1H-Benzimidazole-5,7-disulfonic acid, 2,2'-(1,4-phenylene)bis-, sodium salt (1:2)

Endpoint summary

Description of key information

Short description of key information on absorption rate: 
In vivo dermal absorption in rats: 0.1-03% (key study)
In vitro dermal absorption human skin: <0.3% oil in water formulation; <3% water in oil formulation (supportive data)

Key value for chemical safety assessment

Absorption rate - dermal (%):

1

Additional information

Oral and dermal absorption and elimination

The kinetic behaviour as well as absorption and excretion of the testitem NeoHeliopan® APaq (aqueous solution of NeoHeliopan® AP) were evaluated in male Wistar rats after single oral, dermal andintravenous administration.

After single oral administration of dose levels of 100, 400 and 800 mg/kg bw, maximum plasma levels of 1174, 4883, and 10476 ng/ml were reached at 1-3 hours post administration with elimination half-lives of 7‑9 hours resulting in MRT values of 10-14 hours. After single dermal administration at dose levels of 100, 400 and 800 mg/kg bw, maximum plasma levels of 61, 473, and 1064 ng/ml were reached at 6-8 hours post administration with elimination half-lives of 14-16 hours resulting in MRT values of 22-26 hours. After single intraveneous (i.v.) administration of 8 mg/kg, Cmax observed and Cmax intercept amounted to 12965 and 17208 ng/ml, respectively, with a half-life of 5.4 hours and an MRT value of 7.3 hours. After single oral administration, a strict linear dose dependency was found, while after single dermal administration, an almost linear dose dependency of plasma levels was also seen, taking into account the large standard deviations and the low values at 100 mg/kg bw.

 

Based on the normalized AUCs, AUC value comparisons of oral and dermal administration against i.v. injection showed that within the dose range of 100-800 mg/kg bw, only 1.8-2.1% of the oral dose and only 0.1-0.3% of the dermal dose were absorbed.

 

In addition, the absorption of two formulations (oil in water and water in oil) of the test substance was investigatedin vitroover 24 hours by using human epidermis samples. The results indicated that the test material was not readily absorbed through human epidermis during the 24 h exposure period.The data indicate that the absorption of the test material through human epidermis is, at the most, extremely slow when compared with the absorption rates of other penetrants measured using this in-vitrotechnique (Dugard et al, 1984; Dugard and Scott, 1984).

From the water in oil formulation, the mean percentage of test material recovered from human epidermis was <3% of the applied test material dose, following exposure up to 24h. The results indicate that any test material absorbed from the water in oil formulation will most likely remain in the epidermis, rather than be absorbed through it. From the oil in water formulation, the mean percentage of test material recovered from human epidermis was <0.3% of the applied test material dose, following exposure up to 24h. The test material was not readily absorbed from the oil in water formulation into the epidermis and did not pass through it.

After single oral administration at the dose level of 800 mg/kg bw, excretion of parent test item in urine and faeces amounted together to 16.5% after 48 hours. However, excretion in urine was only about 1%. After single intravenous administration at the dose level of 8 mg/kg bw, excretion of the parent test item in urine and faeces amounted together to 53.7 % after 24 hours with about 60 times less in the faeces. Based on the urinary excretion of about 1% after oral administration, the calculated percentage of absorbed parent test item excreted into faeces via the bile becomes negligible (0.015 %).

 

The results indicate that absorption of the parent test item is very low after oral administration. Taking into account the incomplete excretion after 48 hours the remaining part of the parent test item is assumed to be still present in the intestinal tract.

 

The dermal, oral and i.v. results indicate that after single dermal administration about 10 times lower amounts of parent item were absorbed than after oral administration reflecting about 10 (at 400 and 800 mg/kg bw) and 20 times (at 100 mg/kg bw) lower Cmax values at about 3 times later Tmax values and about two times longer half-lives.

 

Inhalation absorption

Neo Heliopan® AP is a highly water soluble (2g/L at 20°C/pH 2.6) and hydrophilic (log Pow = < -2.4) solid substance. Hence, it can safely be assumed that the substance will not be absorbed by the respiratory tract epithelium. The low volatility (Henry`s law constant (calculated):4.72 * 10^-5Pa m³/mol) and the low vapour pressure (1.4 * 10^-4Pa (20 °C))indicates a marginal potential for inhalation of vapours. Nevertheless, vapours of very hydrophilic substances may be retained within the mucus (ECHA guidance on information requirements and chemical safety assessment – chapter R.7c: Endpoint specific guidance, May 2008).

 

However, the potential for inhalation absorption was addressed as follows:

 

The material was subjected to a test to determine the potential of the dust to be airborne (modified Heubach procedure (DIN 55992-1:2006)), yielding in a nonlinear bimodal regression an MMAD1 of 1.36 µm (12%) with a GSD of 3.8 and MMAD2 of 31.04 µm (88%) with a GSD of 1.6. Based on this information, the fractional deposition in the respiratory tract was calculated with the MPPD model (see appendix).

 

The results of this calculation can be briefly summarised as follows: the deposition frequency in the entire respiratory tract is ~45%. The bulk of this material (i.e. 96.6%) is deposited in the extra-thoracic region, and will therefore be translocated to the GI tract within a few minutes; only a minimal amount (~1%) of the material present in air will be deposited in the tracheo-bronchial region, also cleared to the GI tract by mucociliary flow. Merely 2.4% (see Appendix: 1.07% (PU) of total 45.08%) of the material present in air will be deposited in the alveolar region. Thus, only minimal amounts penetrate to the deep lung tissue, whereas the overwhelming bulk of inhaled material is cleared rapidly to the GI tract, where absorption via the gut epithelium will determine its systemic uptake.

 

Based on the outcome of a toxicokinetic study, oral bioavailability of Neo Heliopan® AP is between 1.8-2.1%.For calculation of inhalation absorption it may be assumed, as a worst-case, that absorption factor both from the alveolar region is 100%, and the GI tract is 2.1% thus yielding an overall inhalation absorption factor of 2%(see appendix) based on particle-size dependant deposition in the lung.

Discussion on absorption rate:

Dermal absorption of the test material was investigated in an in vivo (GLP) study in male Wistar rats. The test material was applied to the skin under occlusive conditions at single dose levels of 100, 400 and 800 mg/kg bw, and the AUCs after dermal and intravenous administration (8 mg/kg bw) were compared after dose normalisation. The results showed that after single dermal administration of the test item at dose levels in the range of 100 to 800 mg/kg, a linear dose dependency of plasma levels was found. Based on AUC comparison between i.v. administration (100% absorbed) and dermal application, the percentage of absorbed test item amounted to about 0.1-0.3 %.

In addition, the absorption of two formulations (oil in water and water in oil) of the test substance was investigated in vitro over 24 hours by using human epidermis samples. The results indicated that the test material was not readily absorbed through human epidermis during the 24 h exposure period. From the water in oil formulation, the mean percentage of test material recovered from human epidermis was <3% of the applied test material dose, following exposure up to 24h. The results indicate that any test material absorbed from the water in oil formulation will most likely remain in the epidermis, rather than be absorbed through it.

From the oil in water formulation, the mean percentage of test material recovered from human epidermis was <0.3% of the applied test material dose, following exposure up to 24h. The test material was not readily absorbed from the oil in water formulation into the epidermis and did not pass through it. No test material (both formulations) was determined in the receptor fluid.

In conclusion, there is sufficient evidence from in vivo and in vitro data that only very limited amounts of the test material will become systemically available after skin exposure. Therefore, an absorption factor of about 1% for risk assessment purposes can be regarded as appropriate and sufficiently conservative, because it was demonstrated that absorption rates were in the range of <=0.3% in vivo and in vitro. However, higher recovery rates (<3%) form human epidermis were obtained in vitro when applied in a water oil formulation to human skin, but it could be demonstrated that the test material remained within the skin and did not pass through it and thus did not become systemically available.