Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., compds. with isopropanolamine

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented publication which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2007

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 10 Fischer 344 rats/sex were given drinking water formulated to supply 0, 100, 500, or 1000 mg DIPA/kg/day for 13 weeks. 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 to assess recovery from any treatment-related effects.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

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

IUPAC Name:

1,1'-iminodipropan-2-ol

Details on test material:

- Name of test material (as cited in study report): Diisopropanolamine
- Analytical purity: ranged from 98.8 % - 99.6 % (GC/FID)

Test animals

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male/female

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

continuously in drinking water

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, 500 or 1000 mg/kg bw/day
Basis:
nominal in water

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prestudy and during the last week of the study
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Anaesthetic used for blood collection: Yes with methoxyflurane or CO2
- Animals fasted: No data
- How many animals: no data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: No data
- How many animals: no data

Standard hematologic and clinical chemistry parameters were evaluated consistent with globally accepted regulatory guidelines (EEC, 1992; EPA, 1998; OECD, 1998; MITI, 1988).

URINALYSIS: Yes
- Time schedule for collection of urine: near end of study
- Metabolism cages used for collection of urine: No data
- Animals fasted: No
Standard urinalysis parameters were evaluated (EEC, 1992; EPA, 1998; OECD, 1998; MITI, 1988).

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
An extensive set of organs consistent with regulatory guidelines (EPA, 1998) including all organ systems and gonads and secondary sex organs of both sexes were examined histopathologically from the control and high dose animals with the kidneys, liver, lungs, urinary bladder and all gross lesions examined from the remaining rats.

Statistics:

Consistent with the variety of data collected, a large number of statistical methods were employed. Means and standard deviations were calculated for all continuous data. These parameters were first examined for equality of variance using Bartlett’s test (a = 0.01; Winer, 1971). If the results of the Bartlett’s test were significant, the data were transformed in an attempt to obtain equality of variances. The order of transformations used was the common log, the inverse and the square root with the best fit used for subsequent statistical testing. Weekly body weights, feed and water consumption, clinical pathology parameters, terminal body weight, and organ weights were analyzed using parametric or non-parametric ANOVA, followed by Dunnett’s or Wilcoxon’s test for comparison to controls. Detailed clinical observations were analyzed by a Z-test of proportions. As statistical interactions (i.e., time by dose or sex by dose) were identified in several of the tests, the alpha levels for interaction terms were set a priori at 0.01–0.10, with Bonferroni’s correction. The alpha level for comparison of individual dose groups to controls was set a priori at 0.05.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
All rats given up to 1000 mg DIPA/kg/day via the drinking water survived the study period and only minor effects from treatment were found.

BODY WEIGHT AND WEIGHT GAIN
High dose males and females gained 4–5% less body weight than controls after 13 weeks of dosing.

FOOD CONSUMPTION
Rats given 1000 mg/kg/day consumed slightly less feed than controls (2–3%).

WATER CONSUMPTION
Total water consumption by high dose males and females decreased 7.5% and 18% relative to controls, respectively.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related changes in ophthalmic parameters were noted.

HAEMATOLOGY
Hematologic parameters and prothrombin times were unaffected by DIPA ingestion.

CLINICAL CHEMISTRY
There were minimal, but statistically identified, differences noted for cholesterol (increased), albumin (decreased) and phosphorus (decreased) for males given 1000 mg/kg/day.

URINALYSIS
Rats given 1000 mg/kg/day had increased urine specific gravity and the females had decreased urine volume.

ORGAN WEIGHTS
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.

GROSS PATHOLOGY and HISTOPATHOLOGY:
Despite the kidney weight increase, there were no gross or histopathologic effects related to treatment.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: increased mean kidney weights.

2

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: increased mean kidney weights.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Effects of DIPA given in drinking water to F344 rats for 13 weeks.

	Dose level (mg/kg/day
	Males				Females
	0	100	500	1000	0	100	500	1000
Body weight - day 90 (g)	348.5	354.2	357.6	340.9	196.7	194.6	195.1	192.1
Body weight gain (g)	176.5	182.1	185.8	169.3	85.4	83.3	83.2	80.8
Water consumption (g)	2048.8	2061.2	2119.0	1985.1	1890.6	1999.3	2045.8	1549.9
Feed consumption (g)	1554.1	1598.8	1593.6	1508.3	1127.0	1138.3	1138.1	1107.9
Cholesterol (mg/dL)	60	60	64	70*	19	18	18	21
Albumin (g/dL)	3.5	3.5	3.5	3.4*	95	98	97	93
Phosphorus (mg/dL)	10.5	10.6	10.4	9.7*	3.4	3.5	3.4	3.3
Serum urea nitrogen (mg/dL)	17	17	17	17	10.2	9.5	9.5	9.6
Urine volume (mL)	4.5	4.4	4.9	4.6	2.9	3.7	3.0	1.4
Urine specific gravity	1.067	1.068	1.072	1.079*	1.070	1.065	1.070	1.114*
Terminal body weight (g)	319.7	329.7	332.9	319.5	179.9	179.4	181.2	181.1
Kidney body weight (g)	2.146	2.357*	2.494*	2.594*	1.276	1.301	1.374*	1.466*
Relative kidney weight (g/100g)	0.671	0.716	0.749*	0.813*	0.709	0.726	0.759*	0.810*

Statisticially different from control mean by Dunnett´s test: α =0.05.

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.

Applicant's summary and conclusion

Conclusions:

Oral administration of DIPA to rats for 90 days resulted in increased kidney weights both in male and female animales. The lowest NOAEL recorded was for males, at 100 mg/kg bw.