Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Physical data as well as information from toxicological data indicate that Reaction mass of N-butylphthalimide and N-sec-butylphthalimide and N-propylphthalimide is absorbed and metabolized in the body. Furthermore, there are no indications for accumulation and the substance or its metabolites are likely eliminated from the body.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

A toxicokinetic assessment based on the physical properties (see ECHA Guidance on Information Requirements and Chemical Safety Assessment, R7c, version 3.0, June 2017) and toxicity data was performed. NOTE: this is mostly a generic assessment based on general statements in the guidance document that are derived from physical parameters.

The substance is an organic multi-constituent substance consisting of the three main constituents N butylphthalimide (BP, CAS No 1515-72-6, 56 % w/w), N sec butylphthalimide (SBP, CAS No 10108-61-9, 31 % w/w) and N propylphthalimide (PP, CAS No 5323-50-2, 14 % w/w).

Based on the low molecular weight (BP: 203 g/mol, SBP: 203 g/mol, PP: 189 g/mol), low water solubility (below 200 mg/l) and moderate log P values (2.5-3.1) of the three main constituents of the substance, absorption through aqueous pores or bulk passage with water through the epithelial barrier and absorption by passive diffusion is possible. The structure of all three constituents (BP, SBP and PP: 2 Carbonyl groups each) suggest that the compounds may be ionized which could hinder their ability to diffuse across biological membranes.

In a combined repeated dose toxicity study with the reproduction/ developmental toxicity screening the substance administered at 50, 100 or 300 mg/kg bw/day by oral gavage did not cause signs of systemic toxicity and did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) in parental male and female Hsd.Han: Wistar rats (NOAEL: 300 mg/kg bw/d). Further, the development of the F1 offspring was not impaired from birth to post-natal day 13 at any dose level after repeated oral administration of dams (NOAEL: 300 mg/kg bw/d).

Various oral acute toxicity test showed high lethality at the dose of =2000 mg/kg bw of the substance. Common clinical symptoms are adverse effects on the CNS (loss of righting reflex, coma, lethargy, ptosis), decreased respiratory rate as well as disturbances of autonomic functions across all doses (increasing with higher doses). All effects were reversible starting one to five days after treatment. These findings suggest that that some of the main constituents are absorbed.

Due to the low volatility (3 Pa) and high boiling point (303°C) the substance is not present in a gaseous state and absorption through inhalation is therefore unlikely. If the substance should still reach the respiratory tract, the moderate log P values of the main constituents suggest that they can cross the alveolar and capillary membranes by passive diffusion. There is no toxicity data available via inhalation but results from acute oral toxicity studies suggest that absorption is likely if the substance is inhaled.

Physical data like physical state (liquid) and medium molecular weight of the main constituents (range between 100 and 500 g/mol) indicate that absorption of the substance via the skin is possible. The water solubility (75-154 mg/l) of the main constituents suggest that dermal uptake of the substance is low to moderate. Although water solubility is low, the log P values between 1 and 4 favor dermal absorption (the values of the main constituents are even considered optimal for dermal absorption). The low vapor pressure (3 Pa at 20°C) of the substance indicates low evaporation resulting in a potentially higher dermal absorption. Animals in the skin irritation test showed no clinical signs regarding corrosion. Additional dermal toxicity data for the substance is currently not available (04/2018: study in progress).

Based on the relatively small size of the main constituents wide diffusive distribution in the body is expected. Based on the log P values (2.5-3.1) distribution into cells is expected. Acute oral toxicity studies have shown effects on the central nervous system (CNS) which indicates that the substances (and/or its metabolites) have distributed to the CNS.

None of the substances have a log P value greater than 4 and are therefore unlikely to accumulate in the lipid rich stratum corneum; substances with a log P value <3 are not likely to accumulate in the adipose tissue with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate dependent on the half-life of the substance.

There is no experimental data available on the metabolism of the multi-constituent substance.

Even though water solubility is low, the low molecular weight (<300) and possible ionization suggest that elimination via the urine is the most likely pathway of excretion. Based on the low molecular weight of the main constituent excretion via the bile is unlikely. Data from acute oral toxicity studies show that adverse effects are reversible starting one day after treatment which could be due to metabolism or fast excretion of the main constituents. Further information about potential excretion pathways of the substance is not available.