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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (limited parameters examined, no daily observation, no data on test substance purity)

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
(limited parameters examined, no daily observation)
GLP compliance:

Test material

Constituent 1
Reference substance name:
Cas Number:
Details on test material:
- Name of test material (as cited in study report): [Trade name]- Physical state/appearance: yellow liquid- Analytical purity: no data

Test animals

Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Taconic, Germantown, NY, USA- Weight at study initiation: males: 379-388 g ; females: 234-239 g- Housing: animals were housed in the exposure chambers (feed and water was removed during exposure)

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Remarks on MMAD:
MMAD / GSD: 1.0 µm/ approx. 1.8
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION- Exposure apparatus: 1000 L stainless steel and glass exposure chambers; chambers contained catch pans between each of three leveles of cages. - System of generating particulates/aerosols: The test material was aerosolized directly from the liquid by a modified Lakin nebulizer on each chamber. The test material was in a straight-walled glass flask and the barrels of the nebulizer were immersed under the level of the liquid in order to maximize the amount of material generated. The distance from the nebulizer to the walls of the flask was approx. 3 cm. After exiting the flask, the aerosol passed through a glass impactor to remove most of the larger particles. The remaining aerosol was mixed with the main air stream for each chamber before entering the chamber. - Temperature and humidity in air chamber (by a Taylor wet/dry bulb hydrometer approx. every 30 min during each exposure): approx. 23 °C, 56 - 64% - Air flow rate: approx. 300 L/min (mean chamber flow per group: 297, 308, 342, and 243 L/min, respectively)TEST ATMOSPHERE- Brief description of analytical method used: gravimetric sampling on glass fiber filters (3 times during each exposure); some filters were additionally analyzed by GC/MS- Samples taken from breathing zone: yesNominal concentrations were determined as the loss of weight of fluid from the generator divided by total air flow through the chamber.
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day5 days/week
Doses / concentrationsopen allclose all
Doses / Concentrations:0.00 ± 0.00, 0.05 ± 0.01, 0.17 ± 0.01, and 0.56 ± 0.02 mg/LBasis:analytical conc.
Doses / Concentrations:0.05, 0.15, and 0.5 mg/LBasis:nominal conc.
No. of animals per sex per dose:
15(Additional 10 male rats per group were included for examination of pulmonary function tests and analysis of pulmonary hydroxyproline following exposure.)
Control animals:
yes, concurrent no treatment
yes, sham-exposed
Details on study design:
- Dose selection rationale: The highest dose was expected to result in abnormal accumulation of test material in the lung and possible impairment of normal clearance mechanisms. The low dose is a factor of 10 above the TLV (treshold limit value) for mineral oil mistes, no untoward effects were expected at this level.


Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: daily (except weekends)DETAILED CLINICAL OBSERVATIONS: No BODY WEIGHT: Yes- Time schedule for examinations: weeklyFOOD CONSUMPTION:- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: NoFOOD 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: NoHAEMATOLOGY: Yes- Time schedule for collection of blood: at study termination- Animals fasted: Yes- How many animals: all core animals- Parameters examined: complete blood count (CBC) (white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and platelets) and differential count.CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: at study termination- Animals fasted: Yes- How many animals: all core animals - Parameters examined: glucose, urea nitrogen, total protein, albumin (A), globulin (G), A/G, sorbitol dehydrogenase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, creatinine colesterol, triglycerides, uric acid, Cl, Ca, Na, K, and PURINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: NoOTHER:Lung function: The animals were anaesthetized and pulmonray function tests were performed (deflation quasistatic pressure-volume cureved, functional residual capactiy, and maximal forced exhalation maneuver). After the pulmonray function tests, the lungs were removed and all lobes were weighed. Lobes were frozen for analysis of hydroxyproline content and analysis of test material remaining in the lung.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes; organ weights (adrenals, kidney, spleen, brain, liver, testes, epididymides, ovaries, thymus, heart, prostate, uterus, right middle lung lobeHISTOPATHOLOGY: Yes (untreated and high-dose): adrenals, ovaries, sternum, pancreas, brain, salivary gland, eye, spleen heart, stomach, colon, testes, duodenum, thymus, kidneys, thyroid, liver, tracheobronchial lymph nodes, lung, nasal turbinates, thigh muscle, urinary bladder, sciatic nerve, and any gross lesions. Only the lungs and tracheobronchial lymph nodes of the untreated controls were processed. 10 males of group 1, 2 and 5 (untreated, sham-exposed, and high-dose) were evaluated for morphology, number of sperm and number of testicular spermatids.
ANOVA and Tukey´s multiple range test: body weighs, male reproductive endpoints, haematology, and serum chemistryANOVA and Duncan´s multiple range test: organ weights, pulmonary function, and pulmonary hydroxyproline

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were observed.
no mortality observed
Description (incidence):
No mortalities observed.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Increased body weights were observed in treated males. The difference compared to control was statistically significant, but as no clear dose-response was seen and the difference was lower than 7%, it was not considered to be of toxicological relevance.
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:
no effects observed
Description (incidence and severity):
No treatment-related changes were observed.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related changes were observed.
Urinalysis findings:
not examined
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):
The lungs had a minimal increase in weight after exposure to 0.50 mg/L. Other organ weights were not affected by exposure to the test substance.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The number of macrophages in the pulmonary alveoli increased slightly. This increase was small considering the high (500 mg/nr) aerosol concentration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic examination of the lungs of animals in the high-dose group revealed one to two plump macrophages with sparse cytoplasmic vacuoles in less than 1.0% of the aveoli (in controls less than 0.1% would be expected). OTHER FINDINGS- Sperm morphology: No treatment-related effects were noted in sperm morophology or in sperm and spermatid counts. - Lung function: There were no significant differences between any groups for any of the pulmonary function parameters. The only parameter affected by exposure was the total weight of the five lung lobes. Weight for the high-dose group was significantly greater than the other groups.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified

Effect levels

Key result
Dose descriptor:
Effect level:
0.5 mg/L air (analytical)
Based on:
test mat.
Basis for effect level:
other: no adverse effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion