4-hydroxybenzoic acid

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

days of exposure: Feb 15 - Feb 26 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable, well-documented study which meets basic scientific principles

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

12 day inhalation toxicity study

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-hydroxybenzoic acid

EC Number:

202-804-9

EC Name:

4-hydroxybenzoic acid

Cas Number:

99-96-7

Molecular formula:

C7H6O3

IUPAC Name:

4-hydroxybenzoic acid

Details on test material:

- Name of test material (as cited in study report): C-194
- Substance type: white powder
- Physical state: solid
- Analytical purity: approximately 100%
- Expiration date of the lot/batch: February 9, 1982
- Supplier: Celanese Corporation, 1211 Avenue of the Americas, New York, New York 10036

Comment by the applicant:
Existing retained samples from batches of C-194 of 1981 were analytically rechecked. The identity was confirmed with a content of 4-HBA of approximately 100% (NMR analysis).

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Sprague-Dawley derived CD
- Source: Charles River Breeding Laboratories, Kingston, New York
- Age at study initiation: males: 41 days; females: 57 days
- Weight at study initiation: males: (mean: 198) 192-210 g; females: (mean: 183) 173-197 gram
- Fasting period before study: no
- Housing:Individual in hung stainless steel, wire mesh-bottom cages
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow (5001) ad libitum
- Water (e.g. ad libitum):Citx-tap water (Elizabethtown Water Co.) ad libitum
- Acclimation period: 12 days

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:glas chamber
- Method of holding animals in test chamber: individual stainless steeel, wire mesh cages
- Air: dry air at a pressure of 5 psi
- System of generating particulates/aerosols: Wright Dust Feed Mechanism
- Air flow rate: 155-245 liters per minute
- Air change rate: every 6.5 - 4.1 minutes

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric sampling, particle size distribution: Batelle cascade impactor
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

gravimetric control of the total airborne concentration

Duration of treatment / exposure:

exposure of 6 hours per day on 5 consecutive days, 2 days interruption and another 5 days exposure for 6 hours per day

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 60, 200 mg/m³
Basis:
nominal conc.

No. of animals per sex per dose:

5 per sex and dose

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice weekly


BODY WEIGHT: Yes
- Time schedule for examinations: before and after exposures 1, 5 and 10.


HAEMATOLOGY: Yes
- Time schedule for collection of blood:before the last exposure period:
- Parameters checked: hemoglobin, hematocrit, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before and after exposures 1, 5 and 10.
- How many animals: control and high dose animals
- Parameters checked: blood urea nitrogen, serum glutamic pyruvic transaminase, glucose, total protein.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes: kidneys, liver, lungs, nasal passages, trachea

Statistics:

The animals were randomly distributed to the groups.
Body weights, organ weights, and organ/body weight ratios were statistically evaluated. Statistical evaluation of equality of means was made by the appropriate one way analysis of variance technique, followed by a multiple comparison procedure if needed.

hematology and clinical chemistry: To statistically determine if the two means were equal, first, test if the variances of the two groups could be considered as equal. If the variances were equal a standard, independent, two sample t-test was used to determine the equality of means. If the variances differed, Welch's t-test was used to determine equality of means.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

for effects see below

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
overall effects: increased instances of dried material around the facial area were detected in all exposure groups,
high dose only (200 mg/m³): ocular irritation (swollen eyelids, injection of conjunctival blood vessels),
hematology: males: elevated hematocrit, reduction in MCHC values, depressed clotting time
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liver
BODY WEIGHT: no effect

HAEMATOLOGY: 200 mg/m³, males: elevated hematocrit, reduction in MCHC values

CLINICAL CHEMISTRY: 200 mg/m³, males: depressed clotting time

ORGAN WEIGHTS: no effect

GROSS PATHOLOGY: no test article related effects

HISTOPATHOLOGY: 200 mg/m³: 2 males, 1 female: increased mitotic activity of parenchymal liver

Particle size distribution:
- Aerodynamic mass median diameter (group II, III, IV) in µm/ % of Particles 10 µm or less in diameter: 4.74; 5.55; 6.26/ 73.51; 77.47; 70.39

Effect levels

Key result

Dose descriptor:

NOEL

Effect level:

60 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical signs; hematology; clinical chemistry; histopathology

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

200 mg/m³ air

System:

respiratory system: upper respiratory tract

Organ:

blood

cornea

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

presumably yes

Any other information on results incl. tables

overall effects:

Increased instances of dried material around the facial area were detected in all exposure groups,

high dose only (200 mg/m³): ocular irritation (swollen eyelids, injection of conjunctival blood vessels)

clinical signs: males: elevated hematocrit, reduction in MCHC values, depressed clotting time,

histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liver

Applicant's summary and conclusion

Conclusions:

An inhalation toxicity study was performed using 4 groups, one control and 3 dose groups, of 5 male and 5 female Sprague-Dawley rats each exposed to C-194, all in all 40 animals. The exposure period lasted for 6 hours per day for 5 days followed by another 5 day exposure period after an interruption of 2 days. The cumulative mean measured/nominal exposure concentrations were: 23.8, 64.0 and 189 mg/m³; 20, 60 and 200 mg/m3.
Physical examinations revealed increased instances of dried material around the facial area in all exposure groups.
20 mg/m³: no differences to the data of the control animals,
60 mg/m³: no differences to the data of the control animals,
200 mg/m³: The observed changes can be explained by an irritative effect of 4 -HBA to the eyes and in the respiratory tract specially in the nose and the lungs and a possible toxic effects on the liver and on the blood.

Executive summary:

An inhalation toxicity study was performed using 4 groups, one control and 3 dose groups, of 5 male and 5 female Sprague-Dawley rats each exposed to C-194, all in all 40 animals. The exposure period lasted for 6 hours per day for 5 days followed by another 5 day exposure period after an interruption of 2 days. The cumulative mean measured/nominal exposure concentrations were: 23.8, 64.0 and 189 mg/m³; 20, 60 and 200 mg/m3.

Physical examinations revealed increased instances of dried material around the facial area in all exposure groups.

20  mg/m³: no differences to the data of the control animals,

60 mg/m³: no differences to the data of the control animals,

200 mg/m³: swollen eyelids (6 animals day 2), area around the eye swollen (1 animal day 9), injection of conjunctival blood vessels (5 animals on day 12)
clinical chemistry: males: elevated hematocrit, reduction in MCHC values;
hematology: males: depressed clotting time
histopathology: Lungs: chronic interstitial pneumonia, 2 males, 2 females; partial atelectasis: 2 females; perivascular edema/cellular infiltrate: 1 female; alveolar septa: polymorphonuclear infiltrate: 1 female; alveolar epithelium: desquamation: 1 female; alveolar haemorrhage: 1 male, 2 females; increased mitotic activity of parenchymal liver: 2 males, 2 females.Increased instances of dried material around the facial area were detected in all exposure groups,
high dose only: ocular irritation (swollen eyelids, injection of conjunctival blood vessels)
clinical chemistry: males: elevated hematocrit, reduction in MCHC values, depressed clotting time,
histopathology: 2 males, 1 female: increased mitotic activity of parenchymal liver

The observed changes can be explained by an irritative effect of 4 -HBA to the eyes and in the respiratory tract specially in the nose and the lungs and a possible toxic effects on the liver and on the blood.