Amidinourea phosphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Waiver

Type of information:

other: Waiver, based on expert evaluation of the datasets for physical chemistry amd toxicology

Adequacy of study:

other information

Study period:

2018

Reliability:

other: Expert judgement and interpretation based on detailed examination of the current database for guanylurea phosphate.

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Waiver based on the expert judgement and interpretation of a detailed examination of the current database for guanylurea phosphate.

GLP compliance:

no

Test material

Specific details on test material used for the study:

Not applicable

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

predicted: 80%

Main ADME results 2

Type:

excretion

Results:

predicted: primarily via the urine and faeces

Main ADME results 3

Type:

distribution

Results:

predicted: widley distributed

Main ADME results 4

Type:

metabolism

Results:

predicted: mostly in the liver and kidneys

Main ADME results 5

Type:

other: dermal absorption

Results:

predicted: low due to the physical chemical characteristics of GUP

Applicant's summary and conclusion

Conclusions:

The physical chemical characteristics of GUP and the data from the repeat dose toxicity study clearly suggest and demonstrate that GUP is likely to be adequately absorbed, distributed and excreted with limited or no bioaccumulation. The data suggest that the liver and kidneys are likely target organs and that enhanced metabolism is predicted to occur, although the toxicity of metabolites is predicted to be limited, as in the genotoxicity studies metabolic activation was without demonstrable effect. Considering these attributes, the most likely route of excretion would be primarily via the urine and secondarily the faeces. GUP was not acutely toxic via the oral or dermal routes, was not a skin or eye irritant or a skin sensitizer. The data from the repeat dose study demonstrated systemic exposure and that GUP was of very low toxicity and was unlikely to be toxic to reproduction, in utero development of the foetus or post-natal survival and development of neonatal rats.

Executive summary:

Opinion on TK/ADME (absorption, distribution, metabolism and excretion).

No compound specific toxicokinetic or ADME investigations, or studies on potential metabolites, were available at the time of this review. However, physical chemical data on the test substance and mammalian toxicity data were available for evaluation from which a reasoned scientific opinion on the ADME parameters of Guanylurea phosphate (GUP) can be predicted.

The physical chemical data were generated specifically on the test substance and were generally GLP and regulatory compliant studies.

An on-line literature search (including: PubChem, TOXNET, ChemIDplus, NITE, NICNAS, eChemPortal, NIOSH) did not reveal any further data that might aid in this prediction.

Key physical chemical data on GUP

The data demonstrated that GUP was reasonably soluble in water (91.6 g/L at 20 °C) and had a partition coefficient (Log Kow) of greater than 0 (values were below the limit of the method); the evidence pointing to a relatively lipophobic substance. The vapour pressure was 1.7 x 10-4 Pa at 20 °C, the melting point was approximately 170 °C, flammability was greater than 400 °C, GUP was not surface active, and the particle size was greater than 470 µm (L50 D). These findings do not suggest that this substance would present a risk of inhalation exposure under ambient environmental conditions. 

A tabular data summary is given in Table 1.

Mammalian toxicity data on GUP

The mammalian toxicity data evaluated were:

•       acute oral and dermal toxicity,

•       in vitro skin corrosion/irritation,

•       in vitro eye corrosion/irritation,

•       in vitro skin sensitization,

•       Ames test, in vitro chromosome aberration test and in vitro gene mutation test,

•       OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction and Developmental Toxicity Screening Test (oral gavage study).

These studies were GLP and regulatory compliant.

A tabular data summary is given in Table 1.

The acute oral and dermal LD50 were greater than 2000 mg/kg bw it may be reasonably concluded that GUP is not acutely toxic. Furthermore, GUP was neither a skin or eye irritant nor a skin sensitizer. The in vitro genotoxicity studies (with and without S9 metabolic activation) demonstrated that there was no evidence for genotoxic potential.

In an OECD 422 study, combined repeat dose toxicity and reproductive/developmental screening study (oral gavage dosed), where the dosages tested were 0, 100, 300 and 1000 mg/kg bw/day (there was also a 14-day dose ranging study at these dosages) the systemic NOAEL was 1000 mg/kg bw/day. There were no demonstrable adverse effects on systemic toxicity markers. Furthermore, there was no evidence for any effects on mating performance, fertility, gestation, parturition or on neonatal survival and development. There was evidence of systemic exposure, this was demonstrated in the kidneys of male rats at 1000 mg/kg bw/day, where hyaline droplets were observed, these represented an accumulation of secondary lysosomes within the cytoplasm and contained alpha-2u-globulin that has been shown to reversibly bind to the inducing xenobiotics and/or their metabolites. Hyaline droplet deposition is known to be a male rat specific event, and it is of no toxicological relevance in humans.

The data from the acute toxicity studies and sensitization and genotoxicity studies clearly indicate a substance with no overt acute systemic or topical toxicity, skin or eye irritation, skin sensitization potential or genotoxicity. However, systemic toxicity was evident in the repeat dose toxicity study in rats.

Opinion on TK/ADME of GUP

Absorption and distribution

The relative lipophobicity, and water solubility, indicates that the substance may not be rapidly absorbed across lipid bilayer cell membranes (limiting systemic availability), when compared to more lipophilic substances, after either oral or dermal exposure. Although absorption via aqueous channels and passive diffusion, and the fact that GUP has a molecular weight of 200 g/mol, suggest that some absorption would be expected. 

With water solubility around 92 g/L and a Log Pow of <0, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and as such dermal uptake for this substance might be expected to be low. The data from the acute toxicity studies do not confirm nor refute evidence of acute absorption via the GI tract or skin.

The OECD 422 study demonstrated local toxicity seen as irritation in the stomach, but apparently little, if any, systemic toxicity. However, the finding of hyaline droplets in the kidney of the male rats at 1000 mg/kg bw/day clearly indicates that some systemic exposure was evident.

The data suggest some systemic exposure and indicate that distribution, bioavailability and bioaccumulation might be limited. The physical chemistry data suggest that it is unlikely that acute inhalation exposure (i.e. would not present an exposure risk as significant exposure would not be expected) would result in toxicity considering the very low toxicity evident in the studies presented. 

Metabolism

It is predicted, from the both the physical chemistry and toxicity data, that metabolism would be primarily via the liver and secondarily the kidneys. In the OECD 422 study the highest dosage tested showed an increase in hyaline droplets in the kidney of the male rats which suggests an increase in metabolic activity in relation to systemic exposure of GUP. The substance is likely to be extensively metabolised in the liver. Regarding potential metabolites, as no genotoxicity was seen either with or without the addition of metabolic activation (+/- liver S9-mix), that data support the view that potential metabolites of GUP may be of limited mammalian toxicity.

Excretion

Given the physical chemical properties of the substance, the nature of the effects seen in the repeat dose toxicity study and probable limited bioaccumulation, it is predicted that excretion would be primarily via the urine and faeces. It is likely that urinary excretion would be the primary route.

Conclusions

The physical chemical characteristics of GUP and the data from the repeat dose toxicity study clearly suggest and demonstrate that GUP is likely to be adequately absorbed, distributed and excreted with limited or no bioaccumulation. The data suggest that the liver and kidneys are likely target organs and that enhanced metabolism is predicted to occur, although the toxicity of metabolites is predicted to be limited, as in the genotoxicity studies metabolic activation was without demonstrable effect. Considering these attributes, the most likely route of excretion would be primarily via the urine and secondarily the faeces. GUP was not acutely toxic via the oral or dermal routes, was not a skin or eye irritant or a skin sensitizer. The data from the repeat dose study demonstrated systemic exposure and that GUP was of very low toxicity and was unlikely to be toxic to reproduction, in utero development of the foetus or post-natal survival and development of neonatal rats.

 

Table 1. Data summary for Guanylurea phosphate (GUP)
Physical chemical data
State of the substance at 20° C and 101,3 kPa	White solid with no reported odour.
Melting/freezing point	The test item started to foam at 169 °C (442K) and completely vanished at 175°C (448K). No melting was observed.
Boiling point	Substance is a solid.
Relative density	1.6120 relating to the nominal density of water at 4°C (0.999972 g/cm^3)
Vapour pressure	1.7E-04 Pa (20°C), 2.6E-04 Pa (25°C) and 1.8E-03 Pa (50°C).
Surface tension	71.7 mN/m at 19.8°C. Since the test item showed a surface tension higher than 6 mN/m under the conditions of the method, GUP is not surface active according to Regulation (EC) No. 440/2008
Water solubility	91.6 g/L (pH 3.04) at 20°C.
Partition coefficient n-octanol/water	The log Pow values were below the limit of the method (log Pow < 0)   US EPA: logP = -1.29
Flammability	The test item did not exhibit any indication of self-ignition up to and including the maximum temperature of the test method, 400°C. The substance does not have a self-ignition temperature.
Granulometry (particle size distribution)	Volume-based particle size: L10 D was determined to be 95.31µm L50 D was determined to be 471.04µm L90 D was determined to be 1110.54µm.
Mammalian toxicity data
Acute toxicity, oral route	LD50cut-off (rat): 2000 mg/ kg bw
Acute toxicity, dermal route	LD50> 2000 mg
Skin irritation (in vitro) EpiDerm	Non-irritant
Eye irritation (in vitro) BCOP	Slight irritation - not classified
Skin sensitisation (in vitro) KeratinoSens	Non-sensitiser.
In vitrogene mutation study in bacteria	Non-mutagenic
In vitrocytogenicity study in mammalian cells	Non-clastogenic
In vitrogene mutation study in mammalian cells	Non-mutagenic
OECD 422 study: Combined Repeated Dose Toxicity Study with the Reproduction and Developmental Toxicity Screening Test	No changes in most of the measured toxicity parameters.   Local irritancy in stomach of rats (M/F), no effects on food consumption. Histopathological evidence corroborated this. Effects not considered as systemic toxicity.   In the stomach, at 1000 mg/kg bw/day, there was minimal to moderate multifocal mixed inflammatory cell infiltrates in the submucosa of the glandular stomach and the limiting ridge; in controls only, slight mixed inflammatory cell infiltrates were observed in the limiting ridge of one rat. This change, at 1000 mg/kg bw/day, was most likely to have been induced by the local irritating effect of the test item and gavage dosing. Additionally, gastric haemorrhage observed in the stomach of one rat at 1000 mg/kg bw/day was considered a local irritating effect of the test item.   In kidneys from male rats at 1000 mg/kg bw/day, hyaline droplets represent an accumulation of secondary lysosomes within the cytoplasm and contain alpha-2u-globulin that reversibly binds to the inducing xenobiotics and/or metabolites. Hyaline droplet deposition is a male rat specific event, and it is of no toxicological relevance in humans.   The Systemic NOAEL of Guanylurea phosphate (GUP) in this study for general toxicity and reproductive toxicity screening is 1000 mg/kg bw/day.