Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

2,2'-methylenebis(6-nonyl-p-cresol) is inferred to be poorly and slowly absorbed following oral exposure, highly absorbed following inhalation exposure (relative to the very low exposures anticipated by this route) and poorly absorbed following dermal exposure. In accordance with guidance, default values of 50% for oral absorption, 100% for inhalation, and 10% for dermal absorption, may be assumed. Absorbed 2,2'-methylenebis(6-nonyl-p-cresol) will be distributed within the body, and metabolised to some extent by the liver and possibly by the GI tract. It is not expected that 2,2'-methylenebis(6-nonyl-p-cresol) will bioaccumulate. The urine and bile are likely to be important routes of excretion. 

Key value for chemical safety assessment

Additional information

In accordance with point 8.8.1 of column 1 (Standard Information Required), Annex VIII of REACH (Regulation EC No. 1907/2006), assessment of the toxicokinetic behaviour of the substance is performed to the extent that can be derived from the relevant available information. The following toxicokinetic assessment was performed based on the available physical-chemical data and toxicological information available. Further testing for the assessment of toxicokinetic behaviour is omitted on this basis.

No toxicokinetic studies are available that directly address absorption, distribution, metabolism, or excretion of 2,2'-methylenebis(6-nonyl-p-cresol) following oral administration; however information is available from existing toxicology studies and the physical chemical properties to infer potential toxicokinetic properties.

The test material is in broad terms a dimer with purity approximately 60%; containing approximately 25% dimeric isomers for which toxicokinetics are probably similar to the test material, and approximately 10% monomeric isomers which might be better absorbed.

Physical-chemical properties of 2,2'-methylenebis(6-nonyl-p-cresol)

Molecular weight

480.7

Relative Density

0.982 at 20°C

Vapour Pressure

<0.0015 Pa at 20°C

Water Solubility (mg/L)

<0.16 mg/Lat 20 °C

Partition Coefficient

Log KOW >6.5

 

Select toxicological end points for 2,2'-methylenebis(6-nonyl-p-cresol)

Acute oral toxicity (rat)

LD50> 2000 mg/kg bw (symptoms profile available)

Acute dermal toxicity

LD50>16 mL/kg (no systemic effect)

In vivoSkin Irritation

Non irritant

In vivoEye Irritation

Non irritant

Skin Sensitization (Draize method)

Not a skin sensitizer

Repeat Dose (13 week, diet)

NOAEL 158 mg/kg bw/day (target organs identified)

Aquatic bioaccumulation factor

230-2500

 

Significance of routes of exposure

 

Oral route: this is not considered a relevant route for occupational exposure or for the general population. Slight exposure may occur via accidental hand-to-mouth contact, but this is not expected to contribute significantly to exposure.

 

Inhalation route: the substance has a low vapour pressure and a high boiling point and therefore is unlikely to volatilize or be released into the air. Under conditions of normal handling and use, the substance will not be aerosolized. Water solubility is low and this can enhance penetration to the inner respiratory tract.

 

Dermal route: this is considered to be the principal route for occupational exposure, and also for exposure of the general population.

 

Absorption

The main physical chemical properties that influence absorption are molecular weight, and water and lipid solubility. The substance has a molecular weight of 480.7, a water solubility <0.16 mg/L, and Log KOW of >6.5. These properties suggest 2,2'-methylenebis(6-nonyl-p-cresol) would be poorly absorbed by the gastro-intestinal tract following oral exposure. However, symptoms and pathology seen in toxicity studies confirm a measure of absorption does occur. There is a possibility of toxicity being associated with the lower molecular weight impurities; also of some limited gastrointestinal conversion (e.g. by lipase, or gut microflora) to enhance absorption. The acute oral toxicity study showed low inherent systemic toxicity, but with symptoms first seen by 4 hours post-dose and peaking at 1-2 days. The profile is consistent with slow absorption, although the possibility of symptoms being attributable to local GI discomfort (hyperaemia of the GI tract was seen in decedents) cannot be dismissed. A default value for oral absorption of 50% is assumed.

 

Based on the very low vapour pressure (<0.0015 Pa at 25°C) 2,2'-methylenebis(6-nonyl-p-cresol) is unlikely to volatilize or be released into the air. It is likely that any (very low) inhalation exposure will be absorbed if inhaled, based on available toxicity data showing a degree of bioavailability after oral exposure. As a worst-case assumption, inhalation absorption of 100% is appropriate for risk assessment purposes.

 

Dermal absorption is likely to be extremely limited, because 2,2'-methylenebis(6-nonyl-p-cresol) is of high molecular weight and extreme lipophilicity. No systemic toxicity was seen after dermal exposure in an appropriate dermal toxicity study. In the absence of specific data on dermal absorption, a dermal absorption value of no more than 10% is appropriate.

  

Distribution

Any 2,2'-methylenebis(6-nonyl-p-cresol) that is absorbed will be distributed via the blood to the liver and other organs and tissues. Liver and kidney are identified as target organs from toxicity studies. The test material is highly lipophilic and might be expected to distribute into fat.

 

Metabolism and potential for bioaccumulation

The test material is highly lipophilic and might be expected to distribute into fat. However, the (aquatic) bioconcentration factor is calculated to be moderate; some measure of mammalian metabolism may be anticipated; and no specific toxicity to organs of high lipid content is seen, so marked bioaccumulation is not expected.Based on its chemical structure, 2,2'-methylenebis(6-nonyl-p-cresol) may be metabolized at least via oxidative metabolism. High molecular weight implies biliary elimination, and high lipophilicity would suggest hepatic conjugation to be important. Metabolism may be incomplete.

 

Excretion

No evidence of substance retention or bioaccumulation is seen in toxicity studies, although absorption and therefore elimination will be slow. Symptoms following acute oral administration persisted for several days. However, since target organ toxicity was identified in subchronic studies it cannot be determined if the prolonged symptoms were due to pharmacokinetic persistence or to residual target organ damage; pharmacokinetic persistence for the observed duration is improbable. High molecular weight (above 400) suggests that biliary excretion will be important; nephrotoxicity indicates urinary elimination is also important. The urinary route would be more relevant for lower molecular weight impurities and metabolites.

 

In summary

 

2,2'-methylenebis(6-nonyl-p-cresol) is inferred to be poorly and slowly absorbed following oral exposure, highly absorbed following inhalation exposure (relative to the very low exposures anticipated by this route) and poorly absorbed following dermal exposure. In accordance with guidance, default values of 50% for oral absorption, 100% for inhalation, and 10% for dermal absorption, may be assumed. Absorbed 2,2'-methylenebis(6-nonyl-p-cresol) will be distributed within the body, and metabolised to some extent by the liver and possibly by the GI tract. It is not expected that 2,2'-methylenebis(6-nonyl-p-cresol) will bioaccumulate. The urine and bile are likely to be important routes of excretion.