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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
1998
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1'-iminodipropan-2-ol
EC Number:
203-820-9
EC Name:
1,1'-iminodipropan-2-ol
Cas Number:
110-97-4
Molecular formula:
C6H15NO2
IUPAC Name:
1,1'-iminodipropan-2-ol
Specific details on test material used for the study:
Commercial DIPA (CAS 000110-97-4) was obtained from the Dow Chemical Company (Midland, MI).
The purities of four lots of DIPA used for these studies ranged from 98.8% to 99.6%, as determined by GC/FID.

Test animals

Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc. (Kingston, New York and Raleigh, North Carolina)
- Age at study initiation: approximately 6 weeks of age
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: not specified
- Diet: ad libitum LabDiet#5002 Certified Rodent Diet (PMI Nutrition International, St. Louis, MO)
- Water: ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21–25
- Humidity (%): 45–60%
- Air changes (per hr): 12–15 room air changes/h
- Photoperiod (hrs dark / hrs light): 12 h photocycle

Administration / exposure

Route of administration:
oral: drinking water
Details on oral exposure:
Drinking water formulated with test article to supply 0, 100, 500, or 1000 mg DIPA/kg/day for 13 weeks
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of DIPA in all dose solutions for all studies ranged from 95% to 105% of target.
Duration of treatment / exposure:
13 weeks (90 days)
Frequency of treatment:
Continuously via drinking water.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: dose levels were based upon the prior 2-week drinking water study.
- Eficiency of the dosing: Water consumption was between 98% and 106% of targeted levels.
- Rationale for selecting satellite groups: assess recovery from any treatment-related effects.
- Post-exposure recovery period in satellite groups: Additional groups of 10 rats/sex were maintained on untreated drinking water for 4 weeks after initially receiving the control or high dose level for 13 weeks.
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked were included.

DETAILED OBSERVATIONS/EXAMINATIONS: Yes
- Time schedule: weekly, detailed (handheld) clinical examinations, body weight, water and feed consumption

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified
- conducted prestudy and during the last week of treatment:

HAEMATOLOGY & CLINICAL CHEMISTRY: Yes
- on blood samples collected at necropsy

URINALYSIS: Yes
on samples collected near the end of each study

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

OTHER:
- electrolyte parameters on blood samples collected at necropsy
Sacrifice and pathology:
Histopathologic examination was conducted on an extensive list of organs from all control and high dose level rats along with selected organs from the low- and middle-dose animals
Other examinations:
- selected organ weights
Statistics:
Weekly body weights, feed and water consumption, clinical pathology parameters, terminal body weight, organ weights: Parametric or non-parametric ANOVA, followed by Dunnett’s or Wilcoxon’s test for comparison to controls
Detailed clinical observations: Z-test of proportions according to Bruning and Kintz

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Not significant, only minor effects from treatment.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
High dose males and females gained 4–5% less body weight than controls after 13 weeks of dosing.
Food efficiency:
no effects observed
Description (incidence and severity):
Rats given 1000 mg/kg/day also consumed slightly less feed than controls (2–3%) and consistently weighed slightly less than controls.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption by high dose males and females decreased 7.5% and 18% relative to controls
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
There were minimal, but statistically identified, differences noted for cholesterol (increased), albumin (decreased) and phosphorus (decreased) for males given 1000 mg/kg/day
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Consistent with decreased water consumption, rats given 1000 mg/kg/day had increased urine specific gravity and the females had decreased urine volume, which were considered secondary adaptive effects.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative kidney weights were increased for males and females receiving 500 or 1000 mg/kg/day and the absolute kidney weight also was increased for males given 100 mg/kg/day. Male kidney weights were increased to a greater extent than the females with the mean relative kidney weight of males receiving 1000 mg/kg/day 21% greater than controls, while the females from this dose level were 14% greater than controls. Despite the kidney weight increase, there were no gross or histopathologic findings in kidney tissue related to treatment.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Details on results:
The endpoints affected by DIPA ingestion were examined in additional groups of control and high dose group rats following the 4-week recovery period. Water consumption of the treated rats remained below controls by approximately the same degree as at the end of the dosing period, but all other affected endpoints demonstrated reversibility. Absolute and relative kidney weights of rats previously given DIPA were still above controls, but the differences were about one-half of those immediately following 13 weeks dosing; mean relative kidney weights were increased 11% and 6.6% relative to controls for males and females, respectively. No treatment-related renal histopathological changes were observed.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
500 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect levels (NOAEL) in the DIPA toxicity studies for systemic toxicity were 100 mg/kg/day for males and 500 mg/kg/day for females in the 13-week drinking water study based upon the increased mean kidney weights.