2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine)

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

dermal absorption, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientifically acceptable calculation.

Qualifier:

no guideline followed

Principles of method if other than guideline:

QSAR calculation using SkinPerm v1.03

GLP compliance:

no

Remarks on result:

other: maximal absorption: 0.00257 mg/cm2/h

Description of key information

Based on physico-chemical properties, oral, inhalative and dermal absorption and distribution through-out the body is expected. These assumptions are supported by the results of single and repeated-dose toxicity studies in vivo were systemic effects are reported and target organs are identified. Bioaccumulation of the substance is not expected after continuous exposure. The test substance and/or its metabolites are expected to be predominantly excreted partially via urine but also via feces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) is a colorless/yellowish liquid with a molecular weight of 238.4 g/mol. The test item has a water solubility of 2.01 g/L at 20°C. The log P_ow is measured to be 2.3at 25°C (pH 10) and the vapor pressure is 0.0008 hPa at 20°C. The substance has a measured melting point of -7.1°C and a boiling point of 342°C at 1013 hPa.

 

Absorption

Oral

Absorption is a property of a substance to diffuse across biological membranes.Generally, oral absorption is favored for molecular weights below 500 g/mol and log P_ow values between -1 and 4. In the GI tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water. Based on the physico-chemical properties of the substance, it can be considered as likely that 2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) becomes bioavailable following the oral route. Since the substance has a pKa value of 10.3, it is deprotonated in acid environments like the stomach and diffusion of non-ionized substances across biological membranes is likely.

Oral uptake is confirmed by results of acute oral and repeated dose reproductive/developmental oral toxicity studies where clinical signs up to mortality were observed indicating systemic bioavailability. In a subchronic oral toxicity study with rats (OECD TG 408), the liver, white and red blood cells, kidneys, adrenal glands and heart were the target organs for toxic effect, showing also histopathological alterations. At the high dose level (60 mg/kg bw/day) body weight development/food consumption was clearly impaired and the general state of health was poor. Comparable effects were observed in the other repeated dose toxicity studies.

 

Inhalation

Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log P_owand water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50°C. Substances with log P_owvalues between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Moderate water solubility will enhance penetration to the lower respiratory tract. Based on the water solubility of 2.01 g/L and log P_owof 2.3 inhalative absorption can be assumed. On the other hand, due to the low vapor pressure of 0.0008 hPa only minor availability of vapors for inhalative absorption is anticipated.

However, in a well conducted 90-day inhalation study (OECD 413) performed in rats systemic effects have been observed after repeated inhalative exposure indicating that absorption occurred. Here, body weight development was impaired and target organ toxicity indicative of a mild anemic effect as well as effects on the liver and kidneys were seen at 48 mg/m³.

 

Dermal

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log P_owvalues between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is between 1-100 mg/L absorption is anticipated to be low to moderate.

In anacute dermal toxicity study, systemic effects were observed indicating dermal absorption. In addition, gross necropsy revealed effects on the heart (acutely dilated, right; acute congestion), lungs (notable congestion, in some animals edema) and liver (gray-white lobular periphery broader). Since the substance is classified for skin corrosion, severe damage to the skin will enhance the penetration of the substance. Nevertheless, internal exposure through dermal contact was calculated using IH SkinPerm model (AIHA) showing a maximal dermal absorption of 0.00257 mg/cm²/h indicating that dermal absorption is slow.

 

Distribution

In general, the smaller the molecule the wider is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, 2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) is expected to distribute throughout the body water. In repeated dose toxicity studies target tissues like liver, kidney and skeletal muscle have been identified which indicates distribution of the substance.

Due to its low log P_ow the test item is unlikely to bioaccumulate in tissue,and there are no other physicochemical properties indicating bioaccumulating properties. A passage over the placental barrier is not expected since in the developmental toxicity study no teratogen or specific embryotoxic effects were reported.

 

Metabolism

Metabolic transformation of 2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) may occur in the liver and may partially be catalysed by cytochrom P-450 enzymes. Phase I reactions may include oxidation or hydroxylation. Most probably metabolism will not render the parent compound more toxic. This assumption is supported by results obtained in the Ames test. The assay shows that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. This clearly indicates that the formation of reactive metabolites is rather unlikely. Phase II reactions may include sulfatation and glucuronidation as well as other conjugation reactions. It is likely that metabolism of the substance will render the molecule more polar, leading to faster excretion via urine and bile (following conjugation).

Excretion

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivates. Therefore, 2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine) is expected to be excreted partially via urine but also via feces.