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Description of key information

Estimated LD50 was considered to be 2015.7 mg/kg bw when Wistar female rats were treated with 1h-isoindole-1,3 (2h)-dione, potassium salt orally by gavage.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
Data is from QSAR Toolbox 3.3.
Qualifier:
according to guideline
Guideline:
other: as below
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Test type:
other: no data
Limit test:
no
Specific details on test material used for the study:
- Name of the test material: Potassium phthalimide
- Molecular formula: C8H5NO2K
- Molecular Weight: 185.223 g/mole
- Substance type: Organic
- Smiles: c12c(C(=O)[NH-]C1=O)cccc2.[K+]
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
No data available
Doses:
2015.7 mg/kg bw
No. of animals per sex per dose:
3 animals
Control animals:
not specified
Details on study design:
No data available
Statistics:
No data available
Preliminary study:
No data available
Sex:
female
Dose descriptor:
LD50
Effect level:
2 015.7 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 50 % mortality observed
Mortality:
No data available
Clinical signs:
No data available
Body weight:
No data available
Gross pathology:
No data available
Other findings:
No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 8 nearest neighbours
Domain  logical expression:Result: In Domain

((((((("a" or "b" or "c" or "d" or "e" )  and "f" )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and "p" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Imides (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Imide by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Imide AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amide, aromatic attach [-C(=O)N] AND Aromatic Carbon [C] AND Carbonyl, olefinic attach [-C(=O)-] AND Carbonyl, one aromatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Anion AND Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Cation AND Heterocyclic compound by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr AND Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens Cl OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as High gene expression AND High gene expression >> N-Acylamides by Keratinocyte gene expression

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by Keratinocyte gene expression

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Polycyclic Aromatic Hydrocarbons by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.36

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.51

Interpretation of results:
other: Not Classified
Conclusions:
Estimated LD50 was considered to be 2015.7 mg/kg bw when Wistar female rats were treated with 1h-isoindole-1,3(2h)-dione, potassium salt orally by gavage.
Executive summary:

Based on the prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, acute oral toxicity was estimated in Wistar female rats were treated with 1h-isoindole-1,3(2h)-dione, potassium salt in the concentration of 2015.7 mg/kg bw orally by gavage. LD50 was estimated to be 2015.7 mg/kg bw for Wistar female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 015.7 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from QSAR Toolbox 3.3

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity:

In different studies, 1h-isoindole-1,3(2h)-dione, potassium salt (CAS no 1074-82-4) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo estimations in rodents, i.e. most commonly in mice and rats for 1h-isoindole-1,3(2h)-dione, potassium salt along with the study available on structurally similar read across substance phthalimide (CAS no 85-14-6). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

Based on the prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, acute oral toxicity was estimated in Wistar female rats were treated with 1h-isoindole-1,3(2h)-dione, potassium salt in the concentration of 2015.7 mg/kg bw orally by gavage. LD50 was estimated to be 2015.7 mg/kg bw for Wistar female rats.

In another prediction done by Danish EPA Model (2017), acute oral toxicity was estimated in mice by using N-potassium phthalimide orally. LD50 was estimated to be 2300 mg/kg bw for mice.

It is further supported experimental data given by J check (2017) on structurally similar read across phthalimide (CAS no 85-14-6), Crj:CD (SD) male and female rats were treated with phthalimide in the concentration of 2000 mg/kg bw in 1 % Carboxymethylcellulose sodium orally to gauge the acute oral toxicity in single dose study. No mortality was observed in treated male and female rats at 2000 mg/kg bw. Similarly, No effects on general appearance and Body weight of treated male and female rats were observed at 2000 mg/kg bw. In addition, No gross pathological and histopathological changes were observed in treated male and female rats at 2000 mg/kg bw Therefore, LD50 was considered to be > 2000 mg/kg bw when rat were treated phthalimide orally by gavage.

In addition to above experimental data study given by OECD SIDS (2005) for similar read across, male and female rats were treated with phthalimide in the concentration of 501, 794, 1260, 2000, 3160, 5000, 7940, 10000 mg/kg bw as a 20% suspension in corn oil orally by gavage. One female died at 10000 mg/kg bw and No mortality was observed in treated male and female rats at 501, 794, 1260, 2000, 3160, 5000, 7940 mg/kg bw. Reduced appetite, reduced activity, and slight lethargy for two to three days were observed in surviving animals. No gross pathological changes were observed in viscera of treated male and female rats. Therefore, LD50 was considered to be > 10000 mg/kg bw when rat were treated phthalimide orally.

Thus based on the above predictions and studies on 1h-isoindole-1,3(2h)-dione, potassium salt and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus comparing this value with the criteria of CLP regulation, 1h-isoindole-1,3(2h)-dione, potassium salt can be not classified for acute oral toxicity.

Justification for classification or non-classification

Based on the weight of evidence for target 1h-isoindole-1,3(2h)-dione, potassium salt (CAS no 1074-82-4) and its read across phthalimide (CAS no 85-14-6) is likely to be non hazardous by oral route of exposure.