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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:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well reported study. not to GLP. Some deviations from a normal protocol but none that would make results unreliable.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report date:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
: 6 week test period. Not all end points examined. Males only
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2-methoxyethoxy)ethanol
EC Number:
203-906-6
EC Name:
2-(2-methoxyethoxy)ethanol
Cas Number:
111-77-3
Molecular formula:
C5H12O3
IUPAC Name:
2-(2-methoxyethoxy)ethanol
Details on test material:
- Name of test material (as cited in study report): Diethylene glycol mono methyl ether
- Physical state: liquid
- Analytical purity: >99.5%. Structure confirmed by IR spectroscopy.
- Other: EK Acc #:907299. TEX#:79-1. PM#:1798. HS&HFL La#:79-431

Test animals

Species:
rat
Strain:
other: CR, COBS, CD, BR albino
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Weight at study initiation: 235.7+/-15.1g
- Housing: individual in suspended wire bottomed cages.
- Diet (e.g. ad libitum): ad libitum, Purina rodent chow 5001
- Water (e.g. ad libitum): ad libitum via automatic watering system
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Doses recalculated weekly to allow for animal growth.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 weeks
Frequency of treatment:
daily, 5 days per week
Doses / concentrationsopen allclose all
Dose / conc.:
900 mg/kg bw/day (nominal)
Dose / conc.:
1 800 mg/kg bw/day (nominal)
Dose / conc.:
3 600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
- Dose selection rationale: based on 50%, 25% and 12.5% of the fasted LD50.
Positive control:
A number of other glycol ethers were assessed in the same study effectively acting as reference controls.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily, except weekends.
- Cage side observations: signs of systemic toxicity, appearance and behaviour. Urine and faeces appearance. Mortality.

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 3, 6, 13, 20, 27, 34, 41.

FOOD CONSUMPTION AND COMPOUND INTAKE - measured at same times as body weight.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: from vena cava immediately prior to autopsy.
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: No data
- Parameters checked : Hgb, Hct, RBC count and indices, total and relative WBC count,

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: from vena cava immediately prior to autopsy.
- Animals fasted: No data
- Parameters checked: glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, ALP, LDH, BUN, creatinine and glucose.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Animals that died spontaneously were autopsied as soon as possible. Moribund animals were sacrificed and similarly autopsied.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes.
HISTOPATHOLOGY: Yes .
Survivors killed by CO2 inhalation. Tissues examined: lung, heart, thymus, kidney, liver, spleen, brain, salivary glands, stomach, cecum, colon, duodenum, jejenum , ileum, pancreas, esophagus, adrenals, pituitary, thyroid, parathyroid, trachea, mesenteric lymph nodes, testes, epididymides, prostate, seminal vesicles, coagulating gland, bone marrow, tongue, nasal cavities, eyes.
Statistics:
No information

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One high dose animal had bloody urine, blood around the nares and an unkempt coat. No compound related clinical signs were seen in the other two dose groups.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant reduction seen in top dose from day 3 onwards (~12%). Slight but not statistically significant reductions were seen in the mid dose group (~7%. No changes were observed in the low dose group animals.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Significant reduction in top group only (~13%).
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A slight statistically significant increase in BUN was seen in the high dose group only (~16%). No other effects.
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):
Changes showed no clear pattern. High dose animals showed an increase in kidney and heart relative weight and spleen absolute weght, a reduction in testes relative weight and a reduction in liver and brain absolute weight. Mid dose animals showed an increase in heart and testes relative weight and a reduction in liver absolute weight. No changes were seen in the low dose animals.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Testicular atrophy was seen in 6/10 high dose animals and of these approximately half also had accompanying degenerated spermatozoa in the epididymides and hypospermia. Stomach hyperkeratosis in a single high dose animal. Renal effects, included hyaline droplet degeneration and proteinaceous in the proximal convoluted tubules. The former were seen in virtually all animals in all dose groups, but these were also seen in all ten control animals so are not regarded as compound related. The proteinaceous were seen in the top dose group only. Other than the aforementioned renal changes, no other effects were observed in the mid and high dose group animals
Histopathological findings: neoplastic:
not examined

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
900 mg/kg bw/day (nominal)
Sex:
male
Remarks on result:
other: no effects seen at this dose
Dose descriptor:
LOAEL
Effect level:
1 800 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
The most significant toxic effect is the adverse histopathological changes to the testes in the high dose animals, although it should be borne in mind tat these were at a dose of 3600mg/kg. The changes seen in the mid dose group were inconsistent increases and decrease in either relative or absolute organ weights. No treatment related changes were seen in the low dose group.
Executive summary:

In a 6 week sub-acute gavage study that broadly followed the standards for the guideline pertaining at the time, standard toxicological end points were studied for rats in doses up to 3600mg/kg of 2 -(2 -methoxyethoxy)ethanol. A number of adverse effects were seen in the high dose group, the most notable being adverse testicular changes. The only effects seen in the mid dose group were inconsistent increases and decreases in either relative or absolute organ weights. No treatment related changes were seen in the low dose group.

Synopsis

NOAEL (rat, oral, 28 days) = 900mg/kg/day