Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Aqueous solution (liquid)

Results and discussion

Main ADME results
Type:
absorption
Results:
For risk assessment purposes, 50% is used for oral and dermal absorption and 100% for inhalation absorption.

Any other information on results incl. tables

After exposure, a substance can enter the body via the gastrointestinal tract, the lungs and the skin. Since different parameters are relevant depending on the route of exposure, the three routes will be addressed individually.

After oral administration, in general, a compound needs to be dissolved before it can be taken up from the gastrointestinal tract. Ammonium dihydrogen citrate is a salt, which is only present in aqueous solution. In solution, it is expected to dissociate into its respective ions. The water solubility is very high. This implies that the substance will readily dissolve into the gastrointestinal fluids and uptake via passive diffusion (passage of small water-soluble molecules through aqueous pores or carriage across membranes with the bulk passage of water) will take place. The moderate molecular weight (approx. 209) will not hamper this process. Ammonium dihydrogen citrate has a moderate log P value (between -1 and 4), which will furthermore facilitate absorption by passive diffusion through lipid membranes.

No data are available on the dissociation constant(s) of ammonium dihydrogen citrate, therefore it is unclear in which state (ionized or not ionized) the substance will be present under physiological circumstances in the stomach or intestinal tracts. Since it is generally considered that ionized substances do not readily diffuse across biological membranes, the state of the substance might hamper uptake.

Considering all data, it can be concluded that there is one factor hampering penetration, its ionicity. On the other hand it can be argued that its water solubility, its moderate log Pow and its moderate molecular size favour oral absorption. Therefore, for risk assessment purposes oral absorption of ammonium dihydrogen citrate is set at 50%. The oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

Once absorbed, distribution of the test substance throughout the body is likely to take place based on its water solubility and moderate molecular weight. Absorbed ammonium dihydrogen citrate is expected to be excreted mainly via urine. Based on its moderate partition coefficient, ammonium dihydrogen citrate is not expected to significantly accumulate in adipose tissue, which is further indicated by its water solubility and moderate molecular size. Therefore bioaccumulation is expected to be low.

Ammonium dihydrogen citrate has a very low vapour pressure (< 1.5 * 10-3 Pa at 20°C), which indicates that exposure to the substance as a vapour is unlikely. Since Ammonium dihydrogen citrate is present in aqueous solution, it is possible that aerosols are formed which can enter the lungs. The deposition pattern in the lung can be determined based on its distribution, although shape and electrostatic properties can influence this as well. Since aerosols are expected to be very small, they may reach the thoracic region and the alveolar region of the respiratory tract. Overall it is expected that the exposure via inhalation will be very limited. However, if the substance reaches the lung regions, ammonium dihydrogen citrate is likely to dissolve in the mucus lining the respiratory tract and to get absorbed and to get absorbed due to its high water solubility and moderate molecular weight. Based on the above data, for risk assessment purposes the inhalation absorption of ammonium dihydrogen citrate is set at 100%.

Dermal uptake of ammonium dihydrogen citrate in an aqueous solution is facilitated by its liquid form. The first layer of the skin, the stratum corneum, is a barrier for hydrophilic compounds. Based on its moderate log Pow (~0), crossing the first layer of the skin, the stratum corneum, is expected to be hampered. Moreover, its ionic state might influence penetration as ions can bind to skin components which would further slow uptake.

According to the guidance on dermal absorption, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log Powis outside the range [-1, 4]. Since the substance has a molecular weight of approx. 209 and a log Powbelow 0, it does not meet either criteria. However, since the uptake via the skin is not expected to exceed uptake via the oral route, the dermal absorption of ammonium dihydrogen citrate for risk assessment purposes is set at 50%. The dermal toxicity data do not provide reason to deviate from the proposed dermal absorption factor.

Applicant's summary and conclusion

Conclusions:
A toxicokinetic assessment was performed based on the available data of ammonium dihydrogen citrate. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 50% (oral), 100% (inhalation) and 50% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.