.
Animals treated with 100 mg/kg/day appeared normal throughout the study with the exception of day twenty when the females showed red/brown staining around the snout and of the fur. This isolated incident was considered not to be treatment-related. A single male from this group showed noisy respiration at the one hour observation only, on· day thirteen. This isolated ab-normality was probably indicative of dosing trauma and was considered not to be attributed to the test material. These minor abnormalities occurring in the 100 mg/kg/day dose group were not considered to be of any toxicological significance.
Control animals and animals treated with 10 mg/kg/day appeared normal throughout the study period.

Then, signs of toxicity were sporadically noted in the high dose group (400 mg/kg/day) throughout the study. Of particular note were respiratory effects including noisy and gasping respiration.
Animals treated with 100 mg/kg/day and 10 mg/kg/day showed no signs which could be considered attributable to treatment with the test material.
Mortality:
mortality observed, treatment-related
Description (incidence):
the decedent animal in the 400 mg/kg/day group had a dark liver with small white areas on the median and left lobe. A small amount of blood was noted around the mouth. The low dose animal which died during bleeding showed signs consistent with anaesthetic trauma. Necropsy of the other animals on day twenty-nine revealed no treatment-related abnormalities.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males treated with 400 mg/kg/day showed slightly reduced bodyweight gain during the first week. Weekly weight gains in these animals were comparable with those in the control group during the remainder of the study. No effects on bodyweight gain were noted in the other dose groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption was slightly reduced in males treated with 400 mg/kg/day during the first week but consumption in these animals was comparable with that seen in controls for the remainder of the study. No effects on food consumption were apparent in the other groups.
Food consumption was slightly reduced in males treated with 400 mg/kg/day during the first week only. No effects on food consumption were apparent in the other groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
Visual inspection of water bottles revealed no intergroup differences.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant reductions were noted for the high dose males in total leucocyte count and in the lymphocyte fraction when compared to control values. This was due to a number of'unusually high values in the control group and was considered not to be indicative of leucopenia. Statisically significant differences were noted in the erythrocyte indices (MCV and MCHC) and the thrombotest time in some test group animals compared to control group animals. However, individual values were entirely within the normal range seen at these laboratories and there was no dose-related response.
There were no changes in the haematological parameters measured that could be attributed to treatment with SA2/1/0A.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Several statistically significant differences were noted between test and control group animals.
Sodium levels were elevated in all treatment groups compared to controls. However, there was no corresponding effect in chloride levels and the individual values were within the normal range seen at these labora-tories. Isolated differences noted fn potassium, alanine aminotransferase, urea nitrogen and bilirubin levels were not dose-related and were considered to be of no toxicological significance.
Elevated inorganic phosphorus levels were noted in males and females treated with 400 mg/kg/day and the males from this group also showed increased values for creatinine and urea nitrogen, In all cases these effects were slight.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Animals treated with 400 mg/ kg/day showed treatment-related changes in behaviour and physical condition.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative spleen weights were reduced in males treated with 400 mg/kg/day. There were no further treatment-related effects on organ weight.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related changes.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
The oral administration of SA2/1/0A to Sprague-Dawley CFY strain rats by gavage for twenty-eight consecutive days produced mild changes in behaviour and physical condition as well as minimal blood chemical effects at a dose level of 400 mg/kg/ day. Animals treated with 10 mg/kg/day and 100 mg/kg/day showed no abnormalities attributable to treatment with the test material. The maximum "no toxic effect level" .was considered to be 100 mg/kg/day.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 10 - <= 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
haematology
mortality
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
400 mg/kg bw/day (nominal)
System:
other: blood chemistry and spleen
Organ:
blood
Treatment related:
yes
Dose response relationship:
no
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
The oral administration of SA2/1/0A to Sprague-Dawley CFY strain rats by gavage for twenty-eight consecutive days produced mild changes in behaviour and physical condition as well as minimal blood chemical effects at a dose level of 400 mg/kg/ day. Animals treated with 10 mg/kg/day and 100 mg/kg/day showed no abnormalities attributable to treatment with the test material. The maximum "no toxic effect level" was considered to be 100 mg/kg/day.
Executive summary:

In an OECD407 study, the oral administration of SA2/1/0A to 10 male and female Sprague-Dawley CFY strain rats by gavage for twenty-eight consecutive days produced mild changes in behaviour and physical condition as well as minimal blood chemical effects at a dose level of 400 mg/kg/ day. Animals treated with 10 mg/kg/day and 100 mg/kg/day showed no abnormalities attributable to treatment with the test material. The maximum "no toxic effect level" was considered to be 100 mg/kg/day.