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Description of key information

The test substance is a liquid with a low molecular weight, a moderate partition coefficient and a high-water solubility. It is expected that oral absorption will be favoured, and the absorption factor is set at 50%. Respiratory absorption is also expected considering the moderate log Kow indicating absorption directly across the respiratory track epithelium. Respiratory absorption will also be favoured by the low molecular weight of the test substance (< 500 g/mol). The respiratory absorption is set at 100%. The substance is found to be corrosive to the skin and the eyes. The corrosivity would favour dermal absorption which could be limited by the moderate partition coefficient indicating that the substance is only weakly lipophilic. Considering also the high water solubility, dermal uptake of the substance is expected to be moderate to high and the dermal absorption factor is set to 50%.

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

JEFFCAT DPA (CAS No 63469-23-8), referred to as “the test substance” hereafter, is a liquid with a high water solubility (miscible), a moderate log Kow (0.0931 at pH 11.5; at physiological pH the substance will be charged and hence more hydrophilic) and a moderate vapour pressure (64 Pa). Its pKa is 10.2. The substance is found to be corrosive to the skin and the eyes.


No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physico-chemical parameters and will allow a qualitative assessment of the toxicokinetic behaviour of the test substance.


 


Absorption


Oral/GI absorption


Following its high water solubility (miscible, 100 g/L as limit value), the test substance will readily dissolve into the gastrointestinal fluids and subsequently pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. Based on its relatively low molecular weight (218 g/mole) and the moderate log Kow (0.0931), absorption by passive diffusion will be the predominant mechanism for absorption in the GI tract.


 


The intestine is where absorption after oral administration is normally produced. Data on intestine pH for different species are rare and most stem from relatively old sources (ECHA guidance on IR&CSA, R.7c). Assuming a median intestinal pH value close to 7, the pKa of test substance suggests that this substance will be predominantly in its ionized form at physiological (GI relevant) pH. It is generally accepted that ionized substances do not readily diffuse across biological membranes.  Therefore, it could be concluded that the diffusion across biological membranes of the test substance will be hampered to a certain extent.


 


The substance is demonstrated to be corrosive (similar to OECD 404; Klimisch 2; Moreno, 1979) and therefore it could enhance penetration by local damage or necrosis of GI tissues.


 


In an acute oral toxicity (similar to OECD 401; Klimisch 2; Auletta, 1979), 5 male/female rats received the doses of 1000, 1400, 2000, 2800 and 4000 mg/kg. The derived LD50 was 2200 mg/kg bw. Mortality was observed at the rate of 1/10 animals at the 1000 mg/kg dose, 0/10 animals at 1400 mg/kg, 2/10 animals at 2000 mg/kg, 9/10 animals at 2800 mg/kg and, 10/10 animals at 4000 mg/kg.  Clinical signs included piloerection, decreased motor activity, red nasal and oral discharge and respiratory rate decrease.   


 


The tests substance has also been tested in a subacute oral toxicity study (OECD 422; Klimisch 2; Martell, 2013). The tested doses were 10, 100, and 500 mg/kg bw/d and   a NOAEL above 500 mg/kg bw/d was derived for male and maternal systemic toxicity as well as embryo-fetal toxicity. The test substance did not cause mortality. Clinical signs included respiratory sounds, dyspnea but these signs were attributed to the dosing procedure rather than test item related in absence of other systemic toxicity.  


 


A 90-day repeated dose toxicity study via oral gavage with the test substance is available (OECD 408; Klimisch 1; Malleshappa, 2021). Male and female Wistar rats were dosed by gavage with 0, 75, 150 or 450 mg/kg bw/d of the substance. No mortality was observed at any dose tested. Transient clinical sign of slight salivation was observed in all animals at 450 mg/kg bw/d soon after the dose administration. As there were no gross or microscopic changes in gastrointestinal tract, it was considered that the transient salivation was a reaction to the taste or irritation of the test article and is therefore of no toxicological significance. Microscopically, test item-related effects were observed at 450 mg/kg bw/d in both sexes; minimal to moderate degree vacuolation in the liver, increased incidences/severity of alveolar macrophages/chronic inflammation in lungs, vacuolated macrophages in red pulp of spleen, vacuolated macrophages in mandibular lymph nodes, decrease in total protein albumin and increased weight of the liver associated with vacuolation of centrilobular hepatocytes. In females, increase in the total leukocyte, neutrophil, lymphocyte and monocyte counts and an increase in total cholesterol, HDL cholesterol and triglyceride were also observed at 450 mg/kg bw/d. These findings were considered as the secondary changes associated with test item related inflammation in the lungs and correlated to the centrilobular vacuolation in the liver. Considering the changes observed in haematology, clinical chemistry, organ weights and microscopic changes at 450 mg/kg bw/d, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity is established to be 150 mg/kg bw/d.


 


In a Prenatal Developmental Toxicity Study in rats (OECD 414; Klimisch 1; Latha, 2021), Four groups of 24 female Wistar rats received the test substance by oral gavage, at dose-levels of 0, 125, 350 or 500 mg/kg/d (once daily from Day 6 until Day 19 post coitum). There were no mortalities, clinical signs or gross necropsy findings in dams at any of the doses tested. The maternal body weight, food consumption, and maternal and litter parameters were not affected at all the doses tested. External, visceral and skeletal examination of fetuses revealed no signs of teratogenicity.
Based on these findings, it is concluded that the No- Observed- Adverse- Effect- Level (NOAEL) for maternal toxicity, developmental toxicity and teratogenicity is considered to be 500 mg/kg bw/d (highest tested concentration without any adverse effects).


 


The results above indicate that absorption in the gastro-intestinal tract has occurred to some extent. Therefore, the oral absorption factor is set to 50%, also based on the anticipated hampered diffusion of the test substance as an ionized substance. The results of the toxicity studies do not provide reasons to deviate from this proposed value.


 


Respiratory absorption


Given the low vapour pressure of 64 Pa, the test substance is not a highly volatile substance and the availability for inhalation as a vapour is limited.


 


Once in the respiratory tract, the very hydrophilic substance may be retained within the mucus, and subsequently absorption may occur. Absorption directly across the respiratory tract epithelium by passive diffusion is favoured in view of the moderate log Kow value.


 


No acute or repeated dose toxicity study with the test substance was performed.


 


Based on the above considerations, the inhalation absorption factor is set to 100%, in a conservative approach, as there is limited information.


 


Dermal absorption


In view of its high water solubility (miscible) and moderate log Kow (0.0931), penetration into the lipid-rich stratum corneum and hence dermal absorption might be limited although its physical form (liquid) and relatively low molecular weight (218 g/mol) favours dermal absorption.


 


As the test substance is a corrosive substance, absorption/penetration will be enhanced.


 


In an acute dermal toxicity study (similar to OECD 402; Klimisch 2, Auletta 1979), the test substance was tested at the doses of 2000, 2800, 4000 and 5600 mg/kg applied on the skin of male/ female rabbits and the LD50 was 3300 mg/kg bw. Mortality was observed as 2/4 animals died at the 2800 mg/kg as well as at the 4000 mg/kg and 4/4 animals died at the 5600 mg/kg. Clinical signs included severe erythema accompanied by necrotic skin and moderate edema, clear nasal discharge, piloerection and motor activity decrease and a slight weight gain. Based on this data, it could be concluded that absorption occurred in some extent after acute dermal exposure.


 


Generally, default values of 10% and 100% are used for dermal absorption, based on molecular weight and log Kow value (ECHA guidance on IR&CSA, R.7c). The dermal absorption factor might therefore set to 100% (default), based on a molecular weight < 500 g/mol and a log Kow in the range of -1 to 4. However, it is also generally acknowledged that dermal absorption will not be higher compared to oral absorption; as a result, the dermal absorption factor for the test substance is set to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value.


 


Distribution


The high water solubility and low molecular weight predict that the substance will distribute widely through the body, due to diffusion through aqueous channels and pores.


The log Kow value was experimentally determined to be 0.0931 (OECD 107; Klimisch 1; Tarran, 2012). This study was performed on the non-ionised form of the substance, at pH 11.5 and hence the log Kow under environmental / physiological conditions is anticipated to be lower due to ionisation at pH values below the pKa of the substance (10.2). The substance is not likely to distribute into cells and hence the intracellular concentration is not expected to be higher than the extracellular concentration.


 


Accumulation


In view of the moderate log Kow and the high water solubility, test substance is not expected to accumulate in the body (lung, adipose tissue, stratum corneum).


 


Metabolism


Once absorbed, the test substance might undergo phase I biotransformation (including aliphatic and aromatic hydroxylation) followed by conjugation reactions (phase II) including glucuronidation and sulfation. Extensive hydroxylation (aliphatic carbons) and oxidative deamination (tertiary and secondary amines), followed by rapid sulfation or glucuronidation is expected.


 


Excretion


Given the high water solubility and relatively low molecular weight, the test substance and its metabolites will be mainly excreted via the urine.