Oleic acid, monoester with oxybis(propanediol)

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

21 March - 4 April 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented study report which meets basic scientific principles (14 day study for dose selection for 3 month and 2 year studies).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Principles of method if other than guideline:

Rats are exposed to the test substance for 14 days by a relevant route to identify potential toxicities and target organs and to assisst in setting doses for 90 day studies. 5 treatment groups with 5 animals per sex (male and female) and a control group recieving the vehicle are treated, observed, weighed and necropsied at the end of treatment.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Oxydipropanol

EC Number:

246-770-3

EC Name:

Oxydipropanol

Cas Number:

25265-71-8

IUPAC Name:

1,1'-oxydipropan-1-ol

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): dipropylene glycol
- Physical state: clear colorless liquid
- Analytical purity: 99 %
- Impurities (identity and concentrations): 0.08 % ± 0.01 % water
- Isomers composition: diastomer ratios - 35:52:13 (1,1'-oxybis(2-propanol):2-(2-hydroxypropoxy)-1-propanol:2,2'-oxybis(1-propanol))
- Lot/batch No.: 0365
- Stability under test conditions: stable up to 96 hours as dose formulations stored exposed to light in drinking water bottles fitted with Teflon-lined septa and sipper tubes at room temperature
- Storage condition of test material: at room temperature protected from light in amber glass containers

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Germantown, NY
- Age at study initiation: 7 weeks
- Weight at study initiation: mean - 130.5 g (male), 107.2 g (female)
- Housing: 5 animals per cage in solid-bottom polycarbonate cages (Lab products Inc., Maywood), changed twice weekly containing hardwood chips
- Diet: NIH-07 open formula pelleted diet (Zeigler brothers Inc. Gardeners, PA), ad libitum
- Water: Charcoal-filtered deionized water via amber glass bottles with plastic Teflon-lined caps and stainless steel sipper tubes, ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 50 % ± 15 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: mixing dipropylene glycol with deionized water

DIET PREPARATION
- Rate of preparation of diet (frequency): at least every 2 weeks
- Mixing appropriate amounts with: deionized water
- Storage temperature of formulations: stored in carboys, protected from light, at room temperature for up to two weeks

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Periodic analyses of the dose formulations were conducted using GC. During the 2 week study the dose formulations were analyzed twice (prepared formulations and samples taken from animal rooms).

Duration of treatment / exposure:

14 days

Frequency of treatment:

once daily, 7 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
5000, 10000, 20000, 40000, 80000 ppm
Basis:
nominal in water

Doses / concentrations 2

Remarks:

Doses / Concentrations:
635, 1450, 2650, 5850, 13000 mg/kg bw (male)
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
850, 1670, 2860, 5420, 11100 mg/kg bw (female)
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: recorded daily

BODY WEIGHT: Yes
- Time schedule for examinations: initially, on day 8 and at the end of the study

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: measured over a 24 hour period on days 5, 7 and 10

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; on all animals, organs weighed were the right kidney and liver
HISTOPATHOLOGY: Yes; performed on the brain, kidney, liver and testes and from all organs that showed evidence of gross lesions

Statistics:

Organ and body weights were analyzed using the parametric multiple comparison procedures of Dunnett (Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Am. Stat. Assoc. 50, 1096-1121) and Williams (Williams, D.A. (1971). A test for differences between treatment means when several dose levels are compared with a zero dose control. Biometrics 27, 103-117; (1972). The comparison of several dose levels with a zero dose control. Biometrics 28, 519-531).

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

in some male rats at highest dose

Mortality:

mortality observed, treatment-related

Description (incidence):

in some male rats at highest dose

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

less compared to control in highest dose group in males and females

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

increased liver and kidney weights

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

minimal focal fatty change in livers of males

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
no animal died during the study, hypoactivity, piloerection and perinasal staining (males only) were observed at 13000 mg/kg bw

BODY WEIGHT AND WEIGHT GAIN
the final mean body weights and body weight ganins of males and females exposed to 13000 and 11100 mg/kg bw, respectively were significantly less than control (see table1)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
water consumption was similar between all groups, some measurements were inaccurate due to leaking water bottles

ORGAN WEIGHTS
liver and kidney weights of males and females generally increased with increasing exposure concentrations (liver weights (absolute and relative) - male: 2650 mg/kg bw and greater; female: 5420 mg/kg bw and greater; kidney weights - male: 5850 mg/kg bw (absolute and relative); female: 5420 mg/kg bw (absolute)) (see table2)

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopically minimal focal fatty change was observed in livers of some males exposed to 2650 mg/kg bw or greater. It consisted of multiple small round clear spaces within the cytoplasm od midzonal hepatocytes (2650 mg/kg bw: 1/5; 5850 mg/kg bw: 2/5; 13000 mg/kg bw: 5/5)

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 450 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: liver and kidney weights, histopathology

2

Dose descriptor:

NOAEL

Effect level:

2 860 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: liver and kidney weights

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table1: Survival and body weights

Concentration		Mean body weight in (g)			Final weight relative to controls
(mg/kg bw)	Survival	Initial	Final	Change	(%)
Male
0	5/5	133 ± 3	198 ± 5	66 ± 2
635	5/5	130 ± 2	196 ± 3	66 ± 2	99
1450	5/5	128 ± 3	197 ± 4	69 ± 1	99
2650	5/5	131 ± 4	199 ± 5	69 ± 1	99
5850	5/5	128 ± 4	192 ± 4	64 ± 2	97
13000	5/5	133 ± 3	158 ± 2**	24 ± 2**	79
Female
0	5/5	107 ± 2	140 ± 2	33 ± 1
850	5/5	109 ± 3	142 ± 2	33 ± 1	102
1670	5/5	108 ± 2	142 ± 2	34 ± 2	102
2860	5/5	107 ± 2	142 ± 2	35 ± 4	102
5420	5/5	106 ± 3	136 ± 3	30 ± 1	97
11100	5/5	106 ± 2	120 ± 3**	13 ± 1**	86

**Significant different (P<0.01) from the control group by Williams' or Dunnett's test

Table2: Organ weights and Organ-weight-to-body-weight Ratios

mg/kg bw (male)	0	635	1450	2650	5850	13000
n	5	5	5	5	5	5
necropsy body weigth	194 ± 5	192 ± 3	194 ± 5	195 ± 4	190 ± 4	157 ± 2**
Kidney
absolute	0.902 ± 0.019	0.912 ± 0.024	0.926 ± 0.037	0.990 ± 0.040	1.054 ± 0.021**	1.206 ± 0.034**
relative	4.644 ± 0.091	4.756 ± 0.173	4.773 ± 0.100	5.069 ± 0.158	5.567 ± 0.151**	7.680 ± 0.194**
Liver
absolute	10.066 ± 0.475	10.580 ± 0.490	11.062 ± 0.457	12.290 ± 0.494**	14.788 ± 0.610**	15.692 ± 0.338**
relative	51.668 ± 1.384	55.011 ± 1.940	57.011 ± 1.294	62.868 ± 1.284**	77.957 ± 2.559**	99.933 ± 1.961**
mg/kg bw (female)	0	850	1670	2860	5420	11100
necropsy body weight	138 ± 2	141 ± 2	141 ± 2	139 ± 2	134 ± 3	121 ± 3**
Kidney
absolute	0.678 ± 0.027	0.692 ± 0.018	0.696 ± 0.022	0.706 ± 0.007	0.716 ± 0.020	0.766 ± 0.010
relative	4.900 ± 0.143	4.903 ± 0.080	4.949 ± 0.117	5.101 ± 0.118	5.328 ± 0.103*	6.351 ± 0.165**
Liver
absolute	6.716 ± 0.259	7.034 ± 0.163	6.976 ± 0.159	6.948 ± 0.240	7.378 ± 0.118*	9.244 ± 0.134**
relative	48.519 ± 1.178	49.865 ± 0.936	49.601 ± 0.426	50.136 ± 1.542	54.937 ± 0.481**	76.545 ± 0.700**

*Significant different (p<0.05) from the control group by Williams' test

**Significant different (p<0.01) from the control group by Willams' test

Applicant's summary and conclusion

Conclusions:

In the present study the test substance did not induce any treatment related deaths. However, effects on kidneys and liver were visible by increased organ weights observed at the end of the 14 day treatment period. The NOAEL for males anf females were determined to be 1450 and 2860 mg/kg bw, respectively.