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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study with acceptable restrictions. No detailed clinical and ophthalmoscopic examinations were performed. Body weight determination, clinical chemistry and haematology analysis only performed in selected animals. Histopathological examination was only performed in 10 animals per sex of the control, 50 and 200 ppm group. Not all recommended standard clinical pathology parameters and organ weights were examined.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1976
Report Date:
1976
Reference Type:
secondary source
Title:
SIDS Initial Assessment Report For SIAM 28 Paris, France, 15-17 April 2009, Chemical Name: 2-(1-methylethoxy)ethanol, CAS Number: 109-59-1
Author:
OECD SIDS
Year:
2009
Bibliographic source:
http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=C1C0D516-D068-4A01-B34D-7C61F59A21D1

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no detailed clinical and ophthalmoscopic examinations; body weights, clinical chemistry and haematology parameters not determined in all animals; histopathological examination only in 10 animals per sex of the control, 50 and 200 ppm group
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): isopropyl OXITOL
- Lot/batch No.: 740731

Test animals

Species:
rat
Strain:
other: Carworth Farms E-strain (CFE)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Tunstall Laboratory
- Age at study initiation: 12-13 weeks
- Weight at study initiation:
- Fasting period before study: animals were fasted prior to every exposure.
- Housing: animals were housed in groups of 4 per cage during acclimatisation. During the entire study, animals were kept in groups of 40 per sex and chamber.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2-19.4
- Humidity (%): not controlled

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: Not applicable.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 10 m³ stainless steel inhalation chamber
- Method of conditioning air:
- System of generating vapours: test atmospheres were generated by vaporising the solvent in an induced air flow to produce a concentrated vapour/air mixture which was then diluted to the desired concentration by the main air flow into the chamber. The vaporizer was a quartz-sheathed heating element wound with glass fibre tape to increase the surface area, and the solvent was fed onto this surface from a solvent reservoir by means of a micro-metering pump. The vaporiser was mounted vertically inside a 4 inch nominal bore section of industrial glass pipeline which was connected by means of a 90° bend to the inlet duct of the exposure chamber. This generation system was designed so that the vaporiser had a minimum solvent hold-up. This meant that at the end of the 6 hour exposure period when the micro-metering pump ceased solvent delivery, solvent vapours quickly cleared from the generator and the concentration of solvent in the test chamber rapidly decreased to zero.
- Temperature, humidity, pressure in air chamber: 17.2-19.4 °C
- Air flow rate: 3.5 m³/min (top dose chamber) and 4.3 m³/min (other 3 dose chambers)

TEST ATMOSPHERE
- Brief description of analytical method used: a Beckman 109A Total Hydrocarbon analyser was used for continuous monitoring of the test atmosphere during the exposure period and a Beckman GC 2A gas chromatograph fitted with a flame ionisation detector and an auto gas sampling valve was used to analyse the test atmosphere from each of the three chambers the daily exposure period.
- Samples taken from breathing zone: yes

VEHICLE
- Concentration of test material in vehicle: 25, 50, 200 ppm (v/v)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Two different analysis systems were used in this experiment. One system, comprising two Beckman 109A Total Hydrocarbon analysers, enabled a continuous monitoring of the test atmospheres to be carried out during the exposure period. These analysers quickly responded to changes made in the atmosphere generation system and/or total chamber air flow rate, so that adjustments could be made to maintain the desired concentration of toxicant in the test atmospheres. This was particularly useful during the start-up period.
The other system consisted of a Beckman GC 2A gas chromatograph (GC) fitted with a flame ionization detector and an auto gas sampling valve. Test atmosphere from each of the three chambers in turn was drawn continuously through the gas sampling system, and a sample was transferred to the column every 6 min. The peak heights were averaged over the sampling period of approximately 75 min. The instrument was calibrated by means of an exponential dilution technique using a 12.5 litre stirred gas flask.
The three test atmospheres were analysed during the daily exposure period on both of the analysis systems, so that while continuous signals were obtained from the two Total Hydrocarbon analysers for two or the test atmosphere, the third atmosphere was being repeatedly chromatographed on the Beckman GC 2A. In this way, the concentrations of the solvent in the three test atmospheres could be determined, and any deviations from the desired values could be quickly spotted. The mean concentrations and ranges of solvent in the test atmospheres over the complete exposure period were 24 (16 to 30) ppm (v/v), 47 (32 to 56) ppm (v/v), and 197 (169 to 230 ) ppm (v/v).
Duration of treatment / exposure:
26 weeks
Frequency of treatment:
6 h/day, 5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
25, 50, 200 ppm (v/v)
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0.106, 0.212 and 0.850 mg/L
Basis:
other: nominal concentration based on a molecular weight of 104.15 g/mol and a molar gas volume of 24.5 L/mol
Remarks:
Doses / Concentrations:
106, 212 and 850 mg/m³
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
24, 47 and 197 ppm (v/v)
Basis:
analytical conc.
No. of animals per sex per dose:
40
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were observed daily for general health and behaviour.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were determined once weekly in 22/40 animals per sex and group at Weeks 0, 1, 2, 9, 10, 12, 18, 21, 23 and 26, respectively.

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

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: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at Weeks 0, 5, 9, 13, 18, 22 and 26
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 12/40 animals per sex and dose at Week 0; 1-3/40 animals per sex at Weeks 5, 9, 13, 18 and 22; 22/40 animals per sex and dose at Week 26
- Parameters checked: haemoglobin (Hb), packed cell volume (PCV), red blood cell count (RBC), white blood cell count (WBC), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), PT (prothrombin time), KCCT (kaolin cephalin coagulation time), osmotic fragilities

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at Weeks 0, 5, 9, 13, 18, 22 and 26
- Animals fasted: No data
- How many animals: 12/40 animals per sex and dose at Week 0; 2-4/40 animals per sex at Weeks 5, 9, 13, 18 and 22; 20-22/40 animals per sex and dose at Week 26
- Parameters checked: protein, urea, ALP (alkaline phosphatase), SGPT (Serum glutamic pyruvic transaminase), SGOT (serum glutamic oxaloacetic transaminase), sodium (Na), potassium (K), chloride (Cl)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals.
HISTOPATHOLOGY: Yes, in 10 randomly selected rats per sex of the control, 50 and 200 ppm group (brain, heart, kidney, lung, spleen, liver, alimentary tract, pancreas, salivary gland, thymus, mesenteric lymph node, gonads, prostate or uterus, pituitary, adrenals, larynx, thyroid, eye and decalcified sections of nasal cavities).
Organ weights of brain, heart, liver, spleen, kidneys and testes were determined in 20-22 animals per sex and group.
Statistics:
Body weights and organ weights were analysed by covariance analysis using initial body weight as the covariate. Reported means were adjusted for initial body weight if a significant covariance relationship existed. Where no significant covariance relationship existed, means were reported unadjusted. Covariance analysis was also used with terminal body weight as the covariance to test whether organ weight differences could be attributed to the differences in terminal body weight or if differences in organ weight were concealed by body weight variation. Reported means were adjusted for terminal body weight if a significant covariance relationship existed. This is not a true covariance analysis since terminal body weights are dependent upon treatment and has only been reported when it aids the interpretation of body and organ weight difference. Clinical chemical and haematological parameters were examined using analysis of variance. The significance of any differences between treatment and control group means was tested using the Williams t-test. However, on some occasions a monotonic dose response relationship could not be assumed, in which case Dunnett’s test was used.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
25, 50 and 200 ppm: sign. increase in 50% osmotic fragility of erythrocytes and decrease in MCH/MCHC; 50 and 200 ppm: sign. increase in 100% osmotic fragility of erythrocytes, sign. decrease in MCH and MCHC; 200 ppm: sign. decrease in RBC, Hb and PCV
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
25, 50 and 200 ppm: significant decrease in potassium levels
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):
200 ppm: significant increase in relative spleen weight
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
50 and 200 ppm: excessive amounts of hemosiderin in red and white pulp of spleen (m, f); 200 ppm: increase in brown pigment in Kupffer cells of liver (f), extramedullary haematopoiesis in spleen (m, f)
Details on results:
CLINICAL SIGNS AND MORTALITY
No treatment-related clinical signs and mortalities were observed.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights were similar between all treated animals and controls.

HAEMATOLOGY
At 200 ppm, a consistent and significant reduction in haemoglobin concentration was observed in male and female rats, which was accompanied by a marginal reduction in packed cell volume (PCV) and a consistently lower erythrocyte count (RBC) during the entire study period. A consistent and significant elevated mean corpuscular volume (MCV) in the male and female rats exposed to 200 ppm was also noted. Small rises in erythrocyte counts and occurred in both male and female rats at 25 and 50 ppm, being indicative of a compensatory regeneration of erythrocytes at the lower dose levels, which however, was not sufficient to compensate the loss in erythrocytes at the highest dose level, as shown by the significant decrease in RBC and haemoglobin compared to controls. Changes in the osmotic fragility of rat erythrocytes occasionally occurred at all exposure levels, indicating a greater susceptibility of erythrocytes to haemolysis. At 25 ppm, the 50% osmotic fragility was statistically significant at Week 22 (p < 0.05) in male rats and at Week 13 (P < 0.05) and Week 18 (p < 0.01) in female rats. At the higher dose levels (50 and 200 ppm), the 50 and 100% osmotic fragility of erythrocytes was statistically significantly increased (p < 0.01) in both males and females at the end of the exposure period (26 weeks). At the same dose levels, mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) were significantly decreased compared to controls in both genders, providing further evidence for the treatment-related haemolytic effects after inhalative exposure.
In addition to the haemolytic effects, a slight reduction in kaolin cephalin coagulation time (KCCT) was observed in male and females at 200 ppm, which was not considered to be of toxicological relevance.

CLINICAL CHEMISTRY
At week 26 (study termination), plasma potassium values were significantly and dose-related decreased in both genders at all dose levels. No further significant changes in clinical parameters were observed.

ORGAN WEIGHTS
The relative weights of spleens were significantly increased in male and female rats exposed to 200 pm compared to controls. There is a correlation between increased spleen weight and the histological changes noted at the 200 ppm exposure level. In males exposed to 200 ppm, relative heart weights were significantly higher and relative liver were significantly lower compared to controls.

GROSS PATHOLOGY
No test-substance-related findings were observed at necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment-related histopathological changes were mainly observed in liver and spleen of animals exposed to200 ppm. Considerable amounts of brown pigment were observed in Kupffer cells of the liver of female rats at 200 ppm, which could be may also be attributable to hemosiderin exposition. In males of the same dose group, small amounts of lipid in the liver parenchyma were only seen in 2/10 animals. Excessive amounts of hemosiderin were noted in the red and white pulp of the spleen in male and female rats of the 50 ppm and 200 ppm groups, respectively. Furthermore, extramedullary haematopoiesis was observed in the spleen of male and female rats exposed to 200 ppm. The accumulation of hemosiderin in spleen and possibly also in liver, as well as the extramedullary haematopoiesis in spleen are further indicative of haemolytic effects and thus correlate with the observed adverse changes in haematological parameters.

Effect levels

open allclose all
Dose descriptor:
LOAEC
Effect level:
25 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: haematology (haemolytic effects): significant increase in the 50% osmotic fragility in erythrocytes and significant decrease in MCH and MCHC; clinical signs: significant decrease in potassium levels
Dose descriptor:
LOAEC
Effect level:
0.106 mg/L air (nominal)
Based on:
test mat.
Remarks:
corresponding to 106 mg/m³
Sex:
male/female
Basis for effect level:
other: nominal concentration based on a molecular weight of 104.15 g/mol and a molar gas volume of 24.5 L/mol

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1. Osmotic fragilities of erythrocytes in male rats

Week No.

Atmosphere
concentration
[ppm]

No. of
rats

Male

Osmotic fragilities % NaCl producing haemolysis

0%

50%

100%

0

0

3

0.611

0.403

0.213

25

3

0.611

0.389

0.233

50

3

0.622

0.393

0.200

200

3

0.590

0.390

0.200

Standard deviation of a single observation

0.0251

0.0162

0.0115

5

0

2

0.720

0.470

0.230

25

3

0.632

0.455

0.203

50

3

0.695

0.466

0.195

200

3

0.760

0.515*

0.257

Standard deviation of a single observation

0.0425

0.0148

0.0230

9

0

3

0.662

0.382

0.173

25

3

0.732

0.383

0.135

50

3

0.730

0.407

0.179

200

3

0.722

0.463**

0.175

Standard deviation of a single observation

0.0421

0.0187

0.0309

13

0

3

0.660

0.369

0.117

25

3

0.665

0.427

0.160

50

3

0.682

0.427

0.128

200

3

0.717

0.473**

0.160*

Standard deviation of a single observation

0.0307

0.0304

0.0203

18

0

2

0.645

0.350

0.113

25

3

0.673

0.397

0.118

50

3

0.657

0.398

0.130

200

3

0.713*

0.467**

0.114

Standard deviation of a single observation

0.0246

0.0339

0.0198

22

0

3

0.660

0.375

0.193

25

3

0.700

0.433*

0.163

50

3

0.725**

0.428*

0.210

200

3

0.744**

0.480**

0.178

Standard deviation of a single observation

0.0254

0.0256

0.0349

26

0

22

0.694

0.398

0.284

25

22

0.708

0.400

0.274

50

22

0.726**

0.431**

0.306**

200

22

0.754**

0.478**

0.317**

Standard deviation of a single observation

0.0361

0.0223

0.0218

Statistical significance is indicated at *p <0.05 and **p<0.01.

Table 2. Osmotic fragilities of erythrocytes in female rats

Week No.

Atmosphere
concentration
[ppm]

No. of
rats

Female

Osmotic fragilities % NaCl producing haemolysis

0%

50%

100%

0

0

3

0.620

0.441

0.283

25

3

0.623

0.444

0.210*

50

3

0.662

0.443

0.210*

200

3

0.655

0.443

0.230

Standard deviation of a single observation

0.0288

0.0126

0.0329

5

0

3

0.608

0.463

0.248

25

3

0.713**

0.490

0.217

50

3

0.708**

0.505*

0.255

200

3

0.799**

0.550**

0.171**

Standard deviation of a single observation

0.0231

0.0159

0.0266

9

0

3

0.677

0.433

0.190

25

3

0.697

0.431

0.158

50

2

0.760**

0.450

0.180

200

3

0.767**

0.523**

0.190

Standard deviation of a single observation

0.0149

0.0296

0.0353

13

0

3

0.653

0.402

0.145

25

3

0.707

0.428*

0.165

50

3

0.730*

0.437*

0.150

200

3

0.774**

0.507**

0.167

Standard deviation of a single observation

0.0303

0.0131

0.322

18

0

1

0.661

0.390

0.160

25

3

0.663

0.423**

0.150

50

3

0.643

0.443**

0.153

200

3

0.750*

0.493**

0.150

Standard deviation of a single observation

0.735

0.528

0.188

22

0

3

0.662

0.420

0.157

25

3

0.663

0.407

0.168

50

3

0.715

0.448

0.227*

200

3

0.735*

0.528**

0.188*

Standard deviation of a single observation

0.0339

0.0336

0.0259

26

0

3

0.671

0.396

0.266

25

3

0.723

0.420

0.266

50

3

0.722

0.452**

0.307

200

3

0.747**

0.488**

0.289

Standard deviation of a single observation

0.0924

0.0565

0.0515

Statistical significance is indicated at *p <0.05 and**p<0.01.

Applicant's summary and conclusion

Conclusions:
Based on the haemolytic effects observed at 25, 50 and 200 ppm (0.106, 0.212 and 0.850 mg/L), the substance is classified as STOT RE 1, H372, inhal, blood.