Hexane-1,3,6-tricarbonitrile

Endpoint summary

Description of key information

The substance Hexane-1,3,6-tricarbonitrile is an organic mono-constituent liquid with a purity of 95 - 100% (w/w), with a typical concentration of 99% (w/w).

A full ADME toxicokinetic study in the rat is not available. The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data. In vivo studies covering the oral route (acute oral toxicity study in rats, 28-day repeated dose toxicity study in rats and prenatal developmental toxicity study in rats) and the dermal route (acute oral toxicity study in rats and LLNA in rabbits) are available. Further details on endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, absorption of Hexane-1,3,6-tricarbonitrile is expected to be moderate via the oral route, low via the dermal and inhalation routes.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

1. Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of Hexane-1,3,6-tricarbonitrile in the body.

Absorption - oral

The molecular weight of Hexane-1,3,6-tricarbonitrile is 161.21 g/mol which is in the range for favourable oral absorption (<500 g/mol). The log Kow (-0.34 at 30.5°C) indicates it is poorly lipophilic and the water solubility (16.85 g/L at 20°C) indicates it is very soluble in water. Oral absorption is expected to occur via aqueous pores or across membranes with the bulk passage of water.

Absorption – dermal

Due to the high hydrophilicity (very water soluble, log Kow<0), uptake of of Hexane-1,3,6-tricarbonitrile via the dermal route is expected to be low.

Absorption – inhalation

Hexane-1,3,6-tricarbonitrile is a liquid substance with very low vapour pressure (0.002 kPa at 25°C), it is considered to be difficult to form steam or aerosol. Therefore absorption via inhalation is expected to be low.

Distribution/Metabolism/Excretion

Based on the molecular weight, water solubility and log Kow, Hexane-1,3,6-tricarbonitrile is likely to be widely distributed, but is unlikely to accumulate, due to poor lipophilicity. An OECD 111/GLP test was conducted and no significant hydrolysis was recorded (less than 10% concentration loss after 5 days at pH 4/7/9 @25°C). Hexane-1,3,6-tricarbonitrile is expected to be excreted in the urine.

2. Information from other studies in the dossier

Absorption – oral

n an acute oral toxicity test in female Wistar rats (OECD 423/GLP), the LD50 cut-off was 2000 mg/kg bw.

In a short-term repeated dose toxicity test (OECD 407/GLP), Hexane-1,3,6-tricarbonitrile (99%) in castor oil was administered to 4 tested groups (G1, G2, G3, G4; 5/sex/group) of Wistar rats by gavage. The dose of G1-G4 was 0, 25, 75, 150 mg/kg bw, respectively based on a 14-day DRF study. There was no test item related effect observed on mortality, clinical signs, body weight development, food consumption, functional observation battery, weekly detailed clinical observations, haematology and blood coagulation, clinical biochemistry, urinalysis and gross pathological findings in males and females. Statistically significant increase in the relative liver weights was observed in the HD females, which was associated with centrilobular hepatocellular hypertrophy. Centrilobular hepatocellular hypertrophy was also observed in males but without any changes in the liver weights. The kidney weights in both sexes were increased in a dose-dependent manner, although no statistically significant differences were observed. The increased kidney weights were likely to be associated with renal lesions recorded microscopically in males (i.e., male rat α2u-globulin nephropathy). Meanwhile, there was no treatment-related microscopic finding in females, and therefore, increased kidney weights in females were deemed to be of no toxicological significance.

The NOAEL was derived as 25 mg/kg bw/day for male and 125 mg/kg bw/day for female.

 

In an prenatal developmental toxicity study (OECD414/GLP), Hexane-1,3,6-tricarbonitrile (99%) in castor oil was administered to 4 tested groups (G1, G2, G3, G4; 46 males and 92 females in total) of Wistar rats by gavage. The dose of G1-G4 was 0, 50, 150, 250 mg/kg bw, respectively based on a 14-day DRF study. No test item-related adverse effect was observed for both maternal animals and fetuses.

The NOAEL was derived as 250 mg/kg bw/day for both gender.

 

Based on the physicochemical data and available in vivo toxicological data, the in vivo data indicates that moderate oral absorption may be expected. For chemical safety assessment purposes, an oral absorption rate of 50% is accepted.

 

Absorption – dermal

In an acute dermal toxicity test in female Wistar rats (OECD 402/GLP), The Acute Toxicity Estimate was determined to be 2000 < ATE ≤ 5000.

 

In a dermal sensitization study (OECD 442B/GLP) with 0, 25, 50 and 100% w/v Hexane-1,3,6-tricarbonitrile (99%) in dimethylformamide, young adult female CBA:J mice (4/group) were tested using the local lymph node assay. The positive control item, eugenol (dilute eugenol with acetone:olive oil(4:1, v/v) to the concentration 25 %), elicited the expected reaction pattern with a significant increase in the Stimulation Index (SI; 2.438). The value of the SI for groups treated at the 100%, 50% and 25% dose levels was 1.314, 1.174 and 1.128, respectively. Under the given test conditions, the test item, Hexane-1,3,6-tricarbonitrile, demonstrated a non-sensitising response in the LLNA assay.

As the substance is a dermal sensitiser, some dermal absorption occurs. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used.

 

In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

 

Absorption – inhalation

No inhalaton test is available. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted

Distribution/Metabolism/Excretion

Based on the information provided from the in vivo studies, there is limited distribution throughout the body, no target organ for toxicity and any water-soluble metabolites will be excreted in the urine.