Semicarbazide hydrochloride

Endpoint summary

Description of key information

TOXICOKINETIC ANALYSIS:

 

There are no specific toxicokinetics or dermal absorption studies available for Semicarbazide hydrochloride (EC209-247-0, CAS 563-41-7). Therefore, in line with ECHA's Guidance on Information Requirements and Chemical Safety Assessment chapter R.7c [1] the main toxicokinetic properties of Semicarbazide hydrochloride are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance.

 

Semicarbazide hydrochloride is a white solid (crystalline powder) at room temperature with a molecular weight of 111.539 g/mol. A log Pow of – 1.9 was measured in an experimental OCED 107 guideline study.

 

The vapour pressure of Semicarbazide hydrochloride was determined to be 3 x 10-4 Pa at 25ºC.

 

The test substance is a monoconsituent with a purity of >99% (w/w).

 

Absorption

 

Oral route

 

Based on its relatively low molecular weight of 111.529 g/mol Semicarbazide hydrochloride is highly likely to be quantitatively absorbed in the GI tract since its molecular weight favours absorption. No current Acute Oral toxicity experimental study has been performed with Semicarbazide hydrochloride, a draft paper from 1982 and information from a book published in 1958 have been used to address this endpoint in the dossier. In this information different species (ie. rat and mouse) and different routes of administration (ie. oral, intravenous, intraperitoneal and subcutaneous) were employed and all demonstrated a LD50 average of 100 mg/kg although it should be noted that the information was assessed as Klimisch 4.

To address the repeat-dose toxicity end-point the information from 4 published studies was considered.  In the 30-day repeat dose toxicity study by Ramos et al. 2012, Semicarbazide treatment induced testicular atrophy accompanied by degeneration of germ cells within the seminiferous tubules, and the tubules were shrunken and greatly depleted of germ cells.

In the 4-week repeat dose toxicity study by Fayza El-Sayed et al. 2016, the results showed that oral administration of semicarbazide induced important changes during juvenile period in rat testicular morphology in the form of testicular damage and germ cell apoptosis which still present after withdrawal and probably may affect reproductive functions. This can be considered relevant for food safety in particular for children who represent a group of major exposure and susceptibility to semicarbazide.

The 28-day repeat dose toxicity study by Maranghi et al. 2009 indicates that the NOAEL in juvenile rats is lower than 40mg/kg for Semicarbazide oral administration.

The conclusion from the 90-days repeat dose toxicity study by Takahashi et al. 2009: Taken together, toxicological effects of sub-chronic exposure to SEM-HCI were mainly observed in the bones, cartilages and aorta. From the histopathological examination, since disarrangement, fissures and deformation of the cartilages were found in both sexes from 250 ppm, the no-observed-adverse-effect-levels (NOAELs) estimated from present study were less than 250 ppm in both sexes, equivalent to 18.1 and 21.1 mg/kg/day in males and females.

In conclusion, oral absorption is considered to be have occurred.

 

Inhalation route

 

The vapour pressure of Semicarbazide hydrochloride was determined to be 3 x 10-4 Pa at 25ºC. Therefore, the substance is not volatile even if used at elevated temperatures, and inhalation to vapours is not relevant.

The particle size distribution of Semicarbazide hydrochloric was determined according to OECD 110 test method using steel sieves and a value of 8%≤45µm was obtained. As there is no information on the value of particle size <10 µm, 8% of the test substance, if inhaled, is considered to have the potential to be inhaled and be deposited in the lungs. A minimum of 92% of the test substance would be expected to be deposited in the upper respiratory tract and may be transported to the stomach via the mucociliary escalator. From here, it would be subjected to the same fate as any test substance that was dosed orally. No experimental study was performed.

In conclusion, absorption via the inhalation route is assumed to be minimal.

 

Dermal route

 

Based on the molecular weight of 111.526 g/mol, high solubility in water, and absence of skin corrosion properties, skin permeability of Semicarbazide hydrochloride is considered to be very possible. However in an Acute Dermal Toxicity guideline study (2017) the LD50 was found to be≥2000 mg/kg/bw and there were no deaths, no signs of dermal irritation, no signs of systemic toxicity, all animals showed expected gains in body weight and no abnormalities were noted at necropsy

As the skin sensitisation assessment was performed considering in vitro studies and a QSAR assessment no further information of systemic can be obtained from this endpoint.

In conclusion, absorption via the dermal route is assumed to be negligible.

 

Distribution

 

As clinical signs were observed in a four repeat dose oral toxicity publications of studies with Semicarbazide hydrochloride, a distribution to potential target organs is considered to have occurred. Furthermore, there was an indication of distribution to certain target organs based on macroscopic and histopathology examinations following repeated oral exposure of Semicarbazide hydrochloride.

In the 30-day repeat dose toxicity study by Ramos et al. 2012, Semicarbazide treatment induced testicular atrophy accompanied by degeneration of germ cells within the seminiferous tubules, and the tubules were shrunken and greatly depleted of germ cells.

In the 4-week repeat dose toxicity study by Fayza El-Sayed et al. 2016, the results showed that oral administration of semicarbazide induced important changes during juvenile period in rat testicular morphology in the form of testicular damage and germ cell apoptosis which still present after withdrawal and probably may affect reproductive functions. This can be considered relevant for food safety in particular for children who represent a group of major exposure and susceptibility to semicarbazide.

The 28-day repeat dose toxicity study by Maranghi et al. 2009 indicates that the NOAEL in juvenile rats is lower than 40mg/kg for Semicarbazide oral administration.

From the 90-days repeat dose toxicity study by Takahashi et al. 2009: toxicological effects of sub-chronic exposure to SEM-HCI were mainly observed in the bones, cartilages and aorta. From the histopathological examination, since disarrangement, fissures and deformation of the cartilages were found in both sexes from 250 ppm(the lowest dose level tested) in both sexes, equivalent to 18.1 and 21.1 mg/kg/day in males and females.

 

 

Metabolism

No specific metabolism study was performed.

In the Ames test with Semicarbazide hydrochloride it was found to be a weak mutagen without S-9 mix and almost inactive in the presence of S-9 mix in terms of mutagenic potency indicating that non genotoxic metabolites were formed in this test system.

A recent paper has shown that semicarbazide is metabolised by members of the cytochrome P-450 family to yield formaldehyde and nitric acid and ammonia which are considered likely to be responsible for the toxicity of Semicarbazide (2).

 

Generally, metabolism will render a xenobiotic molecule more polar and harmless, leading to fast and quantitative excretion.

 

Excretion

 

In the repeated dose oral toxicity studies with Semicarbazide hydrochloride in rats systemic effects were observed. These results indicate that absorption had occurred and excretion via the urine with or without metabolism is likely to represent the main excretion route after oral exposure.

 

Substance characteristics favourable for urinary excretion are low molecular weight (below 300 g/mol in the rat), good water solubility, and ionization at the pH of urine. Semicarbazide hydrochloride fulfils these characteristics.

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential