5H-Cyclopenta[h]quinazoline, 6,6a,7,8,9,9a-hexahydro-7,7,8,9,9-pentamethyl-

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters AmberTonic is expected to be readily absorbed via the oral route and somewhat lower via the inhalation and dermal route. Based on available in vivo data the absorption percentages derived are: 100% oral absorption, 15% dermal absorption and 31.2% inhalation absorption.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

15

Absorption rate - inhalation (%):

31.2

Additional information

Toxico-kinetic behaviour of AmberTonic

Introduction

The test material AmberTonic (CAS no. 1356400-59-3 and 1356399-98-8) is a quinazoline type of substance with an additional ring structure containing 5 carbons and 5 methyl groups. It is a solid with a molecular weight of 244.38 that does not preclude absorption. The test material contains no hydrolysable groups. The substance has a low volatility with a vapour pressure of 0.029 Pa.

Absorption

Oral:The results of the acute and repeat dose oral toxicity studies of the substance show that the substance is being absorbed by the rat gastro-intestinal tract following oral administration. In the acute oral toxicity study mortality was seen. In the repeated dose toxicity study adverse effects were seen on liver and kidney relating to hypertrophy and periportal vacuolation in the liver and alpha 2µ-globulin nephropathy in the kidney. The relatively low molecular weight and the moderate octanol/water partition coefficient (Log Kow 5.43) and water solubility (9.82 mg/l) would favour absorption through the gut. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. This indicates that AmberTonic is likely to be absorbed orally and therefore the oral absorption is expected to be 100%.

Skin: Based on the physico-chemical characteristics of the substance, being a solid, its molecular weight (244.38), log Kow (5.43) and water solubility (9.82 mg/L), indicate that limited dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). AmberTonic is just outside optimal range. Dermal absorption can be derived from acute oral versus acute dermal toxicity data. In view of the mortality seen at 2000 and 300 mg/kg bw in the acute oral toxicity test and absence of mortality in the acute dermal toxicity test at 2000 mg/kg bw, the dermal absorption is at least 6.7 (2000/300) lower compared to oral absorption. Assuming oral absorption to be 100%, this will result in a dermal absorption of 15%.

Lungs: Absorption via the lungs is also indicated based on physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (0.029 Pa), the octanol/water partition coefficient (5.43), indicates that inhalation absorption is possible.Inhalation absorption can be derived from acute oral versus acute inhalation toxicity data. According to ECHA guidance on CLP, 1 mg/kg bw is equal to 0.0052 mg/L/4h. This means at 961 mg/kg bw (5/0.0052) no inhalation toxicity was observed. The inhalation absorption is at least 3.2 (961/300) lower compared to oral absorption. Assuming oral absorption to be 100%, this will result in inhalation absorption of 31.2%.

Distribution

The moderate water solubility of the test substance would limit distribution in the body via the water channels. The log Kow would suggest that the substance would pass through the biological cell membrane. Due to the predicted metabolisation the substance as such is not expected to accumulate in the body fat significantly.

Metabolism

There are no actual data on the metabolisation of AmberTonic. Considering the pyrimidine ring with two nitrogens the substance can be protonated on these nitrogens under acidic conditions. This protonated AmberTonic has a low pKa meaning that the H atom will be removed again under less acidic conditions. After oral exposure the substance may be protonated in the stomach and deprotonated in the stomach and gut. The irritation properties of the substance in the stomach may be related to this. In the liver, considering P450 metabolism, the following steps are predicted by ToxTree (v 3.1.0.1851); aliphatic hydroxylation at position 1 or 2: N-oxidation at position 3; aliphatic hydroxylation at position 4 are anticipated (see Fig. 1). It is likely that the hydroxylation of the cyclohexyl ring occurs because this will be the site of attack for glucuronidation and possibly when overloaded it will be the site of attack for alpha-2u-globulin (expert judgment). The alpha-2u globulin nephropathy seen in the kidneys support this effect.

Fig. 1   The metabolisation pathway of the substance is presented (Toxtree version 3.1.0.1851).

 

Excretion

The route of excretion of the substance and its metabolites is via the urine and/or faeces. Any unabsorbed substance will be excreted via the faeces.

Discussion

The substance is expected to be readily absorbed orally, based on the human toxicological information and physico-chemical parameters. The substance also is expected to be absorbed dermally and via inhalation based on the physico-chemical properties, although the MW and the log Kow are higher than the favourable range.

The IGHRC (2006) document of the HSE and mentioned in the ECHA guidance Chapter 8 will be considered for deriving the final absorption values for the risk characterisation.

In view of the mortality seen in the acute oral toxicity at 300 and 2000 mg/kg bw (1/5 and 3/5) and absence of toxicity via the dermal and inhalation route: > 2000 mg/kg bw and > 5110 mg/m3 more specific absorption percentages can be derived.

Oral to inhalation extrapolation: Though the substance is not a volatile the inhalation exposure will be considered. The substance is not corrosive for skin and eye and the systemic effect will overrule the effects at the site of contact. In the presence of acute oral and inhalation data inhalation absorption can be estimated:According to ECHA guidance on CLP, 1 mg/kg bw is equal to 0.0052 mg/l/4h. This means at 961 mg/kg bw (5/0.0052) no inhalation toxicity was observed. The inhalation absorption is at least 3.2 (961/300) lower compared to oral absorption. Assuming oral absorption to be 100%, this will result in inhalation absorption of 31.2%.

Dermal absorption: can be derived from acute oral versus acute dermal toxicity data. In view of the mortality seen at 2000 and 300 mg/kg bw in the acute oral toxicity test and absence of mortality in the acute dermal toxicity test at 2000 mg/kg bw. The dermal absorption is at least 6.7 (2000/300) lower compared to oral absorption. Assuming oral absorption to be 100%, this will result in a dermal absorption of 15%.

Conclusion

AmberTonic is expected to be readily absorbed via the oral route and lower via the dermal and inhalation route based on physico-chemical and toxicity data. Based on available data the absorption percentages derived are: 100% oral absorption, 15% dermal absorption and 31.2% inhalation absorption. Bioaccumulation potential is expected to be low.

References

Martinez, M.N., And Amidon, G.L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643.

IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals,http://ieh.cranfield.ac.uk/ighrc/cr12[1].pdf