2-isopropoxyethanol

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:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well reported study. not to GLP. Rationale for using a read across substance is included in overall remarks section.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Reference 2

Reference Type:

publication

Title:

Comparative acute and subchronic toxicity of ethylene glycol propyl ether and ethylene glycol monopropyl ether acetate

Author:

Katz GV, Krasavage WJ, Terhaar CJ

Year:

1984

Bibliographic source:

Env Hlth Persp, 57, 165-75

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.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-(propyloxy)ethanol

EC Number:

220-548-6

EC Name:

2-(propyloxy)ethanol

Cas Number:

2807-30-9

Molecular formula:

C5H12O2

IUPAC Name:

2-propoxy-1-ethanol

Details on test material:

- Name of test material (as cited in study report): Ethylene glycol mono propyl ether
- Physical state: liquid
- Analytical purity: >99.1%
- Other: EK Acc #:907124. TEX#:1115-2. PM#:9328. HS&HFL Lab#:79-419

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:

not specified

Duration of treatment / exposure:

6 weeks

Frequency of treatment:

daily, 5 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
195, 390, 780, 1560 mg/kg bw/day
Basis:
nominal in water

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% , 12.5%, 6.25% 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 (GPT), 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, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: No significant mortality seen that could be attributed to the substance. All animals showed bloody urine after first dose. This resolved for the low dose groups but persisted for the mid and high dose animals. Clinical signs (third and high dose groups only) were weakness, prostration, laboured breath and rales.

BODY WEIGHT AND WEIGHT GAIN: Slight but statistically non-significant body weight gain reductions seen in all dose groups. A slight reduction in terminal body weight was seen in the top dose group only.

FOOD CONSUMPTION:The high dose group showed a statistically significant reduction in food consumption during the first 2 weeks.

HAEMATOLOGY: Decreased Hgb, total RBC and in all dose with a clear dose response relationship. No effect on packed cell volume or WBC count. The mid and high dose groups produced increased MCV and MCH and decreased MCHC. The two lower dose groups had no impact on the red cell indices.

ORGAN WEIGHTS: All dose groups showed increased spleen weights. The absolute and relative values were statistically significant in the top two dose groups. Slight but statistically significant increases in liver weight (both relative and absolute) were seen but not regarded as toxicologically significant. All other organ weights, including testes, were normal.

GROSS PATHOLOGY: Enlarged dark spleens at the two higher dose in around half the animals. A single animal showed this in the second dose group but none were seen in the lowest dose goup.

HISTOPATHOLOGY: NON-NEOPLASTIC: Splenic congestion and extramedullary hematopoesis were seen in all but the lowest dose group. Renal proteinaceous casts were seen along with haemosiderin in the proximal convoluted tubules. Liver effects were focal haemosiderin in the high dose group only.

Effect levels

Dose descriptor:

NOAEL

Effect level:

< 195 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: Clinical signs (discoloured urine), Haematology (RBC effects), Gross and histological effects on spleen.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The most significant toxic effects seen were adverse changes to the red blood cells followed by splenic congestion, enlargement and extramedullary haematopoesis. A true no effect level was not observed.

Executive summary:

In a 6 week sub-acute gavage study using 2 -n-propoxyethanol that broadly followed the standards for such tests pertaining at the time, standard toxicological end points were studied for rats in doses up to 1560mg/kg. . The most significant adverse effects were changes to the red blood cells, manifest as reduced RBC count, decreased haemoglobin and increased MCH and MCV from the low dose group upwards. . Splenic congestion and enlargement along with extramedullary hematopoesis were also seen, possible as a secondary consequence of the apparent haemolytic effects. No no effect level was observed because of the haemolytic effects. Because of the structural similarities, 2 -isopropoxyethanol is likely to show similar toxicity.

Synopsis:

NOAEL(6 week, rat, oral gavage) = 195mg/kg/day