Reaction mass of 2,2'-(ethylenedioxy)diethanol and 2,2'-oxydiethanol and ethane-1,2-diol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

yes (incl. QA statement)

Remarks:

testing lab.

Test material

Reference

Name:

Unnamed

Type:

Constituent

Type:

Constituent

Details on test material:

1.2-ethane diole (ethylene glycol) with inhibitors > 92.5% ethylene glycol, < 1.42% na-p-tert-butyl-benzoate

Test animals

Species:

dog

Strain:

other: Beagle

Sex:

male

Details on test animals or test system and environmental conditions:

Age of the dogs: 2 - 2.5 years
Identification: using four-digit numbers, tattooed in the right ear
The animals used were free of any illness signs.
The mean body weight was 16.4 kg at the beginning of the study.
The animals were housed singly in kennels.
The illumination period was the same as the natural day/night rhythm.
Weekly body weight determinations was done and the daily food intake of each animals was determined.
Each dog was offered a pelleted diet (daily 500 g).
Drinking water was available ad libitum during the study period.
Before blood and urine collection as well as before necropsy, a fasting period of 16 hours was warranted.

Administration / exposure

Type of coverage:

other: clipped skin

Vehicle:

unchanged (no vehicle)

Details on exposure:

Before application period, the dogs were shaved on the back, flanks, front and waist. The test substance was given daily (undiluted) to the clipped skin. The application area was about 60% of the total body surface. The test substance was not washed off.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0.5, 2.0, 8.0 ml/kg bw
Basis:
analytical per unit area

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Details on study design:

In range-finding studies over a study period of 14 days (dermal application), no symptoms were seen given the test substance in concentrations of 1.5 ml for 14 days or 3.0 ml for 21 days. 12 ml of the test substance showed lethality after 6 and 14 days of exposure.
For the 4-week dermal study, 8.0 ml were used as highest concentration, 2.0 and 0.5 ml were used as lower concentrations.

Examinations

Observations and examinations performed and frequency:

Daily food consumption and body weight determination.
Clinical symptoms twice a day.

Sacrifice and pathology:

Check of dead animals twice a day.
All animals were assessed by gross pathology and then a histopathological examination was carried out.

Statistics:

yes

Results and discussion

Results of examinations

Details on results:

8.0 ml Glysantin G 105/kg body weight
Clinical findings: The applied test substance led to the premature death of 4 of the 5 male dogs used (3 of them sacrificed in a moribund state; one animal died) and caused apathy and/or somnolence in all male dogs. Individual animals showed further signs of toxicity, such as staggering gait, weakness of the extremities, vomiting, lateral position, diarrhea, etc.; moreover, reduced feed consumption and loss of body weight were observed.
Clinicochemical findings: All male dogs showed signs of renal insufficiency to a varying degree. Increased creatinine and urea levels in the plasma and changes in the urinalyses, such as an increased incidence of calcium oxalate crystals and renal and round epithelial cells, were the main findings. Polyuria and therefore reduced urine specific gravity were also observed. There were numerous other clinicochemical and hematological findings apart from these major changes.
Gross-pathological and histopathological findings: All male dogs had signs of oxalate nephrosis (intratubular oxalate crystals and liquefaction foci) and diffuse impairment of spermatogenesis; testicular atrophy was found in some cases. Uremic gastroenteritis was diagnosed in the dogs that died or were sacrificed prematurely.
2.0 ml Glysantin G 105/kg body weight
Urinalysis findings: There were sporadically calcium oxalate crystals, initial signs of polyuria and an increased incidence of round and squamous epithelial cells in one male dog in each case.
Gross-pathological and histopathological findings: Testicular atrophy with moderate diffuse impairment of spermatogenesis was observed in one animal.
0.5 ml Glysantin G 105/kg body weight
After dermal application of 0.5 ml test substance/kg body weight, there were no definite changes that might be causally related to the test substance applied in any of the examinations carried out.

Effect levels

Dose descriptor:

NOEL

Effect level:

2 other: ml/kg bw

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The oxalate nephrosis observed in the male dogs of the 8.0 ml/kg body weight group with specific clinical, clinicochemical, hematological, urinalysis and gross-pathological and histopathological changes definitely corresponds to the signs that are known from intoxication with pure monoethylene glycol. Further studies are required to establish whether the severe testicular damage that was found in all dogs at 8.0 ml/kg and in one dog at 2.0 ml/kg was caused by Na p-tert.-butyl benzoic acid (PTBBA), a typical testicular toxicant and a minor constituent of Glysantin G 105.
LD50 dermal (dog): > 2000 mg/kg

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