Amines, N-(3-aminopropyl)-N-(C16-18 and C18-unsatd. alkyl)trimethylenedi-

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 0.2 of IUCLID.

Preliminary studies:

No visible toxic effects were observed in the 4 rats that received a single oral dose of 30 mg/kg of non-radiolabelled P4198. The high dose was confirmed as 30 mg/kg.

Type:

absorption

Results:

The gastrointestinal absorption is considered to be 2.5% based on a retained dose.

Details on absorption:

Low level doses:
After single low level doses of 14C-P4198 to three groups of six rats (3 male, 3 female), peak of mean concentrations of radioactivity in plasma were below the limit of reliable measurement. Peak plasma concentration occurred at 4 hours after administration of the test substance.
High level doses:
After single high level doses of 14C-P4198 to three groups of six rats (3 male, 3 female), peak of mean concentrations of radioactivity in plasma of 0.12 (male) and 0.12 (female) µg equiv./ml occurred at 12 hours. Concentrations declined with an approximate half-life (measured between 12 and 48 hours) of 28.5 (male) and 46.3 (female) hours. The area under the concentration v time curve (AUCt) was 4.6 (male) and 5.1 (female) µg equiv./ml.hour.

Details on distribution in tissues:

At 3 hours after administration of the 14C-test compound at a nominal dose level of 3 mg/kg, high concentrations of radioactivity were detected in the oesophagus as well as in the contents of the caecum, small intestine and stomach. Intermediate concentrations of radioactivity were detected in the bladder. Lowest concentrations of radioactivity were detected in the adrenals, blood, kidney, large intestine contents, liver, lungs, pancreas, salivary gland and spleen.
At 6 hours after administration, high concentrations of radioactivity were detected in the oesophagus as well as in the contents of the caecum, small intestine and stomach. Intermediate concentrations of radioactivity were detected in the kidney, liver, lungs and spleen. Lowest levels of radioactivity were detected in the adrenals, brown fat, blood, bone marrow, exorbital lachrymal gland, myocardium, pancreas, preputial gland, pituitary gland, salivary gland, thymus and thyroid.
At 24 hours after administration, high concentrations of radioactivity were detected in the contents of the caecum, large intestine and stomach. Intermediate concentrations of radioactivity were detected in the adrenals, brown fat, Harderian gland, kidney, liver, lung, myocardium, preputial gland, oesophagus, small intestine contents, salivary gland and spleen. Lowest levels of radioactivity were in the blood, bone marrow, exorbital lachrymal gland, intra-orbital lachrymal gland, pancreas, pituitary, thymus and thyroid.
At 48 hours after administration, high levels of radioactivity were detected in the contents of the caecum, the large intestine and the large intestine mucosa. Intermediate concentrations of radioactivity were detected in the kidney, lung, small intestine contents, small intestine mucosa, spleen, stomach contents and stomach mucosa. Lowest concentrations of radioactivity were detectd in the adrenals, blood, bone marrow, exorbital lachrymal gland, Harderian gland, intra-orbital lachrymal gland, liver, myocardium, pancreas, preputial gland, pituitary gland, salivary gland and thymus.
At 120 hours after administration, intermediate concentrations of radioactivity were detected in the kidney, lung, pancreas, salivary gland, smal intestine mucosa, spleen and stomach mucosa. Lowest levels of radioactivity were detected in the adrenals, blood, bone marrow, exorbital lachrymal gland, Harderian gland, liver, intra-orbital lachrymal gland, muscle, myocardium, pituitary gland, thymus, testes and thyroid.

Details on excretion:

Low level dose:
After a single low level oral dose of 14C-P4198 to rats (4 male, 4 female), means of 0.2% (male) and 0.2% (female) were excreted in the urine during 0 – 120 hours. Most of this radioactivity was excreted in the 0 – 48 hour urine (0.1% for both male and female). During the 5 days after dosing 97% (male) and 96% (female) was excreted in the faeces with most of this in the 0 – 72 hour samples (97% male, 95% female). Radioactivity in expired air traps was measured over 48 hours and accounted for 0.1% (male) and 0.2% (female) dose. After sacrifice at 120 hours radioactivity in the gastrointestinal tract accounted for 0.5% (male) and 0.4% (female) dose whilst radioactivity in the remaining carcass accounted for 1.0% (male) and 1.5% (female) dose. Thus, means of 99% (male) and 98% (female) were recovered after 5 days.
High level dose:
After a single high level oral dose of 14C-P4198 to rats (4 male, 4 female), means of 0.2% (male) and 0.2% (female) were excreted in the urine during 0 – 120 hours. Most of this radioactivity was excreted in the 0 – 48 hour urine (0.2% for male and 0.1% for female). During the 5 days after dosing 95% (male) and 90% (female dose) was excreted in the faeces with most of this in the 0 – 72 hour samples (95% male, 89% female). Radioactivity in expired air traps was measured over 48 hours and accounted for 0.4% (male) and 0.4% (female) dose. After sacrifice at 120 hours radioactivity in the gastrointestinal tract accounted for 1.2% (male) and 1.3% (female) dose whilst radioactivity in the remaining carcass accounted for 3.0% (male) and 2.6% (female) dose. Thus, means of 100% (male) and 94% (female) were recovered after 5 days.

Metabolites identified:

yes

Details on metabolites:

Metabolites were quantified using TLC. Samples of faecal extracts were analysed directly. Urine was not analysed as the total radioactivity excreted in the urine was < 0.3%.
Faecal extracts:
In the 0 – 48 hour faecal extracts of rats after administration of 14C-P4198 there was one major radioactive component that accounted for 7 – 13% dose (39 – 51% sample radioactivity). This component co-chromatographed with authentic P4198 in two TLC systems. Six further minor components were detected in faecal extracts accounting for 1 –3% dose after both low and high level doses. One of these components was shown to co-chromatograph with 1-dodecylamine using TLC. The nature of the other components was not investigated further due to the low levels of radioactivity involved (<3% dose).
A large proportion of the dose (66 – 72%) remained unextracted after both low and high level doses. Further extraction with 1M HCl and 2M NaOH extracted a further 17 – 20% (low level) and 20 –25% (high level) dose. Attempts to analyses these extracts (after neutralisation) were unsuccessful.

After single oral doses of 14C-P4 198 approximately 0.2% of the dose was excreted in the urine. Approximately 90-97%
dose was excreted in faeces during 5 days. At sacrifice approximately 1 -3% dose was retained in the carcass and 0.4
- 1.3 % of the dose was recovered in the gastrointestinal tract. Radioactivity in expired air traps accounted for 
0.4% dose. There was no noticeable difference in excretion after the different dosing regimens or between male and
female rats. This indicated that an average of 2.5% of the initial dose was not excreted.

Concentrations in plasma were consistent with low absorption of P4198 from the gastrointestinal tract. After low level
doses, concentrations were generally below the limit of reliable measurement and appeared to peak 4 hours after dose
administration. After high level doses, concentrations of radioactivity in plasma were again low with values generally
less than twice the limit of reliable measurement. The plasma concentrations of radioactivity indicated a fairly
rapid clearance of radioactivity with peak concentrations measured 12 hours after dosing. Qualitative analysis of the
tissue distribution of radioactivity by whole- body autoradiography indicated high levels of radioactivity in
the gastrointestinal tract and its contents. Levels of radioactivity observed in other tissues were consistent with
low absorption from the gastrointestinal tract.
The major component in faecal extracts was unchanged P4198, accounting for 7-13% dose. The assignment was confirmed by
co-chromatography using TLC. Six minor components were also observed in faecal extracts, each accounting for 1 -3 %
dose. One of these was shown to co-chromatograph with 1-dodecylamine.
As the liver showed constant less activity then the kidney in all  radiographs, significant entero-hepatic circulation can be excluded

Executive summary:

After single oral doses of 14C-P4 198 approximately 0.2% of the dose was excreted in the urine. Approximately 90-97% dose was excreted in faeces during 5 days. At sacrifice approximately 1 -3% dose was retained in the carcass and 0.4 - 1.3 % of the dose was recovered in the gastrointestinal tract. Radioactivity in expired air traps accounted for 0.4% dose. There was no noticeable difference in excretion after the different dosing regimens or between male and female rats. This indicated that an average of 2.5% of the initial dose was not excreted.

 

Concentrations in plasma were consistent with low absorption of P4198 from the gastrointestinal tract. After low level doses, concentrations were generally below the limit of reliable measurement and appeared to peak 4 hours after dose administration. After high level doses, concentrations of radioactivity in plasma were again low with values generally less than twice the limit of reliable measurement. The plasma concentrations of radioactivity indicated a fairly rapid clearance of radioactivity with peak concentrations measured 12 hours after dosing. Qualitative analysis of the tissue distribution of radioactivity by whole- body autoradiography indicated high levels of radioactivity in the gastrointestinal tract and its contents. Levels of radioactivity observed in other tissues were consistent with low absorption from the gastrointestinal tract.

The major component in faecal extracts was unchanged P4198, accounting for 7-13% dose. The assignment was confirmed by co-chromatography using TLC. Six minor components were also observed in faecal extracts, each accounting for 1 -3 % dose. One of these was shown to co-chromatograph with 1-dodecylamine.

As the liver showed constant less activity then the kidney in all radiographs, significant entero-hepatic circulation can be excluded.

For details and justification of read-across please refer to the read-across report attached to IUCLID section 0.

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 0.2 of IUCLID.

Absorption in different matrices:

- Skin wash: 58.78%
- Tissue swab: 14.54%
- Cell wash: 5.09%
- Receptor fluid, receptor chamber, donor chamber (in vitro test system): < 0.01% (< 0.01% receptor fluid and <0.01% receptor rinse).
- Stratum corneum: (i.e tape strips) 22.82%.
- Exposed skin: 0.91%
- Unexposed skin: < 0.01%

Total recovery:

102.14%
 

Dose:

6.4 µl

Parameter:

percentage

Absorption:

0.92 %

Remarks on result:

other: 24 hrs

Remarks:

The absorption and dermal delivery were <0.01% and 0.92% of the applied dose, respectively. The steady state flux calculated form the cumulative absorption in 0-24 hr corresponded to 0.3793 ng equiv./cm2/h (0.0004% absorption/hr).

Conclusions:

Percutaneous absorption = 0.92% after 24 hours.
Considering the steady state flux value of 0.0004% per hour it seems both unreasonable and scientifically unjustifiable to include the stratum corneum value of 23% in the dermal absorption.

Executive summary:

OECD Guideline for Testing of Chemicals Draft New Guideline 428 Skin Absorption: In Vitro Method (2002)

OECD Environmental Health and Safety Publications Series on Testing and Assessment No 28 Draft Guidance Document for the Conduct of skin absorption Studies (2002)

An automated flow-through diffusion cell apparatus (Scott/Dick University of Newcastle-upon-Tyne, UK) was used The flow-through cells were placed m a steel manifold heated via a circulating water bath to maintain the skin surface temperature at 32±1°C.  The cells were connected to multi-channel peristaltic pumps from their afferent ports, with the receptor fluid effluent dropping via fine bore tubing into scintillation vials on a fraction collector The receptor chamber volume was 0.25 ml The peristaltic pumps were adjusted to maintain a flow rate of 1.5 ml/h

 

Sections of split-thickness human skin membrane, ca 1.5 x 1.5 cm, were cut out, positioned on the receptor chamber of the diffusion cell, containing a magnetic stirring flea, and the donor chamber was tightened into place with screws The cells were then placed in the heated manifold and connected to the peristaltic pump The Variomag magnetic stirrer was switched on to mix the contents of the receptor chamber An equilibration period of ca 15 mm was allowed while receptor fluid was pumped through the receptor chambers at ca 1.5 ml/hr The effluent was then collected for ca 30 mm and retained as blank samples for use in the barrier integrity assessment The barrier integrity assessment was performed using tritiated water (250 μL, equivalent to ca 100,000 dpm) which was applied to the surface of each skin sample Penetration of tritiated water was assessed by collecting hourly fractions for 2 hours and then analysing the fractions by liquid scintillation counting Any human skin samples exhibiting a Permeability coefficient (Kr) greater than 2 5E-03 cm/hr were excluded from subsequent absorption measurements At the end of the 2 hour period, residual tritiated water was removed from the skin surface by rinsing with water (ca 2 ml) and drying with tissue swabs. An equilibration period of ca 120 mm was allowed prior to collection of the pre-dose sample, which was collected for ca 30 min.

 

Following the collection of the pre-dose sample, 6.4 μLof the test substance in water formulation was applied to the stratum corneum of each of 11 skin samples. The donor chambers were left open to the atmosphere

Receptor fluid was collected in hourly fractions from 0-6 hrs post dose and then in 2 hr fractions from 6-24 his post dose. All receptor fluid samples were mixed with ca 10 ml scintillant and then analysed by LSC At 24 his post dose each diffusion cell was disconnected from the receptor fluid pump lines. The underside of the skin was washed (receptor rinse) with receptor fluid (ca 1.5 ml), which was collected and analysed by LSC. The exposed skin surface was washed (skin wash) with ca 10 ml of a 2% v/v soap solution. The skin wash was collected and analysed by LSC. The donor and receptor chambers were dismantled, and the skin removed The chambers were washed with ethanol/water (cell wash). The solvent was mixed and left to extract the test item for ca 30 min. Aliquots of cell wash were taken for LSC analysis. The stratum corneum was removed with 24 successive strip tapes. The skin under the cell flange (unexposed skin) was cut off from the exposed skin with scissors The stratum corneum tape strip and skin samples were placed into separate Combustocones® for subsequent combustion/LSC analysis.

 

Percutaneous absorption = 0.92% after 24 hours. . Only less than 0.01% completely passed the skin and 0.92% of the applied dose passed the stratum corneum but remained fixed in the skin after 24 hours. This demonstrates a low dermal absorption as well as a low dermal mobility.

 

The mean mass balance was 102.14% of the applied dose. At 24 hrs post dose, 73.32% of the applied dose was washed off. A further 5.09% of the applied dose was contained in the cell wash. Radioactivity associated with the stratum corneum was 22.82%. The absorbed dose (0.0 1%) was made up from the receptor fluid (0.0 1%) and the receptor rinse (0.01%). Dermal delivery (0.92%) was made up from the absorbed dose, exposed skin (0.91%) and unexposed skin (0.01%).

It is remarked here that this dermal absorption study used a 1% concentration for 24 hours, well above the NOAEL level for irritation of 0.15% for 6 hours, and therefore likely overestimates dermal absorption for non-irritating concentrations.

For details and justification of read-across please refer to the read-across report attached to IUCLID section 0.

Additional information

Scope of the group of (branched) Polyamines:

Polyamines are substances that basically contain multiple (2 or more) 1,3-diamine propane (DP) groups linked to a fatty amine. These can be linearly linked based on two DP and fatty amine (triamine structure: alkyl dipropylenetriamine) or 3 DP with a fatty amine (tetramine structure: alkyl tripropylenetetramine), or in a branched form of two DP and a fatty amine.

 

Production starts from the fatty amine that is reacted with equimolar amounts acrylonitrile and subsequent hydrogenation resulting to a diamine. Subsequent additions with acrylonitrile result to linear triamine and then tetramines. However, reactions are not complete, and consequently tetramines also contain for a large part triamines and some diamines, and the triamines can contain a considerable amount of diamines and some tetramines. Consequently, there is some overlap between these substances. Further purification can be obtained by distillation.

Branched triamines (Y-triamine) are produced from the single reaction of primary fatty amine with 2 equivalents of acrylonitrile and subsequent hydrogenation.

 

The common structuresof the polyamines can be represented as:

  Linear triamine: R – NH – [CH₂]₃– NH - [CH₂]₃– NH₂

  Y-triamine : R – N [– [CH₂]₃– NH - [CH₂]₃– NH₂]₂and

  Linear tetramine: R – NH – [CH₂]₃– NH - [CH₂]₃– NH - [CH₂]₃– NH₂

respectively, where the R is an alkyl chain ranging from 10 (Dodecane) to 18 (Octadecane), depending on the source of the fatty amine. For alkyl chain lengths, largely the following ranges are implied in this group:

           Tallow  C16    25-40%

                       C18    50-75 %

           Oleyl    C18    > 70 %

           Coco   C12    45-62%,

                       C14    15-25%

 

At first glance the PPA group seems to consist of two substructures, for which the similarity needs to be ascertained in order to obtain confidence for cross reading within the whole group. Structurally, both are very similar: a linear alkyl chain and a primary amine at the end, with 2 or 3 secondary amines in between. Consequently, they share the same chemical reactivity and their physico-chemical properties are very similar from which a comparable toxicological profile can be expected.

Within a specific structure, the variability of the alkyl chain length is considered to have a possible modifying activity, which is related to modification of the physiological properties of the molecule by the increase or shortening of the apolar alkyl chain part. This is suspected to influence aspects related to bioavailability, but not chemical reactivity and route of metabolisation, aspects that influence specific mechanisms of toxicity such as sensitisation and genotoxicity. For these reasons, many of the studies can best be performed on the substance with the shortest chain length within the sub-category, as this is considered to result to the lowest NOAEL or most likely able to show specific effects. The data obtained so far indicate that the length of the alkyl chain determines more the level of toxicity then the number of propylene groups. Within the group, results from the shortest chain length can be considered a worst-case approach for the longer chain lengths.

 

This dossier is in support of branched triamine C16-18 (Y-triamine) based on tallow alkyl chian distribution.

 

Toxicological profile branched triamine C16 -18

 

For the hazard evaluation of branched triamine C16-18, use is made of cross-reading withthe structurally similar branched triamine C12. Branched triamine C16-18 only differs in the length of the alkyl chain, which is suspected to influence bioavailability, but not chemical reactivity and route of metabolisation, aspects that influence specific mechanisms of toxicity. For these reasons, many of the studies can best be performed on the substance with the shortest chain length within a group of substances with the same chemical structure, as this is considered to result to the lowest NOAEL or most sensitive for identification of specific health hazards.

 

The acute oral toxicity of branched triamine C16-18 indicates a LD50 of 766 mg/kgbw. Other polyamines show comparable results where those with on average shorter alkyl chains show a somewhat higher toxicity compared to those with longer alkyl chain lengths. The number of propylene groups (dipropylenetriamine or tripropylenetetramine) does not seem to be of influence.

Potential exposure to PPA is mainly dermal. As the active substance is corrosive to the skin, dermal irritation/corrosion is a major concern when dealing with PPA formulations.Effects following dermal exposures will be characterized by local corrosive effects that are related to duration, quantity and concentration of the substance, rather than by systemic toxicity due to dermal uptake.

Physical-chemical properties of polyamines indicate a low likelihood for exposure via inhalation having a boiling point > 300 °C and a low vapour pressure (1.4 x 10-4 Pa at 25°C for thebranched triamine C12, with a shortest average alkyl chain length representing the highest vapour pressure for the group of branched polyamines).

Branched triamine C16-18 is corrosive to skin.

 

There is no sensitization study available for branched triamine C16-18.However, the molecular structure of the substance does not contain toxicophores indicating a concern for sensitization. Polyamines show further low dermal penetration, and no reactivity and protein binding (processes needed for haptenisation). Data available from sensitisation studies on structurally similar branched triamine C12 and primary amines, also indicate no concern for sensitisation.

 

For the evaluation of repeated dose toxicity of branched triamine C16-18, read-across is applied from branched triamine C12. A NOAEL of 7 mg/kg bw/day was established in a 90-day study with rats, based on tubular nephropathy in the kidney and the appearance of foamy macrophages in mesenteric lymph nodes at the next dose level. In a 90-day study with dogs, a NOAEL of 20 mg/kg bw/day was established, based on decreased body weight, increased absolute and relative gall bladder weight and increased potassium and ALAT and ASAT activities in plasma. In a combined chronic repeated dose toxicity/carcinogenicity diet study with rats a NOAEL of 4 mg/kg bw/day was established, based on increased ASAT activity, increase of lymphohistiocytic inflammatory reactions in the kidney, skeletal muscle and heart, and foamy macrophages in the mesenteric lymph nodes and alveoli of the lungs at the next dose level.

Branched triamine C12 was tested for carcinogenic potential in a carcinogenicity study according to OECD 453 and showed no carcinogenic potential in rats when given via the diet daily for 104 weeks.

 

Based on the results of a two-generation oral reproductive toxicity study with rats, branched triamine C12 does not cause adverse effects on fertility. Based on clinical sings of systemic toxicity, combined with decreased food consumption and decreased body weight in high dose animals of the P and F1 generation, a NOAEL for systemic toxicity was set at 9 mg/kg bw/day. As no adverse effects on fertility and reproductive performance were noted at the highest test dose, a NOAEL for reproductive toxicity was set at 27 mg/kg bw/day.

 

Genotoxicity was also evaluated with branched triamine C12, which was found to be non-mutagenic in a bacterial mutagenicity test (Ames) and in a mammalian mutagenicity test with mouse lymphoma cells. The branched triamine C12 was not clastogenic in an in vitro mammalian chromosome aberration test with human lymphocytes. Also studies on other polyamines indicate no concerns for genotoxicity. Furthermore, polyamines do not react with DNA or react to protein.

 

 

Toxicokinetics, metabolism and distribution

 

The mode of action of for polyamines follows from its structure, consisting of an apolar fatty acid chain and a polar end of a primary amine linked to a secondary amine. The structure can disrupt the cytoplasmatic membrane, leading to lyses of the cell content and consequently the death of the cell.

The very high water solubility can be explained by the fact that the terminal amine groups are completely protonated under environmental conditions. The water solubility of polyamines is strongly influenced by pH.

The polyamines are all corrosive to skin. This is probably related to their structure causing disruption of cytoplasmatic membranes. Toxicity following dermal exposure is characterised by local tissue damage, rather than the result of percutaneously absorbed material.

 

The toxicokinetic properties of triamine have been investigated in the rat in a single dose in vivo study and an in vitro percutaneous absorption study (Huntingdon Life Sciences, 1996 and Inveresk Research, 2003).

In the in vivo toxicokinetic study rats were given a single dose of 3 mg/kg or 30 mg/kg bw radiolabelled triamine. None of the animals showed signs of systemic toxicity. Over a period of 5 days the majority of the administered dose, 90-97%, was excreted in faeces, approximately 0.2% of the dose was excreted in the urine and radioactivity in expired air traps accounted for < 0.4% dose. At necropsy 1 -3% dose was retained in the carcass and 0.4 - 1.3 % of the dose was recovered in the gastrointestinal tract. This leaves about 2.5% of the initial dose that is not excreted. As the liver showed constant less activity then the kidney in all radiographs, significant entero-hepatic circulation can be excluded.

 

There was no noticeable difference in excretion after the different dosing regimens or between male and female rats. Concentrations in plasma were consistent with low absorption of triamine from the gastrointestinal tract. At the low level dose, concentrations were generally below the limit of reliable measurement and appeared to peak 4 hours after dose administration. At the high level dose, concentrations of radioactivity in plasma were again low with values generally less than twice the limit of reliable measurement. The plasma concentrations of radioactivity indicated a fairly rapid clearance of radioactivity with peak concentrations measured 12 hours after dosing. Qualitative analysis of the tissue distribution of radioactivity by whole-body autoradiography indicated high levels of radioactivity in the gastrointestinal tract and its contents. Levels of radioactivity observed in other tissues were consistent with low absorption from the gastrointestinal tract.

The major component in faecal extracts was unchanged substance, accounting for 7-13% dose. The assignment was confirmed by co-chromatography using TLC. Six minor components were also observed in faecal extracts, each accounting for 1 -3 % dose. One of these was shown to co-chromatograph with 1-dodecylamine.

 

In addition the primary route of exposure will be via dermal contact from which absorption is expected to be lower than via the oral route. In an in vitro dermal absorption study using human skin, only less than 0.01% completely passed the skin and 0.92% of the applied dose passed the stratum corneum but remained fixed in the skin after 24 hours. This demonstrates a low dermal absorption as well as a low dermal mobility.

As this dermal absorption study used a 1% concentration for 24 hours, which is well above the NOAEC for irritation of 0.15% for 6 hours, it likely even overestimates dermal absorption for non-irritating concentrations. Systemic toxicity is not seen at doses which did not cause severe irritation. The lack of systemic toxicity at lower dermal doses indicates a repeat dose toxicokinetic study via the dermal route would not provide any further information on the systemic effects observed from dosing via the oral route.

The above listed studies indicate that oral absorption is about 2-5%, whereas only less than 0.01% completely passed the skin and 0.92% of the applied dose passed the stratum corneum but remained fixed in the skin after 24 hours. This demonstrates a low dermal absorption as well as a low dermal mobility. For risk assessment purposes a very conservative factor of 3 will be used for route-to-route extrapolation of oral NOAEL levels for systemic toxicity to dermal NOAEL exposure levels.

 

Physical-chemical properties of polyamines indicate a low likelihood for exposure via inhalation, with a boiling point > 300 °C and low vapour pressure (1.4 x 10-4 Pa at 25°C for the branched triamine C12, with the shortest average alkyl chain length representing the highest vapour pressure for the group of branched polyamines).

 

These substances are almost completely protonated under ambient conditions and will therefore not easily be transported over biological membranes. The ready biodegradability is a strong indication that these substances are also quickly metabolized. Due to the cationic surface-active PPA adsorb strongly onto organic material which could be a limiting factor for intestinal uptake.