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Diss Factsheets

Administrative data

Description of key information

Acute toxicity - oral route: LD50 > 2000 mg/kg bw and < 5000 mg/kg bw (OECD 401, not GLP compliant, K, rel.2 and Read-Across, OECD 401, not GLP compliant, S, rel.1)

Acute toxicity - inhalation route: Waiver and LD50 > 1.0 mg/L and < 5 mg/L (Read-Across, OECD 403, GLP compliant, S, rel.1)

Acute toxicity - dermal route: Waiver (corrosivity)

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
Study period:
From January, 31 1996 to March, 21 1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
Well described study performed according to a standardised method with acceptable deviations. Acceptablme for assessment.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
Only males were tested. No necropsies were performed.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
4-chloroformylphthalic anhydride
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Japan SLC, Inc
- Age at study initiation: 5-week old
- Weight at study initiation: 130.4 - 166.3g
- Fasting period before study: at least for 16 hours on the day before treatment
- Diet (e.g. ad libitum): cubed diet (the Funabashi farm, F-2)
- Water (e.g. ad libitum): tap water from town water
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Humidity (%): 45-65
- Air changes (per hr): 15 to 25 air change rates/hour
- Photoperiod (hrs dark / hrs light): lighting 12 hours/day (7:00 to 19:00)
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 25% w/v

DOSE VOLUME APPLIED: 5.4 - 20.0 ml/kg
Doses:
1347, 1751, 2276, 2959, 3846, and 5000mg/kg (common ratio 1.3)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily (each morning). During the first day after exposure, observations were made immediately after ingestion and then at 30 min, 1 hour, 2 hours and 4 hours after ingestion.
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
3 192 mg/kg bw
Based on:
test mat.
95% CL:
2 744 - 3 773
Mortality:
100% mortality at the highest tested dose of 5000 mg/kg during the first day after ingestion.
0% mortality observed at 2276 mg/kg.
All dead were observed during the first 3 days after ingestion.
Clinical signs:
other: At 1347 mg/kg during the first day of exposure salivation was observed on 5 animals , lacrimation was observed on 2 animals and loose stool was observed on 5 animals. At 1751 mg/kg, main clinical effects are diarrhea which was observed on 2 animals and lo
Interpretation of results:
Category 5 based on GHS criteria
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 of Trimetillic anhydride mono-chloride is estimated 3192 mg/kg bw in male rats. The LD50 is above 2000 mg/kg bw.
Executive summary:

In an acute oral toxicity study, performed according to a standard method equivalent to the OECD 401 Guideline, the substance 4 -chloroformylphthalic anhydride (TMAC) was administered by oral gavage, to male Sprague-Dawley rats at the doses of 1347, 1751, 2276, 2959, 3846, and 5000 mg/kg (5 animals/dose level). The test substance was diluted in olive oil. Clinical signs were checked for a period of up to 14 days.

Oral LD50in male rats = 3192 mg/kg bw

Clinical effects were observed at all tested doses. Animals died at concentrations from 2959 mg/kg to 5000 mg/kg.

Clinical effects observed were salivation, lacrimation, diarrhea or loose stool, hematuria, decrease in locomotor movement and decrease in respiration. All survival animals recovered from clinical signs after 5 days.

 

Based on the results of this study, 4 -chloroformylphthalic anhydride is not classified for acute oral toxicity according to the Regulation (EC) 1272/2008 (CLP) but is classified Acute Toxicity Oral Category 5 according to the UN GHS Regulation. This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
3 192 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:
supporting study
Justification for type of information:
The report for read-across justification is attached below.
Reason / purpose for cross-reference:
read-across source
Specific details on test material used for the study:
4-chloroformylphthalic anhydride
Preliminary study:
No preliminary results
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.55 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Nose-only exposure.
Mortality:
Three animals died during the course of the study. Mortalities were reported in one female and two males in the 2.33 mg/L bw dose group. At 2.33 mg/L there was 20% mortality in females and 40% mortality in males. Deaths occurred near the end of the exposure, approximately 1.5 hour and one day after exposure.
Clinical signs:
other: Animals showed signs of laboured breathing in four males, rales in five males and two females, redness around the nose/eyes in four males and two females, discoloration around the mouth in two males and one female, discoloration of the paws in three males
Body weight:
All surviving animals gained weight during the course of the study.
Gross pathology:
At necropsy, all the surviving rats displayed red foci on their lungs. Two males that died during the course of the study showed dark red coloured lungs. Other findings noted included fluid filled, enlarged or mottled appearance of the lungs.
Other findings:
No other findings reported.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The inhalation LD50 of trimellitic anhydride mono-chloride determined by applying the correcting factor based on the molecular weights is 2.55 mg/L i.e. 2550 mg/m^3 (the maximum achievable concentration). Based on the clinical and gross necropsy observations which suggest a severe pulmonary irritation, Trimellitic anhydride mono-chloride is classified Acute Toxicity Inhalation Category 4 according to the Regulation (EC) 1272/2008 (CLP) and the UN GHS Regulation.
Executive summary:

This acute inhalation toxicity study (limit test) was performed according to OECD Guideline 403 and in compliance with GLP. Sprague Dawley rats (5 animals/sex) were exposed by inhalation - nose only exposure to a single dose (2.33 mg/L) of the test substance (dust) for a single 4 h period. Clinical signs and body weights were recorded over a 14 day post exposure period. All animals that died during the course of the study and all surviving animals were necropsied.

Mortalities were reported in one female and two males. Clinical signs reported included laboured breathing, rales, redness around the nose/eyes, discoloration around the mouth and of thepaws, clear nasal discharge, wet inguinal fur and lacrimation. All surviving animals gained weight during the course of the study.At termination, all the surviving rats displayed red foci on their lungs. Two males that died during the course of the study showed dark red coloured lungs. Other findings noted included fluid filled, enlarged or mottled appearance lungs.

By analogy, under the test conditions, the inhalation LD50 of trimellitic anhydride mono-chloride determined by applying the correcting factor based on the molecular weights is 2.55 mg/L i.e. 2550 mg/m3 (the maximum achievable concentration). Based on the clinical and gross necropsy observations which suggest a severe pulmonary irritation, Trimellitic anhydride mono-chloride is classified Acute Toxicity Inhalation Category 4 according to the Regulation (EC) 1272/2008 (CLP) and the UN GHS Regulation.This study is considered as acceptable and satisfies the requirement for acute inhalation toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
2 550 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity

One key study and one supporting study were identified for the acute toxicity via oral route.

A key study (Environmental Biological Life Science Research Center, 1996, Rel.2) was performed to assess the acute toxicity of the test substance after oral administration. This standard acute oral toxicity study was performed according to a standard method equivalent to the OECD 401 Guideline (not GLP compliant) in which the substance 4 -chloroformylphthalic anhydride was administered by oral gavage, to male Sprague-Dawley rats at the doses of 1347, 1751, 2276, 2959, 3846, and 5000 mg/kg (5 animals/dose level). The test substance was diluted in olive oil. Clinical signs were checked for a period of up to 14 days. Mortality was observed from 2959 to 5000 mg/kg bw and clinical effects were observed at all tested doses. Salivation, lacrimation, diarrhea or loose stool, hematuria, decrease in locomotor movement and decrease in respiration were observed. All survival animals recovered from clinical signs after 5 days.

Under the test conditions, the oral LD50 for Trimellitic anhydride mono-chloride is 3192 mg/kg bw in rats.

Based on this information, it can be concluded that TMAC is of very low toxicity after oral exposure.

Although TMAC is classified for corrosivity to the skin, it is likely that the corrosivity effects were reduced in this study due to the use of olive oil as vehicle.

A supporting study (ITT Research Institute, 1991, Rel.2) was performed with 1,3 -dioxo-2 -benzofuran-5-carboxylic acid (trimellitic anhydride), an analogous of the test item, to assess the acute toxicity of the test substance after oral administration. This standard acute oral toxicity study was performed according to a standard method equivalent to the OECD 401 Guideline and under GLP compliance. Trimellitic anhydride was administered to three groups of 5 animals/sex at 2000 mg/kg bw, 3500 mg/kg bw and 5000 mg/kg bw. Clinical signs and body weights were recorded over a 14 day post exposure period.

All animals that died during the course of the study and all surviving animals were necropsied. Mortality incidences were 2 females in the 2000 mg/kg bw, 2 males and 5 females in the 3500 mg/kg bw and all animals in the 5000 mg/kg bw. The clinical signs reported included hypoactivity, ataxia, hypothermia, lacrimation, salivation, redness around the nose, discoloration around the mouth, wet/discoloured inguinal fur and discoloured paws. Treatment related lesions observed at necropsy included thinning of the stomach walls in the 2000 mg/kg bw, stomach ulcerations in two, five and nine rats that died in the 2000 mg/kg bw, 3500 mg/kg bw and 5000 mg/kg bw, respectively, and discoloured areas as a sign of haemorrhage and necrosis was also reported in the stomach of several animals in the 3500 and 5000 mg/kg bw dose levels. Based on these observations, it can be concluded that the mortality did not result in a systemic toxicity but rather to necrosis and stomach bleeding. Under the conditions of this test, the oral LD50 of trimellitic anhydride for combined sexes was 2730.0 mg/kg bw. The oral LD50 of trimellitic anhydride mono-chloride determined by applying the correcting factor based on the molecular weights is 2992.0 mg/kg bw.

These studies are considered as acceptable and satisfy the requirement for acute oral toxicity endpoint.

Acute inhalation toxicity

In accordance with point 8.5 of column 2 of REACH Annex VII, the acute study does not need to be conducted as the substance is classified as corrosive to the skin and an acute toxicity study via oral route is already available. In addition the exposure by inhalation is unlikely (hygroscopic solid).

However a study was identified (ITT Research Institute, 1992, SS, rel. 2). In this acute inhalation toxicity study (limit test) performed with 1,3 -dioxo-2 -benzofuran-5 -carboxylic acid (trimellitic anhydride), an analogous of the test item, according to OECD Guideline 403 and in compliance with GLP, a group Sprague Dawley rats (5 animals/sex) were exposed by inhalation - nose only exposure to a single dose (2.33 mg/L) of the test substance (dust, MMAD <5 μm with 90% or more ≤10 μm) for a single 4 h period.

Clinical signs and body weights were recorded over a 14 day post exposure period. All animals that died during the course of the study and all surviving animals were necropsied. Mortalities were reported in one female and two males. Clinical signs reported included laboured breathing, rales, redness around the nose/eyes, discoloration around the mouth and of the paws, clear nasal discharge, wet inguinal fur and lacrimation. All surviving animals gained weight during the course of the study.At termination, all the surviving rats displayed red foci on their lungs. Two males that died during the course of the study showed dark red coloured lungs. Other findings noted included fluid filled, enlarged or mottled appearance lungs.

Under the conditions of this test, the inhalation LC50 of trimellitic anhydride was greater than 2.33 mg/L, the maximum achievable concentration. However, the clinical and gross necropsy observations suggest that a single exposure to this concentration produced severe pulmonary irritation resulting in the death of 3/10 rats. Indeed, the formulation of the test substance, i.e. aerosol, and the particle size induced a deep penetration of the substance in animal lungs.

The inhalation LD50 of trimellitic anhydride mono-chloride determined by applying the molecular weight correcting factor is 2.55 mg/L i.e. 2550 mg/m3. This study is considered as acceptable and satisfies the requirement for acute inhalation toxicity endpoint.

Acute dermal toxicity

No data was available regarding the acute toxicity assessment via dermal route, therefore the substance should not be classified for the acute dermal toxicity due to the lack of data. However, the substance is corrosive that justify the absence of study. Indeed, in accordance with point 8.5 of column 2 of REACH Annex VII, the acute study does not need to be conducted as the substance is classified as corrosive to the skin and an acute toxicity study via oral and inhalation route are already available.

Justification for classification or non-classification

Harmonized classification:

4 -chloroformylphthalic anhydride does not have an harmonized classification according to the Regulation (EC) No. 1272/2008.

Self-classification:

Acute toxicity (oral):

Based on the information available, 4 -chloroformylphthalic anhydride is not classified for acute oral toxicity according to the Regulation (EC) 1272/2008 (CLP) as LD50 is > 2000 mg/kg bw. However, the LD50 is estimated between 2000 and 5000 mg/kg bw; the substance is therefore classified in Category 5, H303 according to GHS criteria.

Acute Toxicity (inhalation):

Based on the information available on TMA, 4 -chloroformylphthalic anhydride (TMAC) is classified Acute Toxicity Inhalation Category 4 according to the Regulation (EC) 1272/2008 (CLP).

Moreover, labelling as EUH071 "corrosive to respiratory tract" is added as the mechanism of action is expected to be corrosivity inducing mortality if inhalation of TMAC occurs.

In addition, based on the information provided under section 5.1.2. (Hydrolysis), contact of the substance with water may lead to release of hydrogen chloride (HCl). The gas is classified for Acute Toxicity by inhalation in cat.3 (H331), therefore the additional hazard statement "EUH029 — Contact with water liberates toxic gas." is proposed to be added (precautionary principle).

Acute toxicity (dermal):

No data was available regarding the acute toxicity assessment via dermal route, therefore the substance should not be classified for the acute dermal toxicity due to the lack of data (the substance is corrosive).

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and for a Category 2 classification (2000 mg/kg bw ≥C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects and respiratory tract irritation were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (inhalation - vapours) for a Category 1 classification (C≤ 10 mg/L) and for a Category 2 classification (20 mg/L ≥C > 10 mg/L). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects. STOT-SE3 is not relevant as EUH071 for labelling is already considered.

Specific target organ toxicity: single exposure (Dermal):

No information was available.