Hexanedioic acid, polymer with 2,2'-oxybis[ethanol]

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: basic information given.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1976

Report date:

1976

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

1976

Report date:

1976

Materials and methods

Principles of method if other than guideline:

The present experiments were initiated to provide adequate short-term investigations, with particular reference to effects on urinary oxalate excretion, using a DEG sample with a low (less than 0-01%) MEG content.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-oxydiethanol

EC Number:

203-872-2

EC Name:

2,2'-oxydiethanol

Cas Number:

111-46-6

Molecular formula:

C4H10O3

IUPAC Name:

2,2'-oxydiethanol

Details on test material:

The sample of DEG sed was supplied by Imperial Chemical Industrial Ltd. (Petrochemical Divisions) and gave the following analysis:
Colour (Hazen units), less than 5; specific gravity (15.5/15.5°C), 1 .120; initial boiling point, 244.4 °C; dry point, 250.3 °C; ash (w/w), less than 0.002%; acidity (as acetic), 0.0015; water (w/w), 0.035%; iron, less than 0.1 ppm; monoethylene glycol (w/w), less than 0.01%; triethylene glycol (w/w), 0.03%.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: obtained from a specified-pathogen-free colony
- Housing: five per cage
- Diet: Spillers' Laboratory Small Animal Diet, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1°C
- Humidity (%): 40 - 50%

Administration / exposure

Route of administration:

oral: feed

Duration of treatment / exposure:

225 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 64, 128, 300, 1500 mg/kg bw (= 0.085%, 0.17%, 0.4%, 2.0%)
Basis:
nominal in diet

No. of animals per sex per dose:

10

Control animals:

yes, plain diet

Examinations

Observations and examinations performed and frequency:

The animals were weighed initially, on days 1, 4 and 8 and then at approximately weekly intervals throughout the study.
Food and water intake over a 24-hr period were measured at the same intervals.
Urine samples were collected in week 8, 13 and 19 from the males and in week 9, 14 and 19 from the females over 24-hr periods, during which the rats were denied access to food and water. These samples were rendered strongly acid with hydrochloric acid and analysed for oxalic acid by the method of Hodgkinson & Williams (1972). Urine analyses, renal concentration and dilution tests and urinary cell counts on samples collected during the last week of the study, post mortem examinations, organ-weight analyses and collection of blood for haematological examination were carried out.

Sacrifice and pathology:

In the haematological examination the reticulocyte and differential leucocyte preparations were not examined. Histological examination was confined to the kidneys.

Results and discussion

Results of examinations

Details on results:

Dietary concentrations of 0.4 and 2.0 % resulted in oxalate crystalluria and mild defects in renal function as measured by concentration tests. The only finding at a dietary level of 0.176 was a 13.2 % increase in urinary oxalate excretion in male, while with the lowest level (0.085%) no effects were observed.
Extrapolation: Since no effects were observed at the dietary level of 0.085 %, application of a safety factor of 100 in the extrapolation to man indicates an acceptable daily intake for a 70 kg man of 38 mg, and on a pro rata basis a lesser or greater value for individuals of different body weight. The significance of the 13.2 % increase in oxalate excretion found in rate on the 0.17% dietary level is debatable. If this level is considered to have no significant effect on the oxalate concentration of kidney and bladder urine, the acceptable daily intake (calculated as above) would be 76 mg/day for a 70 kg individual.

Effect levels

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: overall effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Since no effects were observed at the dietary level of 0.085%, application of a safety factor of 100 in the extrapolation to man indicates an acceptable daily intake for a 70-kg man of 38 mg, and on a pro rata basis a lesser or greater value for individuals of different body weight. The significance of the 13.2% increase in oxalate excretion found in rate on the 0.17% dietary level is debatable. If this level is considered to have no significant effect on the oxalate concentration of kidney and bladder urine, the acceptable daily intake (calculated as above would be 76 mg/day for a 70-kg individual.
Elevated levels of oxalic acid in urine in this study were considered to be a biomarker and do not indicate toxicity. Mild defects of renal function at 0.4% DEG (increased urine volume) were therefore considered to define the LOAEL as 230 mg/kg bw/d, and the NOAEL as 100 mg/kg bw/d.