1,3-dichloropropan-2-ol

Basic toxicokinetics

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 requirements of Annex VIII (8.8).

Data source

Reference

Reference Type:

other:

Title:

Unnamed

Year:

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

Test material information

1

Reference substance name:

1,3-dichloropropan-2-ol

EC Number:

202-491-9

EC Name:

1,3-dichloropropan-2-ol

Cas Number:

96-23-1

Molecular formula:

C3H6Cl2O

IUPAC Name:

1,3-dichloropropan-2-ol

Test material form:

liquid

Radiolabelling:

no

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

In rats, oral administration of 1,3-DCP (50 mg/kg [0.39 mmol/kg] bw) daily for 5 days resulted
in the detection of β-chlorolactate (~5% of the dose), N,N'-bis(acetyl)-S,S'-(1,3bis(cysteinyl))propan-2-ol
(1%), and N-acetyl-S-(2,3-dihydroxypropyl)cysteine in the urine. The epoxide epichlorohydrin was proposed as an intermediate,
which can then conjugate with glutathione (GSH), forming mercapturic acid derivatives.
The metabolic conversion of 2chloropropane-1,3-diol to N-acetyl-S-(2,3-dihydroxypropyl)cysteine
confirmed that an epoxide intermediate was involved. Additionally, epichlorohydrin may
hydrolyze to 3-MCPD, which can undergo further metabolism to produce β-chlorolactate (Jones and Fakhouri, 1979)

In another rat study, a single subcutaneous (s.c.) injection of 1,3-DCP (~68 mg/kg [0.53
mmol/kg] bw) resulted in ethyl acetate-extractable metabolites in the 24-hour urine—
1,2-propanediol (0.43% of the dose) and 3-MCPD (0.35%). The parent compound comprised
2.4% (Koga et al., 1992).

Jones, A.R., and Fakhouri, G. 1979. Xenobiotica 9(10):595-599.
Koga, M., Inoue, N., Imazu, K. Yamada, N., and Shinoki, Y. 1992. J. Univ. Occup.
Environ. Health Jpn. 14:13-22.

Any other information on results incl. tables

TOXICOKINETIC BEHAVIOUR

1,3 -dichloropropan-2 -ol is a relatively non-volatile liquid with a vapour pressure of 150 Pa at 20 celsius, however the supporting toxicological information from occupational accident reports show that inadvertent inhalation or dermal exposure in confined spaces is likely to lead to an elevation in systemic toxicity. 1,3 -dichloropropan-2 -ol was identified to be a skin and eye corrosive substance based upon the effects to in vitro organotypic models.

These results in conjunction with the result from the acute dermal toxicty study and the molecular weight and log Pow indicate that absorption occurs via the dermis. Acute oral toxicity results showed the LD50 to be @100 mg/kg body weight, based upon the molecular weight and log Pow, significant absorption form the Gastrointestinal tract can be anticipated.

Absorption

The general physico-chemical properties of 1,3 -dichloropropan-2 -ol including the molecular

weight and log Pow would indicate that significant absorption is possible by oral , dermal and inhalation exposure

Distribution

Information relating to the distribution of 1,3 -dichloropropan-2 -ol is limited; however, the chemical

characteristics and findings from the inhalation Repeated Dose Toxicity and drinking water carcinogenicity Study implies

widespread systemic distribution occurs following oral administration/ gastric absorption or inhalation exposure.

Metabolism

The negative findings in systemic genotoxicity assays in vivo indicate that reactive

genotoxic metabolites, if formed, must be too transient for 1,3-DCP to be genotoxic in vivo or

that the target tissues and/or endpoints evaluated are not relevant to 1,3-DCP-induced

genotoxicity.  The observation of a positive COMET assay in the glandular stomach of treated mice adds further evidence to this proposition.

In rats treated with 1,3-DCP, the significantly increased hepatic malondialdehyde level was associated with decreases of liver GSH S-transferase activity and GSH content.  Lipid peroxidation was suggested as a causative mechanism of the hepatotoxicity [diffuse massive

necrosis] (Katoh et al., 1998; Kuroda et al., 2002).  Inhibition of CYP2E1 lowered the hepatotoxicity in the animals (Stott et al., 1997).

Excretion

The substance is known to undergo hepatic metabolism with glutathione conjugation and hydrolysis; toxic effects are also noted in the kidneys in the repeat dose inhaltion study and 2 year carcinogenicity study . Consequently the main route of excretion for 1,3 -dichloropropan-2 -ol and its metabolites is through the urinary tract.

Katoh, T., Haratake, J., Nakano, S., Kikuchi, M., Yoshikawa, M., and Arashidani, K.  1998. Ind. Health 36:318-323.  

Kuroda, Y., Fueta, Y., Kohshi, K., Nakao, H., Imai, H., and Katoh, T.  2002.  J. UOEH 24(3):271-280.

Stott, I., Murthy, A., Robinson, A., Thomas, N.W., and Fry, J.R.  1997.  Hum. Exp. Toxicol. 16(5): 262-266.  

Applicant's summary and conclusion

Conclusions:

The available information demonstrates that absorption of substance from the gastrointestinal tract following oral ingestion occurs given the test items physico-chemical characteristics.
These characteristics together with the observed dermal toxicity and corrosive properties of 1,3-dichloropropan-2-ol also indicate absorption via dermal exposure of test item occurs. Absorption via the inhalation route occurs and results in widespread systemic distribution of the substance resulting in significant toxicological lesions. It is known that 1,3-dicholoropropan-2-ol undergoes hepatic transformation and subsequent renal clearance.