Isophthaloyl dichloride

Endpoint summary

Description of key information

Oral: ALD; rat; gavage; reliability = 2; NOT CLASSIFIED.
Dermal: LD50; rabbit; reliability = 2; CLASSIFIED: Cat 4.
Inhalation: 4-hr LC50; rat; reliability = 2; CLASSIFIED: Cat 3; [CAS# 100-20-9].

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

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

Remarks:

No test article analysis. Non GLP. Non-guideline study design.

Principles of method if other than guideline:

Groups of 1 rat exposed to 7 concentrations of the test substance. Mortality, clinical signs, and pathology were monitored and an oral ALD was reported.

GLP compliance:

no

Test type:

acute toxic class method

Species:

rat

Strain:

other: ChR

Sex:

male

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on oral exposure:

VEHICLE
25% Solution in Peanut Oil.

Doses:

Single doses of 7500, 5000, 3400, 2250, 1500, 1000, 670 mg/kg

No. of animals per sex per dose:

1

Control animals:

not specified

Details on study design:

No guidelines provided.

Sex:

male

Dose descriptor:

other: Approximate Lethal Dose (ALD)

Effect level:

5 000 mg/kg bw

Mortality:

1/1 at 7500, 5000 mg/kg
0/1 at 3400, 2250, 1500, 1000, 670 mg/kg

Clinical signs:

other: Discomfort and found dead following day: 7500, 5000 mg/kg doses Weight Loss: 3400, 2250 mg/kg No toxic signs observed: 1500, 1000, 670 mg/kg

Gross pathology:

Severe Injury to stomach: 7500, 5000 mg/kg doses
No pathological changes: 3400, 2250, 1500, 1000, 370 mg/kg doses

Interpretation of results:

GHS criteria not met

Conclusions:

Approximate Lethal Dose of the test substance was found to be 5000 mg/kg of body weight. Lethal doses caused severe gastritis. Clinical signs of toxicity were not observed in those rats receiving sublethal doses, nor was pathology observed when the rats were killed 10 days later.

Executive summary:

Approximate Lethal Dose of the test substance was found to be 5000 mg/kg of body weight. Lethal doses caused severe gastritis. Clinical signs of toxicity were not observed in those rats receiving sublethal doses, nor was pathology observed when the rats were killed 10 days later.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of 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:

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

Remarks:

Study was conducted under non-standard guideline (Class B Poison Test).

Justification for type of information:

The test substance is structurally similar to terephthaloyl dichloride (TCL). Therefore, the study with TCL is being used to fulfil this data requirement. Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.

Reason / purpose for cross-reference:

read-across: supporting information

Principles of method if other than guideline:

Six young adult male rats per dose level were exposed whole body to 0.12, 0.38, 0.60, 0.66, 2.31 mg/L of the test substance for four hours. Rats were sacrificed and necropsied at one, two, and six days after exposure to 0.12 mg/L and 14 days after exposure to 0.6 mg/L.

GLP compliance:

not specified

Test type:

other: Class B Poison Test

Species:

rat

Strain:

other: ChR-CD

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 250-280 grams.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: air; (nitrogen was used to pass chemical into exposure chamber where it was then mixed with oxygen and diluting air to give an 20% O2 (v/v) concentration)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Bell jar.
- Exposure chamber volume: 16 litre.
- Method of holding animals in test chamber: Whole body.
- System of generating particulates/aerosols: The test substance was put in a three-neck glass flack in a heated (100°C) mineral oil bath. Aerosols of the compound were prepared from this molten test substance by a stainless steel nebulizer submerged into the melt. Nitrogen was passed through the nebulizer to carry the vapours into a 16-liter bell-jar containing six young adult male rats. Oxygen and diluting air were added to the stream prior to entering the exposure changer to give 20% oxygen (v/v) in the chamber atmosphere and to adjust the concentration.

TEST ATMOSPHERE
- Brief description of analytical method used: Concentration determined at least three times during each 4 hour exposure by drawing a known volume of chamber atmosphere through two impingers in series. n-Heptane was the scrubbing solvent. The solution was analyzed by ultraviolet light absorption at 254mµ.
- Samples taken from breathing zone: Yes.

VEHICLE
- Composition of vehicle (if applicable): Nitrogen was used to pass chemical into exposure chamber where it was then mixed with oxygen and diluting air to give an 20% O2 (v/v) concentration.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Concentration determined at least 3 times during each 4 hour exposure by drawing a known volume of chamber atmosphere through 2 impingers in series. n-Heptane was the scrubbing solvent. The solution was analyzed by ultraviolet light absorption at 254mµ.

Duration of exposure:

4 h

Concentrations:

0.12, 0.38, 0.60, 0.66, 2.31 mg/L.

No. of animals per sex per dose:

6

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: Up to 14 days.
- Frequency of observations and weighing: Weight measured daily.
- Necropsy of survivors performed: Yes. Rats were sacrificed at one, two and six days after exposure to 0.12mg/l and 14 days after exposure to 0.6mg/L. Tissues examined included: lungs, liver, kidney, brain, lymph nodes, spleen, testes, gastrointestinal tract, thyroid, adrenal, skin, bone marrow, pancreas, epidedymis, thymus, and eye.
- Other examinations performed: Clinical signs during exposure.

Statistics:

Statistical analysis by method of Litchfield, J. T., Jr. and F. Wilcoxon, J. Pharmacol. and Expt'l. Therap., 96:99 (1949).

Sex:

male

Dose descriptor:

LC50

Effect level:

0.7 mg/L air

95% CL:

>= 0.46 - <= 1.06

Exp. duration:

4 h

Mortality:

0/6 at 0.12 mg/L; 1/6 at 0.38 mgL; 2/6 at 0.60 mg/L; 3/6 at 0.66 mg/L; and 6/6 at 2.31 mg/L.

Clinical signs:

other: 0.12mg/L- During exposure: Slight difficulty breathing, otherwise normal 0.38mg/L- During exposure: Heavy breathing, occasional face pawing, gasping. One death at 2.5 hours 0.60mg/L- During exposure: Lacrimation, face pawing, heavy breathing and gasping.

Body weight:

0.12mg/L- Down to 82% of their initial body weight on the 1st day.
0.38mg/L- Down to 76% of initial body weight on the 2nd day post-exposure, normal recovery thereafter.
0.60mg/L- Down to 83% of initial body weight on the 1st day of recovery, normal recovery thereafter.
0.66mg/L- Down to 82% of initial body weight 1st day post-exposure. All but one started to recover 2nd day post-exposure. The one was down to 75% of initial body weight on the 5th day of recovery and gained normally thereafter.

Gross pathology:

Rats were sacrificed at one, two, and six days after exposure to 0.12 mg/L and 14 days after exposure to 0.6 mg/L. The rat which died during exposure to 0.38 mg/L and one of those which died during exposure to 2.31 mg/L were also necropsied for gross and histopathologic examination. Gross examination at necropsy revealed severe pulmonary oedema and congestion.
Slight pulmonary congestion and oedema were still noted in rats sacrificed one day post-exposure. They also showed acute necrotic tracheobronchitis, hyperplasia of granular alveolar cells and depletion of hepatic cell glycogen.
The rats sacrificed two days post-exposure showed no evidence of pulmonary oedema, but glycogen depletion of the hepatic cells was still evident.
Rats sacrificed at six and 14 days post-exposure exhibited regeneration of the tracheobronchial epithelium and had normal amounts of glycogen in the hepatic cells.
Depletion of glycogen in the hepatic cells was considered a transient change due to stress and anorexia following exposure and reflected the nutritional condition of the test rats.

Other findings:

Decreased body weight days 1-5 days post exposure and normal thereafter. Slight pulmonary congestion and oedema; acute necrotic tracheobronchitis, hyperplasia of granular alveolar cells; and depletion of hepatic cell glycogen were observed one day post exposure. At two days post exposure, no evidence of pulmonary oedema was observed, but glycogen depletion of the hepatic cells was still evident. At 6 and 14 days post exposure regeneration of the tracheobronchial epithelium and normal amount of glycogen in the hepatic cells were observed. Depletion of glycogen in the hepatic cells was considered a transient change due to stress and anorexia following exposure and reflected the nutritional condition of the test rats.

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

LC50 = 0.7 mg/L

Executive summary:

Male rats were exposed to the test substance for 4 hours by inhalation at concentrations of 0.12, 0.38, 0.60, 0.66 and 2.31 mg/L. The LC50 was 0.7 mg/L. Decreased body weight was observed on days 1-5 days post exposure and was normal thereafter. Slight pulmonary congestion and edema; acute necrotic tracheobronchitis, hyperplasia of granular alveolar cells; and depletion of hepatic cell glycogen were observed one day post exposure. At two days post exposure no evidence of pulmonary edema was observed but glycogen depletion of the hepatic cells was still evident. At 6 and 14 days post exposure regeneration of the tracheobronchial epithelium and normal amount of glycogen in the hepatic cells were observed. Depletion of glycogen in the hepatic cells was considered a transient change due to stress and anorexia following exposure and reflected the nutritional condition of the test rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

700 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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

Principles of method if other than guideline:

Penetration of rabbit skin was estimated by a technique similar to the one-day cuff method of Draize and associates (Draize, J. H., G. Woodard, and H. O. Calvery (1944). "Methods for study of irritation and toxicity of substances applied topically to the skin and mucous membranes" J. Pharmacol. Exp. Therap., 82:377).

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Type of coverage:

occlusive

Details on dermal exposure:

TEST SITE
- Area of exposure: entire trunk
- Type of wrap if used: impervious plastic film

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24-hr contact period under film, then film is removed and animals are observed for 14 days

TEST MATERIAL
- Concentration (if solution): <20 mL/kg

Duration of exposure:

24-hr contact period under film, then film is removed and animals are observed for 14 days

No. of animals per sex per dose:

4

Control animals:

not specified

Details on study design:

Penetration of rabbit skin was estimated by a technique similar to the one-day cuff method of Draize and associates (Draize, J. H., G. Woodard, and H. O. Calvery (1944). "Methods for study of irritation and toxicity of substances applied topically to the skin and mucous membranes" J. Pharmacol. Exp. Therap., 82:377). Groups of 4 male albino rabbits weighing 2.5 to 3.5 kg were used. The fur was clipped from the entire trunk and the dose of the test substance was retained beneath an impervious plastic film. The rabbits were immobilized during the 24-hour exposure period, after which the film was removed and the rabbits were caged for the subsequent 14-day observation period. The LD50 value and its fiducial range were estimated by the method of Thompson (Thompson, W. R. (1947). "Use of moving averages and interpolation to estimate median effective dose" Bacteriol. Rev., 11:115) using the Tables of Weil (Weil, C. S. (1952). "Tables for the convenient calculation of median effective dose and instructions for their use" Biometrics, 8:249).

Sex:

male

Dose descriptor:

LD50

Effect level:

1 410 mg/kg bw

95% CL:

>= 870 - <= 2 310

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The dermal LD50 was calculated to be 1.41 mL/kg (1410 mg/kg bodyweight) with confidence limits of 870 - 2310 mg/kg bodyweight).

Executive summary:

Penetration of rabbit skin by the test substance was estimated by a technique similar to the one-day cuff method of Draize and associates (Draize, J. H., G. Woodard, and H. O. Calvery (1944). "Methods for study of irritation and toxicity of substances applied topically to the skin and mucous membranes" J. Pharmacol. Exp. Therap., 82:377). Groups of 4 male albino rabbits weighing 2.5 to 3.5 kg were used. The fur was clipped from the entire trunk and the dose of the test substance was retained beneath an impervious plastic film. The rabbits were immobilized during the 24-hour exposure period, after which the film was removed and the rabbits were caged for the subsequent 14-day observation period. The LD50 value and its fiducial range were estimated by the method of Thompson (Thompson, W. R. (1947). "Use of moving averages and interpolation to estimate median effective dose" Bacteriol. Rev., 11:115) using the Tables of Weil (Weil, C. S. (1952). "Tables for the convenient calculation of median effective dose and instructions for their use" Biometrics, 8:249). The dermal LD50 was calculated to be 1.41 mL/kg (1410 mg/kg bodyweight) with confidence limits of 870 - 2310 mg/kg bodyweight).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 410 mg/kg bw

Additional information

Toxicity Description: The substance has low oral toxicity (lethality) with a rat ALD value of 5000 mg/kg, a moderate dermal toxicity (lethality) with a rabbit LD50 value of 1410 mg/kg and a moderate inhalation toxicity (lethality) with a rat 4 -hour LC50 value of 700 mg/m³.

Justification for classification or non-classification

Based on a rabbit dermal LD50 value of 1410 mg/kg and a rat 4-hour inhalation LC50 value of 700 mg/m³, the substance is classified as Cat 4 (harmful in contact with skin) for acute dermal toxicity and Cat 3 (toxic if inhaled) for acute inhalation toxicity according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.