Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Study period:
The assessment was conducted in May 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requ irements of Annex VIII (8.8).

Data source

Reference
Reference Type:
other:
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
n accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behaviour has been
conducted to the extent that can be derived from the relevant available information.The assessment
is based on the Guidance on information requirements and chemical safety assessment R.7c:
Endpoint specific guidance (ECHA, November 2014)
GLP compliance:
no
Remarks:
No relevant for assessment

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
additive
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Identification : Substance CQ
Physical State/Appearance : White Powder
Purity : 99.112%
Batch Number : G315830
Label : CQP BX G315830 DOM 26 APR 2017 Shelf Life
Expires: 26 OCT 2017
Date Received : 04 May 2017
Storage Conditions : Store cold at approximately 4ºC in darkness,
used/formulated in light and ambient temperature
Expiry Date : 26 October 2017
Radiolabelling:
no

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

TOXICOKINETIC BEHAVIOUR

CQ intermediate is a white colored powder with physico-chemical properties which imply the risk of particle inhalation of CQ to be minimal. Furthermore, the supporting toxicological information suggests any inadvertent inhalation is unlikely to lead to an elevation in systemic toxicity. CQ was identified to be a potential ocular irritant based upon its constituents ; the in vitro genotoxicity panel indicates that there are no concerns for genotoxicity.

The results from a single dermal dose toxicity study, in conjunction with the molecular weight and log Pow indicate only limited absorption might occur via the dermis. Acute oral toxicity results showed the LD50 to be >5000 mg/kg body weight, however the Oral (Gavage) Repeated Dose Toxicity Study in the rat resulted in hepatic effects resulting in death at the highest dose, indicating gasto-intestinal absorption.

Absorption

The general physico-chemical properties of CQ including the relatively high molecular

weight and the low water solubility would be factors that would inhibit significant absorption.

Supporting results from the Oral (Gavage) Repeated Dose Toxicity Study indicated absorption from the gut, this is likely absorption of the constituent dimethylformamide following dissociation of the compound.

Distribution

Information relating to the distribution of CQ is limited; however, the chemical

characteristics and findings from the Oral (Gavage) Repeated Dose Toxicity Study implies

systemic distribution would most likely occur via the serum following oral administration and gastric

absorption. Furthermore while the properties (i.e. poor water solubility) of CQ suggest a

potential to accumulate in adipose tissue, none of the studies conducted showed any evidence of this.

Metabolism

There is evidence of test item or metabolite influenced hepatic metabolism from the Oral (Gavage) Repeated Dose Toxicity Study, with centrilobular necrosis and concomitent vacuolar degeneration. Increased mitosis and hepatocyte hypertrophy indicates an adaptive response to the substance.

Excretion

The most plausible route of clearance for relatively low water soluble chemicals would be by transfer of

test material and/or metabolites from the plasma to the bile through the hepatocytes leading to clearance

of any metabolic breakdown products primarily via the faeces. However histopathological effects were observed in the kidneys at the highest dose, indicating renal excretion of substance or metabolites.

Applicant's summary and conclusion

Conclusions:
The available information suggests that absorption of substance from the gastrointestinal tract following oral ingestion is likely despite the test items physico-chemical characteristics.
These characteristics together with the low volatility of CQ also indicate absorption via inhalation or dermal exposure of test item to be unlikely. Any absorbed test material has the potential to undergo hepatic transformation and subsequent reanal clearance, however the physical characteristics of the substance also indicate that clearance can also be expected to be via the bile with subsequent excretion in the faeces.