Phthalimide

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Phthalimide - CAS No: 85-41-6

Author:

OECD SIDS

Year:

2005

Bibliographic source:

SIDS Initial Assessment Report for 20th SIAM, UNEP Publications

Reference 2

Reference Type:

other company data

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Principles of method if other than guideline:

Animals were exposed 6 hours per day, 5 days a week for 4 weeks (20 treatments)

GLP compliance:

no

Remarks:

GLP was not mandatory at the time of the study

Test material

Test material information

Constituent 1

Reference substance name:

Phthalimide

EC Number:

201-603-3

EC Name:

Phthalimide

Cas Number:

85-41-6

Molecular formula:

C8H5NO2

IUPAC Name:

1H-isoindole-1,3(2H)-dione

Details on test material:

- Name of test material (as cited in study report): phthalimide
- Analytical purity: not reported

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

inhalation

Details on inhalation exposure:

Animals were exposed in specially constructed stainless steel and glass whole-body inhalation chambers.
Phthalimide was heated to just above its melting point (230 °C): the fumes were generated by passing a stream of nitrogen gas over the heated material. Just prior to introduction into the chamber, an additional stream of filtered air was employed to force the fumes into the chamber. Nitrogen gas and additional air flow rates were maintained at 7 and 40 liters per minute, respectively. The concentration of the testmaterial fumes present in the exposure chambers were measured by sampling the test atmosphere in the breathing zones of the animals being exposed by gas chromatography.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 w

Frequency of treatment:

6 h/d, 5 d/w

Doses / concentrations

Remarks:

Doses / Concentrations:
0.051, 0.154 or 0.523 mg/L
Basis:

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: no

Examinations

Observations and examinations performed and frequency:

Mortality and reactions:
Checks for mortality and abnormal behavioural reactions were made daily during the investigational period.


BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined before the first exposure and weekly thereafter. Body weight at four-weeks were determined 24-hours prior to sacrifice, thus there were only 6 days between this and the week-three determination.


HAEMATOLOGY: Yes
Blood studies, including determinations for erythrocyte count, total leukocyte count, hemoglobin concentration, hematocrit value, differential leukocyte counts, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were conducted on all test and control animals on the day following the final exposure.

CLINICAL CHEMISTRY: Yes
All animals were investigated at the same time as the hematologic studies were performed. These studies included blood urea nitrogen (BUN) concentration, serum alkaline phosphatase (SAP) activity, serum glutamic-pyruvic transaminase (SGPT) activity and fasting blood glucose concentration.


URINALYSIS: Yes
Determination of glucose, albumin, microscopic elements, and pH were conducted at the same time as blood studies. Urine samples were collected during the 24-hours period prior to collection of blood samples.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. On the day after the final exposure (following blood collection) all animals were sacrificed for pathologic studies. The weights of the brain, gonads, heart, kidneys, liver, lung, and spleen of each animal were recorded. Gross necropsies were performed and tissues and organs were taken from T-3 and control animal and preserved in 10% formalin (brain, bronchi, gonads, heart, kidneys, liver, lung, lymph node, pituitary gland, spleen, trachea, urinary bladder, testes or ovaries). Examinations were scheduled to be done on abnormal tissues from all test groups.

Results and discussion

Results of examinations

Details on results:

Phthalimide exposure/dose: Four groups of 10 animals (5 male and 5 female per group) were exposed to 0.0 (control), 51 (T-1), 154.3 (T-2), and 522.8 mg/m3 phthalimide (T-3), respectively, as described in the Method section.

Mortality and reactions: No deaths or abnormal behavioural reactions noted in any of the animals.

Body weight data: No significant differences were observed between the average body weight or body weight-gains of control and treatment groups.

Hematology: No differences were observed between treatment and control groups.

Clinical chemistry: No differences were observed between treatment and control groups.

Urinalyses: No differences were observed between treatment and control groups.

Pathology: male rats: No gross or histopathologic alteration attributable to the effects of phthalimide were observed

Female rats: No gross or histopathologic alteration attributable to the effects of phthalimide was observed in all organs, except lungs. A significant, dose dependent, decrease in lung weights were seen in all treatment groups (control, T-1, T-2, and T-3: 2.200, 1.728, 1.640, and 1.576 g, respectively). The lung to body weight ratio, decreased also dose dependent, but significant decrease was seen only in the highest exposure group (lung/ body weight ratio: 1.093 (control), 0.8703 (T-1), 0.8069 (T-2), 0.7276 (T-3)).

Histopathologic evaluation of the lungs gave no evidence of compound related effects (only control and T-3 group animals were investigated).

Effect levels

Dose descriptor:

NOAEL

Effect level:

154.3 mg/m³ air

Basis for effect level:

other: Based on the statistically signficant lower lung to body weight ratio in the highest dose group in females rats

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

Phthalimide exposure/dose:
Four groups of 10 animals (5 male and 5 female per group) were exposed to  
0.0 (control), 51 (T-1), 154.3 (T-2), and 522.8 mg/m3 phthalimide (T-3),  
respectively, as described in the Method section.

Mortality and reactions:

Animal no./    gross             microscopic  observation               grade
dose group   observation                 lung                           (0-4)
-------------------------------------------------------------------------- --------------
6/control          -             murine pneumonia, chronic                1
7/control   lesion, multiple, red, diffuse  murine pneumonia, chronic    0-1
                 interstitial pneumonia, subacute, diffuse                1
8/control       -                 murine pneumonia, chronic               1
9/control       -                 murine pneumonia, chronic              0-1                   
10/control      -                 murine  pneumonia, chronic              1

36/T-3           -                murine pneumonia, chronic               1
37/T-3     lesion, multiple, red, diffuse  murine pneumonia, chronic      1
                interstitial pneumonia, subacute, diffuse                 1
38/T-3           -                murine pneumonia, chronic              0-1
39/T-3           -                murine pneumonia, chronic              0-1
                 -                interstitial pneumonia, subacute,  diffuse   1
40/T-3           -                murine pneumonia, chronic                      1
(grading system: 0: no finding, 1: minimal, 2: mild,... 5: extreme)