Registration Dossier

Skin Irritation:

The dermal irritation potential of N-Hydroxyphthalimide was estimated using OECD QSAR toolbox version 3.4 with logPow as the primary descriptor.

N-Hydroxyphthalimide was estimated to be irritating to the skin of albino rabbits.

Based on the estimated result, N-Hydroxyphthalimide can be considered to be irritating to skin and can be classified under the category “Category 2”as per CLP regulation.

Eye Irritation:

The ocular irritation potential of N-Hydroxyphthalimide was estimated using OECD QSAR toolbox version 3.4 with logPow as the primary descriptor.

N-Hydroxyphthalimide was estimated to be irritating to the eyes of New Zealand White rabbits.

Based on the estimated result, N-Hydroxyphthalimide can be considered to be irritating to eyes and can be classified under the category “Category 2”as per CLP regulation.

Reference

Endpoint:

skin irritation: in vivo

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 OECD QSAR toolbox v 3.4 and teh QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

Substance Name: N-Hydroxyphthalimide
Molecular formula: C8H5NO3
Molecular weight: 163.132 g/mol
Substance Type: Organic
Physical State: Solid

Species:

rabbit

Strain:

other: albino

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

undiluted 0.5g

Duration of treatment / exposure:

5 minutes

Observation period:

24,48,72 hours and 5 days

Number of animals:

6

Details on study design:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 5 days

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Irritation was observed

Estimation method: Takes mode value from the 5 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 "l") and "m") and("n" and(not "o")) ) and("p" and(not "q")) ) and("r" and(not "s")) ) and "t") and "u") and("v" and "w") )

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 saturated heterocycles AND Hydroxamic acid AND Imide AND N-Hydroxylamine derivatives by Organic Functional groups

Domain logical expression index: "c"

Referential boundary:The target chemical should be classified as Aryl AND Fused saturated heterocycles AND Hydroxamic acid 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 Hydroxy, nitrogen attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] AND Oxygen, nitrogen attach [-O-] AND Oxygen-subtution at N on [-CO-N-CO-] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary:The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative 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 Non-Metals by Groups of elements

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as Halogens by Groups of elements

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "j"

Referential boundary:The target chemical should be classified as Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "k"

Similarity boundary:Target: ON1C(=O)c2ccccc2C1=O
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Similarity boundary:Target: ON1C(=O)c2ccccc2C1=O
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Similarity boundary:Target: ON1C(=O)c2ccccc2C1=O
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Referential boundary:The target chemical should be classified as Stable form by Tautomers unstable

Domain logical expression index: "o"

Referential boundary:The target chemical should be classified as Imine form - 1,3-H shift OR Keto form (5-membered heteroarenes) - 1,3-H shift by Tautomers unstable

Domain logical expression index: "p"

Referential boundary:The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "q"

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> Ring opening acylation at a carbonyl OR Acylation >> Ring opening acylation at a carbonyl >> Anhydrides OR Pro-Michael Addition OR Pro-Michael Addition >> Pro-quinone and related OR Pro-Michael Addition >> Pro-quinone and related >> Phenylenediamines OR SN2 OR SN2 >> Ring opening SN2 OR SN2 >> Ring opening SN2 >> Epoxides by Respiratory sensitisation

Domain logical expression index: "r"

Referential boundary:The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "s"

Referential boundary:The target chemical should be classified as Substituted indoles by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "t"

Referential boundary:The target chemical should be classified as weeks - months by Biodeg ultimate (Biowin 3) ONLY

Domain logical expression index: "u"

Similarity boundary:Target: ON1C(=O)c2ccccc2C1=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "v"

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

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.96

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

N-Hydroxyphthalimide was estimated to be irritating to the skin of albino rabbits.

Executive summary:

The skin irritation potential of N-Hydroxyphthalimide was estimated using OECD QSAR toolbox version 3.4 with logPow as the primary descriptor.

N-Hydroxyphthalimide was estimated to be irritating to the skin of albino rabbits.

Based on the estimated result, N-Hydroxyphthalimide can be considered to be irritating to skin and can be classified under the category “Category 2”as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irritating)

Reference

Endpoint:

eye irritation: in vivo

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 OECD QSAR toolbox v3.4 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

Substance Name: N-Hydroxyphthalimide
Molecular formula: C8H5NO3
Molecular weight: 163.132 g/mol
Substance Type: Organic
Physical State: Solid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

100 mg

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

24,48 and 72 hours post instillation

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

3

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Irritation was observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain logical expression:Result: In Domain

(((((((("a" or "b" or "c" or "d" or "e") and("f" and(not "g")) ) and("h" and(not "i")) ) and "j") and "k") and "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 saturated heterocycles AND Hydroxamic acid AND Imide AND N-Hydroxylamine derivatives by Organic Functional groups

Domain logical expression index: "c"

Referential boundary:The target chemical should be classified as Aryl AND Fused saturated heterocycles AND Hydroxamic acid 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 Hydroxy, nitrogen attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] AND Oxygen, nitrogen attach [-O-] AND Oxygen-subtution at N on [-CO-N-CO-] by Organic functional groups (US EPA)

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Acyl halide OR Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Oxyphenistain (Hepatotoxicity) Alert OR Phthalate esters (Testicular toxicity) Rank C OR Tamoxifen (Hepatotoxicity) Alert OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary:The target chemical should be classified as Discrete chemical by Substance Type ONLY

Domain logical expression index: "l"

Referential boundary:The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (extension) ONLY

Domain logical expression index: "m"

Referential boundary:The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "n"

Referential boundary:The target chemical should be classified as > 100 days OR 1 to 10 days by Ultimate biodeg

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.852

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.28

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

N-Hydroxyphthalimide was estimated to be irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of N-Hydroxyphthalimide was estimated using OECD QSAR toolbox version 3.4 with logPow as the primary descriptor.

N-Hydroxyphthalimide was estimated to be irritating to the eyes of New Zealand White rabbits.

Based on the estimated result, N-Hydroxyphthalimide can be considered to be irritating to eyes and can be classified under the category “Category 2”as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irritating)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies, N-Hydroxyphthalimide has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across substances Potassium Phthalimide (CAS: 1074-82-4) and Phthalimide (CAS: 85-41-6). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated forN-Hydroxyphthalimide. N-Hydroxyphthalimidewas irritating to albino rabbit skin.

This result is supported by the experimental study conducted by Shayne C. Gad et.al (Journal of Toxicology: Cutaneous and Ocular Toxicology; Vol 5(3); Pg. no. 195 -214; 1986)structurally similar read across substance Potassium Phthalimide (CAS: 1074-82-4). 6 New Zealand White rabbits were used for the study.Animals were held for 14 days after arrival in the facility but prior to use in tests to ensure that they are healthy. Each animal served as its own control. Along with the test substance, a positive control substance (a known skin irritant, 1% sodium lauryl sulfate in water) and a negative control (plain gauze patch) are applied to the skin. A vehicle control patch was also used in case the chemical was moistened with a vehicle or suspended in vehicle. Four test sites, two on each side of the rabbit's back, were utilized for administration of test chemical and controls. A standard random pattern of administration ensured that the test substance and controls are applied to each position at least once in each test group. Each test or control substance is held in place with a 1x1 inch2 12-ply surgical gauze patch. The gauze patch is applied to the appropriate skin site and secured with 1-inch wide strips of Blenderm surgical tape, at the four edges, leaving the center of the gauze patch non-occluded. A 0.5-g portion of Potassium Phthalimide was weighed and placed on the gauze patch prior to application of the patch. The test substance and patch are then placed on the appropriate skin site and secured. The patch is subsequently moistened with 0.5 ml physiological saline.The study was on performed on both abraded and non-abraded animals. The negative control site is covered with an untreated 12-ply surgical gauze patch (1X1 inch2). The impervious material (Saran Wrap) aids in maintaining the position of the patches and retards evaporation of volatile test substances. A Saf-T-Shield collar is fitted and fastened around the neck of each test animal. The collar remains in place for a 24 hr exposure period. The collar prevents the animal from removing the wrapping and patches.After the exposure period, the test substance skin site is wiped with dry gauze to remove any test substance still remaining.Dermal irritation scores for erythema and edema formation was evaluated by the scale proposed by Draize.The primary dermal irritation index (PDII) was calculated by dividing the sum of total irritation scores by the number of observations, and classifying the test substance: 0.00 = non-irritant ,>0.00 - 0.50 = negligible irritant, >0.50 -2.00 = mild irritant, >2.00-5.00 = moderate irritant, >5.00-8.00 = severe (primary) irritant. Moderate irritation effect was observed when the rabbits were exposed to the test substance potassium phthalimide for 24 hrs. The Primary Dermal Irritation Index (PDII) for Potassium Phthalimide after 24 hours was 2.3

Based on the scores, Potassium phthalimide can be considered to be moderate skin irritant.

The above results are further supported by the study summarized in SIDS Initial Assessment Report for Phthalimide, 2005, for the structurally similar read across substance Phthalimide (CAS: 85-41-6). The compound was applied to the intact skin of 3 albino male and female rabbits as a 25% suspension in corn oil in 0.5 ml under a one inch by one inch patch, two single layers thick. The patches were held in place with a adhesive tape for 24 hours. Animals were observed for 7 days. The average maximum scores were 1.3 out of possible 8 in twenty-four hours. Hence the test chemical, Phthalimide (CAS No: 85-41-6) was considered as slightly irritating when applied as a 25% suspension in corn oil on albino rabbits.

Based on the available data for the target and read across substances and applying the weight of evidence approach, N-Hydroxyphthalimide can be considered to be not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Eye Irritation:

In different studies, N-Hydroxyphthalimide has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across substances Potassium Phthalimide (CAS: 1074-82-4) and 2 -[(trichloromethyl)sulfanyl]-1H-isoindole-1,3(2H)-dione [Folpet] (CAS: 133-07-3).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated forN-Hydroxyphthalimide. N-Hydroxyphthalimidewas irritating to New Zealand White rabbit eyes.

This result is supported by the experimental study conducted by Shayne C. Gad et.al (Journal of Toxicology: Cutaneous and Ocular Toxicology; Vol 5(3); Pg. no. 195 -214; 1986)structurally similar read across substance Potassium Phthalimide (CAS: 1074-82-4). 9 New Zealand white rabbits were used for the study. The contralateral eye of each test animal remains untreated and served as a control. 1 hr prior to instillation of the test substance, both eyes of each of at least 12 rabbits were examined for signs of irritation and corneal defects with a handheld slit lamp. Eyes are stained with a 2.0% sodium fluorescein and examined for confirming the absence of corneal lesions. At least 1 hr after fluorescein staining, the test substance is placed on one eye of each animal by gently pulling the lower lid away from the eyeball to form a cup (conjunctival cul-de-sac) into which the test substance is dropped. The upper and lower lids are then held gently together for 1 sec to prevent immediate loss of material. All corneas are examined with the aid of sodium fluorescein. If fluorescein staining appears, diagrams of the staining patterns of the corneal area involved are recorded. If signs of irritation persist at 7 days, reading are continued on day 10. If irritation is still persistent on day 10, then readings are taken on day 14. Most lesions, if reversible, will heal or clear within 21 days. Therefore, if ocular irritation is present at the 14-day reading, a 21-day reading is required to determine whether the ocular damage is reversible or non-reversible. The Federal Hazardous Substances Act (FHSA) Regulations was used to determine whether the test substance was an eye irritant or not. Interpretation of data was made using only the six test eyes not irrigated with water, and only data from days 1, 2, and 3.Grading and scoring of ocular irritation are performed in accordance with the standard Draize grades for ocular lesions.

When the test animals were exposed to the test substance potassium phthalimide, mean Draize score was determined to be 64.0. Based on the mean Draize scores, Potassium phthalimide can be considered to be moderately irritating to New Zealand White rabbit eyes.

The above results are further supported by the study summarized in Draft Assessment Report (DAR) – Folpet, Volume 3, Annex B B.6; Rapporteur Member State: Italy; April 2005, for the structurally similar read across substance, 2-[(trichloromethyl)sulfanyl]-1H-isoindole-1,3(2H)-dione [Folpet] (CAS: 133-07-3).

0.1 mL of the test substance (87 mg), was placed into the conjunctival sac of the right eye of 6 New Zealand White rabbits. The left eye remained untreated and served as control. An assessment of the initial pain reaction was made after treatment of the first animal before further animals were treated. Assessment of ocular damage/irritation was made according to Draize, approximately 1, 24, 48 and 72 hours following treatment. Additional observations were made 7 and 14 days after treatment to assess the reversibility of the ocular effects. Animals with zero scores on Day 7 were not assessed on Day 14. A modified version of the system described by Kay and Calandra was used to classify the ocular irritancy potential of the test substance. Incidences of vascularisation of the cornea were noted at 7 and 14 days in two animals and pale areas, petechial haemorrhage or haemorrhage of the nictitating membrane in three animals. Four animals appeared normal 7 or 14 days after treatment.

Folpet(CAS No: -133-07-3) technical produced a maximum group mean score of 27.3 and thus was considered as a MODERATE IRRITANT to the rabbit eye according to the modified Kay and Calandra classification system.

Hence, Folpet can be considered as moderately irritating to rabbit eyes.

Based on the available data for the target and read across substances and applying the weight of evidence approach, N-Hydroxyphthalimide can be considered to be not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Available studies for N-Hydroxyphthalimide indicate that it is irritating to eyes and skin.

Hence, N-hydroxyphthalimide can be classified under the category “Category 2” for skin and eyes.