Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: written assessment based on available information
Adequacy of study:
key study
Study period:
October 2019
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non-GLP assessment report
GLP compliance:
no

Summary and discussion of toxicokinetics - CAS 68412-48-6 (2-Propanone, reaction products with diphenylamine)

This assessment of the toxicokinetic properties of 2-Propanone, reaction products with diphenylamine is based on the results obtained with the test substance for the toxicological end‑points listed below and with reference to relevant physico-chemical data:

 ·      acute oral toxicity

·       acute dermal toxicity

·       skin irritation

·       skin sensitisation

·       screening for reproductive / developmental toxicity

·       bacterial reverse mutation test

·       in vitro chromosome aberration test

·       in vitro mammalian gene mutation test

2-Propanone, reaction products with diphenylamine is a UVCB substance. The substance is a very complex mixture of multiple constituents to which the molecular weight averages 1830 g/mol. The substance has an estimated water solubility of less than 5.76 mg/L at 20°C and a log Kow which ranges between 3.17 to > 6.5. The MMAD for the substance is 25.629 μm.

The acute oral toxicity of 2-Propanone, reaction products with diphenylamine was evaluated and conducted in accordance with OECD Guideline 423. The female rats were administered with 2000 mg/kg bw of the test substance, no mortality, body weight and gross pathology did not reveal any abnormalities indicative of toxicity. The review of the clinical observations revealed that half of the animals treated were observed to have a hunched back, there were no other treatment related effects reported. The oral LD50 value was therefore determined to be > 2000 mg/kg bw.

A single dermal application of >2000 mg/kg body weight of the test substance onto female rats produced no deaths. There were no signs of local irritation, systemic clinical signs, changes in body weight or abnormalities observed at necropsy. The dermal LD50 value was therefore determined to be >2000 mg/kg body weight. 

The results on in vivo skin irritation studies and reports (Toxicological Investigations, 16 CFR 1500.41 and OECD 404) indicated that the substance was not classified as a skin irritant when applied to rabbit skin.

Skin sensitisation was assessed on the basis of OECD guideline 442D: in vitro skin sensitisation: ARE-Nrf2 Luciferase test method (KeratinoSens assay) the results of the study indicates that the substance is a skin sensitiser.

A 28 day repeated dose toxicity study by the oral route was conducted with the test substance at doses levels of 100, 300 and 1000 mg/kg bw. Under the conditions of the study no mortality associated with the test substance occurred. Transient piloerection was seen in the High dose females around the parturition. No changes at neurological assessment were seen at the end of the treatment period.

During the first 1-2 weeks of treatment, the Mid and High dose males had reduced body weight gain and the Low, Mid and High dose females had body weight loss. After that, the body weight gain in all male and female dose groups were near parallel to controls.

At clinical pathology, there were no test item-related findings.

At necropsy, no test item related macroscopic changes were seen. Slightly higher liver weights were recorded in the male High dose group. At histopathology, hepatocellular hypertrophy and vacuolation were seen in the male High dose group. These findings were considered, adaptive, non-adverse changes.

No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD14. There were no adverse effects on the F1 offspring viability, clinical signs or at observations following euthanasia.

No developmental or endocrine changes were seen in the pups at any of the dose levels (anogenital distance, thyroid gland weights, thyroid hormone level, etc.).

The NOAEL for Reproductive effects was considered to be 1000 mg/kg bw/day.

The NOAEL for Pup development and survival was considered to be 1000 mg/kg bw/day.

The NOAEL for Systemic toxicity for the adults was considered to be 1000 mg/kg bw/day.

In an Ames Test, the test substance was not mutagenic with or without metabolic activation. In vitro chromosome aberration test provided negative results for structural and numerical chromosome aberrations, with or without metabolic activation with the dose levels examined (12.5 to 125 µg/mL) and was determined not to be clastogenic on this basis. In an vitro Mammalian Cell Gene Mutation Test (Mouse Lymphoma Assay) the substance was determined to be not mutagenic in L5178Y TK +/- 3.7.2 C cells.

Toxicokinetic parameters

Absorption

Oral

The acute oral toxicity study conducted on 2-Propanone, reaction products with diphenylamine did not reveal any significant treatment related effects, with the only notable effects being hunched back of half of the dosed animals. A 28 day combined repeated dose and reproductive/developmental screening study also reported a distinct lack of substance related effects; slightly higher liver weights, hepatocellular hypertrophy and vacuolation were seen in males which were in high dose group however these effects were attributed to being an adaptive response and therefore considered non-adverse.

The substance is complex mixture of multiple constituents which are considered to show a range of water solubilities (<5.76 mg/L at 20°C), additionally the particle sizes appears to be relatively small (MMAD 25.629 μm) and as such certain components could be expected to readily dissolve into the gastrointestinal fluids. Absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substances partitions out of the gastrointestinal fluid. It also has a variable partition coefficient (log Kow between 3.17 - >6.5) which suggests that some of the constituents will favour passive diffusion (constituents between 3.17 - 4). Any lipophilic compound may be taken up by micellular solubilisation but this mechanism may be of particular importance for highly lipophilic constituents (log P >4).

As a worst case, for risk assessment purposes the oral absorption of the test substance is set at 100%.

Dermal

The results from dermal studies including the acute dermal toxicity study and in vivo skin irritation studies do not provide evidence to support significant skin absorption. The in vitro KeratinoSens assay however did indicate that the substance would expected to be a skin sensitiser.

The substance is a solid and of relatively small size (25.629 μm), but high molecular weight (1830 g/mol) the dry particulates would have to dissolve into the surface moisture of the skin before absorption may begin. With the substance being only anticipated to be partially soluble in water (< 5.76 mg/L at 20°C) there is a low to moderate chance of partitioning from the stratum corneum into the epidermis. Log P values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow.

As a worst case, for risk assessment purposes the dermal absorption of the test substance is set at 100%.

Inhalation

Currently there are no studies associated with 2-Propanone, reaction products with diphenylamine that were conducted via the inhalatory route. The substance is not highly volatile, with a vapour pressure (4.23 x 10-02Pa at 20 °C) therefore a significant inhalation exposure to vapours is not expected. Moderate log Kow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. The substance as a variable log Kow value (3.17 - > 6.5) therefore certain constituents may be taken up by micellular solubilisation particularly those which may be poorly soluble in water. The size of the substance (25.629 μm) indicates that it is likely to reach the thoracic region.

As a worst case, for risk assessment purposes the inhalation absorption of the test substance is set at 100%.

Distribution

Acute oral toxicity study revealed that the substance had attributed to the hunched backs of half of the rats that were administered 2000 mg/kg bw. A 28 day repeated dose oral toxicity study revealed transient piloerection seen in the high dose females around the parturition, slightly higher liver weights were recorded in the male high dose group following necropsy however these effects were considered to be adaptive and non-adverse for males and comparable to control animals for females.

The substance is large, with a molecular weight of 1830 g/mol, therefore high distribution is not expected. However the substance shows a range of water solubilities, with some molecules being more soluble than others, therefore there is a potential for certain constituents only to diffuse across the aqueous channels and pores. The test substance is lipophilic therefore it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. Substances with a log Kow > 4 tend to have longer half-lives unless their large volume of distribution is counterbalanced by a high clearance. There is the potential for highly lipophilic substances to accumulate in individuals that are frequently exposed to that substance. Once exposure stops, the concentration within the body will decline at a rate determined by the half-life of the substance. Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissue with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous.

Highly lipophilic constituents of this substance (log P between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off.

Metabolism and excretion

There is no data available to evaluate the rate and extent of metabolism in organisms. Given the lack of effects noted in the in vivo studies and the lack of positive responses in in vitro germ cell mutagenicity studies, it is anticipated that the substance does not metabolise towards toxic or genotoxic metabolites.

Based on the available data, elimination of the test substance is likely to occur primarily via the urine unchanged or in the form of water soluble metabolites and via the faeces since substances with a molecular weight above 300 g/mol are generally preferentially excreted via the faeces in rodents.

Conclusion

In conclusion, it is likely that 2-Propanone, reaction products with diphenylamine would be significantly absorbed via the oral, dermal and inhalatory route and due to the lipophilic properties it is possible to distribute through the body, accumulating in individuals that are frequently exposed to the substance. However once exposure stops, the concentration within the body will decline at the half-life rate of the substance. The substance is not anticipated to metabolise towards toxic/genotoxic metabolites and likely to be excreted via the faeces.

 

Conclusions:
In conclusion, it is likely that 2-Propanone, reaction products with diphenylamine would be significantly absorbed via the oral, dermal and inhaltory route and due to the lipophilic properties it is possible to distribute through the body, accumulating in individuals that are frequently exposed to the substance. However once exposure stops, the concentration within the body will decline at the half-life rate of the substance. The substance is not anticipated to metabolise towards toxic/genotoxic metabolites and likely to be excreted via the faeces.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

In conclusion, it is possible that 2-Propanone, reaction products with diphenylamine would be significantly absorbed via the oral, dermal and inhaltory route and due to the lipophilic properties it is possible to distribute through the body, accumulating in individuals that are frequently exposed to the substance. However once exposure stops, the concentration within the body will decline at the half-life rate of the substance. The substance is not anticipated to metabolise towards toxic/genotoxic metabolites and likely to be excreted via the faeces.

As a worst case, for risk assessment purposes the oral absorption of the test substance is set at 100%.

As a worst case, for risk assessment purposes the dermal absorption of the test substance is set at 100%.

As a worst case, for risk assessment purposes the inhalation absorption of the test substance is set at 100%.