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Commission Regulation No 844/2012

Status: Active Update: 14-12-2012 https://echa.europa.eu/registration-dossier/-/registered-dossier/1194

1H-Isoindole-1,3(2H)-dione, 3a,4,7,7a-tetrahydro-: Does not have an individual approval but may be used under an appropriate group standard

Emergency treatment: Phthalimide fungicides; Captan and Captafol are of low order of acute toxicity. Both are skin sensitizers that in animal experiments can cause cancer and liver, reproductive, and developmental toxicity. [HSDB] Mildly irritating to rabbit skin; Teratogenic effects observed in hamsters dosed by gavage at 1,000 mg/kg; No teratogenic effects noted in rabbits but minor increase in resorptions observed; No evidence of mutagenicity; [IUCLID] See Captan and Captafol.

Euopean Chemicals Bureau; IUCLID Dataset for 1,2,3,6-Tetrahydrophthalimide (85-40-5) contains information on use, toxicology, and environmental effects of this chemical as supplied to the European Union by industry.[Available from, as of March 3, 2011: http://ecb.jrc.ec.europa.eu/iuclid-datasheet/85405.pdf]

Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. Effective date 9/29/2006; Reporting date: 11/28/2006.

Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1H-Isoindole-1,3(2H)-dione, 3a,4,7,7a-tetrahydro- is included on this list. Effective date: 9/29/2006; Sunset date: 11/28/2006.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal and plant life; and conformance with environmental and public health regulations.

Tolerances are established for the combined residues of the fungicide, captan (N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide) and its metabolite 1,2,3,6-tetrahydrophthalimide (THPI), measured at THPI, in or on the following commodities: [Table#4995]

1,2,3,6-Tetrahydrophthalimide is a urinary metabolite of captan, a foliar fungicide used on many crops in California, particularly strawberries and grapes. The compound was detected in personal air samples of pesticide applicators at a range of 0.9 to 15.5 ug/cu m. Urine levels ranged from 0.024 to 0.059 ppm(1).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 20(SRC), determined from a structure estimation method(2), indicates that 1,2,3,6-tetrahydrophthalimide is expected to have very high mobility in soil(SRC). Volatilization of 1,2,3,6-tetrahydrophthalimide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.0X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(3). 1,2,3,6-Tetrahydrophthalimide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Utilizing the Japanese MITI test, 0% of the Theoretical BOD was reached in 4 weeks(5) indicates that biodegradation is not a rapid environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 20(SRC), determined from a structure estimation method(2), indicates that 1,2,3,6-tetrahydrophthalimide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.0X10-8 atm-cu m/mole((SRC), developed using a fragment constant estimation method(4). Bioconcentration in aquatic organisms is low(5). Utilizing the Japanese MITI test, 0% of the Theoretical BOD was reached in 4 weeks(5) indicates that biodegradation is not a rapid environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2,3,6-tetrahydrophthalimide, which has an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C((SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases. Vapor-phase 1,2,3,6-tetrahydrophthalimide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.6 hrs(SRC), calculated from its rate constant of 7.8X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). 1,2,3,6-Tetrahydrophthalimide does not contain chromophores that absorb at wavelengths >290 nm(4), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Reproductive Toxin - A chemical that is toxic to the reproductive system, including defects in the progeny and injury to male or female reproductive function. Reproductive toxicity includes developmental effects. See Guidelines for Reproductive Toxicity Risk Assessment.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 1,2,3,6-tetrahydrophthalimide can be estimated to be 20(SRC). According to a classification scheme(2), this estimated Koc value suggests that 1,2,3,6-tetrahydrophthalimide is expected to have very high mobility in soil.

/BIOMONITORING/ The contribution of dermal and respiratory exposure to captan (133062) to levels of tetrahydrophthalimide (85405) (THPI) in urine was studied among 26 fruit growers applying captan in orchards in the Netherlands. The workers used an air blast sprayer pulled by a tractor to treat an orchard. Personal air samples were used to assess pesticide particle concentrations. Skin pads were used to measure dermal exposure. Skin pads and air samples were analyzed for captan levels using high performance liquid chromatography. Urine samples were collected and analyzed for THPI by gas chromatography with chemical ionization and mass spectrometry. Estimates of total dermal exposure were based on extrapolation to total body exposures from skin pad exposures and compared to estimates based on exposure of skin pads on specific body areas. The highest dermal exposure was on the forehead, followed by the wrists and neck. Average air spraying duration was 211 minutes with a standard deviation of 84 minutes. The amount of captan handled per spraying varied from 1.7 to 22.5 kilograms. Respiratory exposure to captan was not found to contribute to urinary THPI; however, a clear association with urinary THPI was found from the estimations of exposure on the skin pads from the ankles and neck. Other factors such as use of a cabin on the tractor, wearing of gloves during mixing and loading, and the use of rubber boots also correlated very well in THPI in the urine. The authors conclude that dermal exposure data can be better linked to biological monitoring based on empirical findings as gathered in a pilot study rather than on estimates of total skin dose.

/BIOMONITORING/ ... Occupational exposure to captan resulted in detectable excretion of both 2-thiothiazolidine-4-carboxylic-acid (TTCA) and tetrahydrophthalimide (THPI) in urine. The authors conclude that THPI and TTCA have promise as parameters for the biological monitoring of occupational exposure to captan.

1,2,3,6-Tetrahydrophthalimide's production and use as a chemical intermediate(1) may result in its release to the environment through various waste streams; it's formation as a metabolite of the fungicide Captan(2) will result in 1,2,3,6-tetrahydrophthalimide's direct release to the environment(SRC).

AEROBIC: 1,2,3,6-Tetrahydrophthalimide, present at 100 mg/L, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/L in the Japanese MITI test(1). A 0%COD removal was reported when the compound was incubated in a batch system using an adapted activated sludge inoculum obtained from a sewage treatment plant and a chemical test concentration of up to 200 mg/L COD(2).

The Henry's Law constant for 1,2,3,6-tetrahydrophthalimide is estimated as 3.0X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates from water and moist soil surfaces(2). 1,2,3,6-Tetrahydrophthalimide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Acute Exposure/ Tetrahydrophthalimide (THPI) did not produce skin or eye irritation or skin sensitization in laboratory animals. Its acute oral toxicity in rodents was moderate to low.

/LABORATORY ANIMALS: Acute Exposure/ Slightly irritating to rabbit skin in standard assay.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Repeated inhalation by rats and mice produced effects including changes in the liver, spleen, lungs, blood composition and nervous system activity, and increased kidney and spleen weights.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ,2,3,6-tetrahydrophthalimide given orally or by injection to hamsters, mice and rabbits was foetotoxic and induced malformations at doses that caused no overt maternal toxicity.

For more Non-Human Toxicity Excerpts (Complete) data for 1,2,3,6-TETRAHYDROPHTHALIMIDE (11 total), please visit the HSDB record page.

The rate constant for the vapor-phase reaction of 1,2,3,6-tetrahydrophthalimide with photochemically-produced hydroxyl radicals has been estimated as 7.8X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of 1,2,3,6-tetrahydrophthalimide with ozone has been estimated as 7.0X10-16 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.3 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). 1,2,3,6-Tetrahydrophthalimide is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(3). 1,2,3,6-Tetrahydrophthalimide does not contain chromophores that absorb at wavelengths >290 nm(3), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Commission Regulation No 844/2012

Status: Active Update: 14-12-2012 https://echa.europa.eu/registration-dossier/-/registered-dossier/1194

1H-Isoindole-1,3(2H)-dione, 3a,4,7,7a-tetrahydro-: Does not have an individual approval but may be used under an appropriate group standard

Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. Effective date 9/29/2006; Reporting date: 11/28/2006.

Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1H-Isoindole-1,3(2H)-dione, 3a,4,7,7a-tetrahydro- is included on this list. Effective date: 9/29/2006; Sunset date: 11/28/2006.

... Five possible metabolites of captan: 1,2,3,6-tetrahydrophthalimide (THPI), cis-3-hydroxy-1,2,3,6-tetrahydrophthalimide (C3), cis-5hydroxy-1,2,3,6-tetrahydrophthalimide (C5), trans-3-hydroxy-1,2,3,6-tetrahrahydrophthalimide (T3), and trans-5-hydroxy-1,2,3,6-tetrahydrophthalimide (T5) ...

The use of tetrahydrophthalimide (85405) (THPI) and 2-thiothiazolidine-4-carboxylic-acid (TTCA) as potential parameters for the biological monitoring of occupational exposure to captan (133062). Male Wistar-rats were treated orally with 400, 814, and 1250 mg/kg and intraperitoneally with 20, 50 and 75mg/kg. Urine was collected for 48 hours in metabolism cages. Urine spot samples were collected from eight male fruit growers after spraying captan and from six nonexposed men. Capillary gas chromatography in combination with mass or sulfur selective detection was suitable for the qualitative and quantitative determination of THPI and TTCA in rat and human urine. The cumulative urinary excretion of THPI and TTCA accounted for about 5% of the delivered dose of captan. In nonexposed subjects, neither THPI nor TTCA could be detected using the currently available techniques. Occupational exposure to captan resulted in detectable excretion of both TTCA and THPI in urine. The authors conclude that THPI and TTCA have promise as parameters for the biological monitoring of occupational exposure to captan.

Feeding 54% LD50 dose of captan to rats produced 2 metabolites in the blood: tetrahydrophthalimide and tetrahydrophthalic acid.

Used as a chemical intermediate for the fungicides Captan and Captafol; [HSDB]

Captan is produced by reaction of 1,2,3,6-tetrahydrophthalimide with trichloromethanesulfenyl chloride (perchloromethylmercaptan) in the presence of sodium hydroxide.

CHEM INT FOR PESTICIDES (EG, CAPTAN AND CAPTAFOL)

(1977) No Data

(1979) No Data

(1977) No Data

(1979) No Data

(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS

(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS

1H-Isoindole-1,3(2H)-dione, 3a,4,7,7a-tetrahydro- is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438).

Production volumes for non-confidential chemicals reported under the Inventory Update Rule. [Table#4998]

Transformation products

Environmental transformation -> Pesticide transformation products (metabolite, successor)

1H-Isoindole-1,3(2H)-dione, 3a,4,7,7a-tetrahydro-: ACTIVE

A method for destruction of captan usuitable for use is discussed. Captan was decomposed to nontoxic tetrahydrophthalimide..