Registration Dossier

Administrative data

Description of key information

Surrogate substance (ethoxypropoxypropanol) Oral: NOAEL (90 day) >1000mg/kg
Inhalation: NOAEC (9 day) >1.4mg/L. NOAEC (90 day)=1.266mg/L
Surrogate substance (methoxypropanol) Dermal: NOAEL(21 day)~2080mg/kg

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to a guideline study.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Animals were uniquely identified by numbers tattooed into the ears. In addition, ear punching identified animals with numbers in excess of 99.

TEST ANIMALS
- Source: Charles River UK Ltd.
- Age at study initiation: Approximately 6-7 weeks old when received on 27 March. The first exposures occurred on 8 April.
Group mean body weight at initiation of exposures:
Males – 243 to 248 g
Females – 180 to 186 g
- Housing: Except during exposures, the rats were kept, 5 of the same sex per cage, in suspended polypropylene holding cages with stainless steel mesh tops and floors. Plastic trays, lined with absorbent paper were placed below the cages. The paper was changed daily. Clean cages were introduced at intervals throughout the study.
The rats were kept in a single room and once exposures began, the cages for rats in each group were positioned on individual cage batteries. These were kept in isolated ventilated areas within the same room to avoid the possibility of inhalation of the test material from the fur of rats in other groups.
- Diet: While in their cages, rats had access to a weighed quantity of a standard quality controlled laboratory rat food (Labsure LAD 1).
- Water: Tap water was available from polypropylene bottles at all times when the rats were in the cages. Water bottles were rinsed and refilled daily, and thoroughly cleaned at intervals during the study.
- Acclimation period: 11 days.

ENVIRONMENTAL CONDITIONS
- Temperature: Holding room: 18 – 26 degrees C
- Humidity: Holding room: 36 – 64 % relative humidity
- Photoperiod: Lighting was controlled to give 12 hours light (0800 – 2000) and 12 hours dark during each 24 hours.

IN-LIFE DATES: From: To:
Fist exposure – 8 April 1985
Final necropsy – 5 August 1985
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Weekly counts of the number of particles in a 1 minute sample of chamber atmospheres were estimated using an optical particle monitor. Particles found were all less than 5 um in diameter. As the chamber concentrations were well below the saturated vapour concentrations it was considered unlikely that these particles were droplets of test material.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The vapour was produced by metering the liquid to a stainless steel concentric jet atomizer and passing the aerosol into a glass column in which it evaporated. To facilitate vaporisation, at the high dose air to the atomizer was passed through a water bath maintained at 75 degrees C. The vapour passed through the vertical glass column into the chamber inlet duct.The exposure chambers were constructed from stainless steel and glass and were approximately 500 liters internal volume. The chambers were of square cross section and fitted with a squat pyramidal base and top. An H-shaped extraction plenum was fitted in the base of the chambers.
- Method of holding animals in test chamber: During exposures the rats were housed in stainless steel wire mesh cages, which were supported on two mesh shelves. The position of male and female animals were alternated on these shelves each day
- Source and rate of air: Dry, oil-free, compressed air was passed to the annulus of the atomizer tip at a pressure of 40-50 psi. This produced a flow to the atomizer tip of approximately 10 liters per minute.
- Temperature, humidity, pressure in air chamber: Air temperature, relative humidity and air pressure in each exposure chamber were monitored continuously and recorded at approximately 30 minute (pressure) or hourly intervals (temp, humidity) throughout each exposure.
Chamber temperatures during exposure were similar for all groups.
Relative humidity tended to be higher in the high dose chamber.
- Air flow rate: Total volume flow to the exposure chambers was 90 litres per minute. The airflow into each chamber was monitored continuously using tapered-tube flowmeters and was recorded at approximately hourly intervals throughout each exposure.
-Treatment of air: The chamber atmosphere was extracted by means of individual air handling units fitted with filters. The extract flow was adjusted by means of a gate valve so as to maintain the chamber pressure approximately 3 mm of water below that of the surrounding room.

TEST ATMOSPHERE
- Brief description of analytical method used: After 6 hours exposure, the syringe pumps were switched off. The volume of test material remaining in each syringe and any ‘run-off’ from the glass column was recorded and the volume used during the exposure calculated.
In addition, the concentration of ethoxypropanol present in the exposure chambers was determined at hourly intervals during each exposure. Samples of the test atmosphere were withdrawn through a gas absorption tube and the amount of ethoxypropanol in these samples determined by thermal desorption methods.
- Samples taken from breathing zone: yes
Sampling was performed to determine the spatial distribution of ethoxypropanol within the chambers. Results indicated that distribution of the test substance in the exposure chamber was adequately uniform.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See details of inhalation exposure above.
Duration of treatment / exposure:
6 hours per day for 13 weeks. Exposures were shortened on days during which urine and blood samples were taken (Week 1 and Week 12).

Ten male and ten female rats from the control and high dose groups were maintained for 4 weeks, without exposure, following termination of exposures.
Frequency of treatment:
5 days each week
Remarks:
Doses / Concentrations:
0, 0.425, 1.275, 8.5 mg/L
Basis:
other: target concentrations
Remarks:
Doses / Concentrations:
0, 0.614, 1.658, 11.19 mg/L
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 0.426, 1.266, 8.36 mg/L
Basis:
analytical conc.
No. of animals per sex per dose:
Controls and high dose groups: 25 males and 25 females Low and mid dose groups: 15 males and 15 females. 10 of each in a recovery group of high dose and control animals.
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Approximately equal group mean body weights at study initiation.
- Post-exposure recovery period in satellite groups: 4 weeks
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily and during exposure.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Initially for allocation to exposure groups, 1 week prior to start of exposures, on the first day of exposure, at weekly intervals thereafter, and at study termination.

FOOD CONSUMPTION:
- Other: The quantity of food consumed by each cage of 5 rats was recorded commencing 1 week before the start of exposures and weekly thereafter.

WATER CONSUMPTION: Yes
- Other: The quantity of water consumed by each cage of rats was recorded daily commencing one week before the start of exposures and weekly thereafter.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Once pre-exposure and during Week 12.
- Dose groups that were examined: All animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to exposure and during Weeks 1 and 12
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals: 5 males and 5 females per group: pre-exposure and Week 1
10 males and 10 females per group: Week 12
- Parameters checked in table [No.?] were examined: Packed cell volume (PCV), haemoglobin (Hb), red cell count (RBC), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV), total white cell count (WBC total) and differential count (Diff), platelet count (Plts), thrombotest (TT), reticulocyte count (Retic).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to exposure and during Weeks 1 and 12
- Animals fasted: Yes
- How many animals:
5 males and 5 females per group: pre-exposure and Week 1
10 males and 10 females per group: Week 12
- Parameters checked in table [No.?] were examined: Glucose, total protein, albumin, globulin, albumin/globulin ration (A/G), urea nitrogen, creatinine, alkaline phosphatase (AP), glutamic-pyruvic transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), gamma glutamyl transferase (gamma GT), ornithine carbamoyltransferase (OCT), total bilirubin, sodium (Na), potassium (K), calcium (Ca), inorganic phosphorus (P), chloride (Cl), cholesterol (Chol).

URINALYSIS: Yes
- Time schedule for collection of urine: Prior to exposure and during Weeks 1 and 12
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table [No.?] were examined: Volume, colour, pH, osmolality, protein, total reducing substances, glucose, ketones, bile pigments, urobilinogen, haem pigments, microscopy.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
-The macroscopic appearance of all tissues was noted.

HISTOPATHOLOGY: Yes
-H&E sections were examined as follows: All tissues from ten male and ten female rats from the control and high dose groups sacrificed at the end of exposure.

The following tissues were preserved in 10% neutral buffered formalin (except eyes which were preserved in Davidson's fixative) and examined:
-Nasal passage, tongue, pharynx, larynx, trachea, lungs & bronchi, heart, aorta, oesophagus, stomach (glandular and non-glandular), duodenum, jejunum, ileum, caecum, colon, rectum, kidneys, urinary bladder, testes, epididymides, seminal vesicle, prostate, ovaries, uterus, liver, spleen, pancreas, salivary glands, thymus, thyroids, adrenals, lymph nodes(tracheaobronchial, cervical, axillary), brain(sections of medulla/pons, cerebellar cortex and cerebral cortex), pituitary, eyes, sciatic nerve, sternum(for bone marrow), spinal cord, muscle(thigh), skin, mammary gland, femur, remaining head, all gross lesions.

All tissues observed to be macroscopically abnormal.
Lungs of all control and high dose rats in the withdrawal phase.
Lungs of 10 male and 10 female low- and mid-dose rats sacrificed at the end of exposure.
Other examinations:
The following organs were dissected free and weighed from each animal: adrenals, kidneys, liver, brain, spleen, lungs, thymus, testes, heart, pituitary.
Statistics:
The following statistical tests were used to analyze bodyweight, food and water consumption, organ weight and clinical pathology data: Bartlett’s test for heterogeneity of variance between treatments; followed by a one-way analysis of variance (no significant heterogeneity or satisfactory transformation identified) and Student’s ‘t’ test and Williams’ test; or the Kruskel-Wallis analysis of ranks (significant heterogeneity that could not be removed by a transformation) and non-parametric equivalents of the ‘t’ test and Williams’ test.
Food and water consumption was analyzed on a cage basis
Where appropriate, analysis of covariance was used in place of analyses of variance.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs indicative of an irritation and sedation were observed in the high dose animals only during exposure. These signs readily reversed. A reduced ‘startle response’ was also noted in the high dose animals during exposure.
Mortality:
mortality observed, treatment-related
Description (incidence):
One female rat in the mid-dose group was found dead during Week 5.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Minimal increases in cumulative food intake was noted for male rats in the mid- and high-dose groups (11% for mid dose and 7% for high dose). Since there was no clear dose response relationship and change was minor and an increase, the significance of this change is not clear.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
Minimal increases in the amount of water consumed were noted in the high dose animals. The differences seen were not regarded as toxicologically significant.
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Increased OCT values were seen in three high-dose male rats during Week 1 compared to control values. Only one of these values was above the laboratory’s upper normal limit, and the group mean was within the normal range.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Increases in urine volume were noted for high dose animals during Weeks 1 and 12, and for mid-dose animals during Week 12. Decreased urine pH was noted in high-dose male rats during Weeks 1 and 12 (pH6.3 reduced to pH5.9). These findings were not accompanies by serum changes or microscopic pathology indicative of a toxic effect.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There was evidence of a slight increase in liver and brain weights in the high dose female rats and kidney weights in high dose males. This is consistent with liver enlargement reported in previous studies of ethoxypropanol and the liver and kidney weight changes could be attributed to treatment.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
An increased incidence of pale foci in the lungs was noted in the high and mid dose animals at termination and the effect persisted at the end of the recovery period.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Slightly increased incidence of focal, minimal macrophage aggregation in high dose animals only. A slight increased incidence of focal, minimal macrophage aggregation was seen in the high dose animals at termination. This finding is regarded as a normal physiological response to inhaled particles and was also seen among control animals. This effect disappeared in males but not females at the end of the recovery period. It is therefore not considered to be toxicologically significant.
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEC
Effect level:
1.266 mg/L air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed at this concentration
Dose descriptor:
LOAEC
Effect level:
8.36 mg/L air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
organ weights and organ / body weight ratios
gross pathology
Critical effects observed:
not specified

Results for urinanalysis by dose group:

 

MALE

FEMALE

Group

Urine volume (ml)

pH

Urine volume (ml)

pH

WEEK 1

Control

3.9

6.3

2.5

6.3

Low

3.6

6.4

2.2

6

Medium

4.6

6.2

2.4

6.1

High

6.6*

5.9*

5.7*

6.3

WEEK 12

Control

3.8

6.4

3.1

6

Low

4.5

6.4

4.2

6.2

Medium

5.7*

6.4

4.5*

6.2

High

5.3*

6.1*

4.5*

5.9

*statistically significant.

Macroscopic incidence of pale foci

Group

MALE

FEMALE

Control

1/25

1/25

Low

1/15

1/15

Medium

1/15

3/15

High

6/25

3/25

 Control (recovery)  0/10  1/10
 High (recovery)  1/10  4/10

Male Organ weights – (absolute – relative not significant)

Group

Kidney (g)

Control

3.03

Low

3.11

Medium

3.25

High

3.53*

Control (recovery)

3.03

High (recovery)

3.41*

*=Statistically significant

Female Organ weights – (absolute – relative not significant)

Group

Brain (g)

Liver (g)

Control

1.77

10.2

Low

1.83

11.3

Medium

1.81

10.5

High

1.87*

12.1*

Control (recovery)

1.87

10.2

High (recovery)

1.86

10.7

*=Statistically significant

Microscopic incidence of minimal focal macrophage aggregation

Group

MALE

FEMALE

Control

2/10

1/10

Low

3/11

0/10

Medium

2/11

2/12

High

5/12

4/11

Control (recovery)

2/10

0/10

High (recovery)

0/10

3/10

Conclusions:
90-day inhalation NOAEC in rats is equal to or greater than 1.266 mg/l.
Executive summary:

In a guideline and GLP 90-day whole-body inhalation study in rats, exposure to ethyoxypropanol vapour at a concentration  of 8.36 mg/l for 6 hours per day, 5 days per week, for 13 weeks resulted in clinical signs indicative of irritant properties, and reduced ‘startle response’ during exposure. Increases in liver weight were also noted in female rats exposed at the 8.36 mg/l exposure level.  Animals exposed at concentrations of 1.266 or 0.426 mg/l did not exhibit any evidence of adverse effects (clinical signs, body weight, food and water consumption, opthalmoscopy, haematology, blood chemistry, urinalysis, organ weights, gross or microscopic pathology).  On the basis of these findings 1.266 mg/l is considered to be a subchronic NOAEC for ethoxypropanol vapour under the conditions of this study.

Endpoint conclusion
Dose descriptor:
NOAEC
1 266 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1954
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Principles of method if other than guideline:
Study pre-dated OECD test guidelines.
GLP compliance:
no
Remarks:
Study pre-dates GLP
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum): Commercial rabbit chow (Rockland)
- Water (e.g. ad libitum):
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):


IN-LIFE DATES: From: To:
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: abdomen
- % coverage:
- Type of wrap if used: A pad of absorbent cotten, about 3 x 3 inches in size and sufficiently thick to just absorb the volume of test material, was applied to the clipped or shaved abdomen and covered with an impervious saran film about 5 x 5 inches. The saran film was covered with a heavy cloth, and the whole application was then strapped onto the animal with adhesive tape.
- Time intervals for shavings or clipplings:


REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:


TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Constant volume or concentration used: yes/no
- For solids, paste formed: yes/no


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes/no
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Three months.
Frequency of treatment:
Five times per week
Remarks:
Doses / Concentrations:
0.0, 2.0, 4.0, 7.0 or 10.0 ml/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 to 11
Control animals:
other: Yes, control animals were similarly exposed to water
Details on study design:
no further data
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes / No / No data
- Time schedule:
- Cage side observations checked in table [No.?] were included.


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


DERMAL IRRITATION (if dermal study): Yes / No / No data
- Time schedule for examinations:


BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed before the application of each daily dose of test material.


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data


WATER CONSUMPTION: Yes / No / No data
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Before start of the study and on the 30th and 90th days of treatment.
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters examined: Hemoglobin, red blood cell count, white blood cell count (total and differential)


CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.


URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: liver, kidneys, spleen, adrenals, heart, lungs and occasionally stomach.
Other examinations:
None
Statistics:
No data
Clinical signs:
effects observed, treatment-related
Dermal irritation:
no effects observed
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Details on results:
Doses of 7 and 10 ml/kg produced narcosis which generally led to the death of the animal. These animals showed a terminal loss in body weight, probably related to decreased food consumption. Deaths seen in the groups receiving 2 or 4 ml/kg were associated with respiratory infections and were not correlated with narcotic effects or histological changes in any of the organs examined except the lungs. These doses did not effect body weight gain. Haematological parameters were normal, and organ weights were normal except in animals that died. No gross or histological pathology was seen in the lungs, heart, adrenals, testes, stomach or intestines of animals that survived the study. Animals that exhibited narcosis and died often showed pneumonia and empyema. Pyelonephritis or early interstitial nephritis was observed in occasional animals, and moderate to marked renal tubular necrosis was observed in three rabbits that died from the 7 or 10 ml/kg groups.

Careful gross and histological examinations of the skin revealed occasional scaling and erythema, but there was no significant difference between the skin of the treated animals and the control animals similarly treated with water only.

The study authors concluded that the dosage level of 2 ml/kg was well tolerated by the animals.
Dose descriptor:
NOAEL
Effect level:
1 800 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: slight liver and kidney changes
Critical effects observed:
not specified

 Dose (ml/kg)  No. Deaths / No. Treated
 0.0  0/5
 2.0  1/6*
 4.0  2/7*
 7.0  8/9
 10.0  11/11

* Deaths were associated with respiratory infections and were not attributed to the test material.

Conclusions:
A NOAEL of 2080mg/kg can be established for the repeat dose toxicity by the dermal route for the submission substance.
Executive summary:

In a 90-day dermal toxicity study, occluded application of methoxypropanol (a close structural analogue of ethoxypropanol) to the clipped abdominal skin of rabbits at doses of 7.0 ml/kg or higher 5 days per week resulted in narcosis and death. No effects were noted on body weight, organ weight or haematological parameters in animals that survived the study. Slight liver and kidney changes were noted at the higher doses. No effects seen on the skin by gross or histological examination. The study authors concluded that doses of 2 ml methoxypropanol/kg (1800 mg/kg) were well tolerated by the animals. On a molar basis this would be equivalent to a dose of 2,080 mg/kg of ethoxypropanol.

Endpoint conclusion
Dose descriptor:
NOAEL
1 840 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit

Additional information

In a guideline and GLP 90-day whole-body inhalation study in rats, exposure to ethoxypropanol vapour at a concentration of 8.36 mg/l (1967 ppm) for 6 hours per day, 5 days per week, for 13 weeks resulted in clinical signs indicative of irritant properties, and reduced ‘startle response’ during exposure. Increases in liver weight were also noted in female rats exposed at the 8.36 mg/l exposure level. Animals exposed at concentrations of 1.266 or 0.426 mg/L (298 or 100 ppm, respectively) did not exhibit any evidence of adverse effects (clinical signs, body weight, food and water consumption, opthalmoscopy, haematology, blood chemistry, urinalysis, organ weights, gross or microscopic pathology). On the basis of these findings 1.27 mg/L (298 ppm) is considered to be a subchronic NOAEC for ethoxypropanol vapour under the conditions of this study.

There is no sub-chronic data on ethoxypropanol by the oral route. In a guideline and GLP 90 day repeat dose oral gavage toxicity study using the closely related substance ethoxypropoxy propanol, a no adverse effect level of 1000mg/kg/day was established. The study also included a functional observation battery and a satellite 4 week recovery group. Observed effects attributed to treatment included salivation post dosing. At the end of the study, slight differences were seen in clinical chemistry, in liver and kidney weight and histopathology and in one of the FOB parameters. All of these were seen in the high dose animals and were attributed to treatment. Slight haematological statistically significant changes were seen but were not attributed to treatment. Of the treatment related changes seen, all were fully reversed in the recovery group animals and were therefore regarded as being adaptive and reversible changes that were not adverse. Because of the structural similarities and the similarity in metabolic pathways (covered in the toxicokinetics chapter 7.1), the results for this substance can be considered as relevant to predict the repeat dose oral toxicity of the substance ethoxypropanol. .

In a 90-day dermal toxicity study, occluded application of methoxypropanol (a close structural analogue of ethoxypropanol) to the clipped abdominal skin of rabbits at doses of 7.0 ml/kg or higher 5 days per week resulted in narcosis and death. No effects were noted on body weight, organ weight or haematological parameters in animals that survived the study. Slight liver and kidney changes were noted at the higher doses. No effects seen on the skin by gross or histological examination. The study authors concluded that doses of 2 ml methoxypropanol/kg (1800 mg/kg) were well tolerated by the animals. On a molar basis this would be equivalent to a dose of 2,080 mg/kg of ethoxypropanol.

An extensive justification for read across is contained in the read across justification attached to chapter 13 of this dossier.

Justification for classification or non-classification

The direct and indirect evidence for the repeat dose toxicity of ethoxypropanol indicates that repeat dose toxicity is very low and does not meet any of the criteria for classification for repeat dose effects or specific target organ toxicity.