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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published paper. Small group sizes for some studies; tissue distribution results based on qualitative assessment of radioactivity, not parent compound; considered acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Metabolic fate of chlorinated paraffins: Degree of chlorination of [1-14C]-chlorododecanes in relation to degradation and excretion in mice.
Author:
Darnerud PO, Biessmann A and Brandt I
Year:
1982
Bibliographic source:
Arch. Toxicol. 50: 217-226
Reference Type:
secondary source
Title:
Unnamed
Year:
2000

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Autoradiographic evaluation of tissue distribution with quantitative assessment of metabolites in liver and fat and elimination in excreta following oral exposure to one of three C12 chlorinated paraffins (17, 56 and 69% chlorination).
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):(i) monochlorododecane (MCDD); (ii) polychlorododecane I (PCDD I); (iii) polychlorododecane II (PCDD II)
- Substance type: pure active substance
- Physical state: no data
- Analytical purity: > 98%
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: (i) MCDD-17.4% chlorination; (ii) PCDD I - 55.9% chlorination; (iii) PCDD II - 68.5% chlorination
- Purity test date: no data
- Lot/batch No.: none
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): no data
- Specific activity (if radiolabelling): (i) MCDD - 599 GBq/mol; (ii) PCDD I - 599 GBq/mol; (iii) PCDD II - 851 GBq/mol
- Locations of the label (if radiolabelling): [1-14C]
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: no data
- Storage condition of test material: no data
Radiolabelling:
yes

Test animals

Species:
mouse
Strain:
C57BL
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Anticimex (Solna)
- Age at study initiation: no data
- Weight at study initiation: 22 ± 1 g except for pregnant animals.
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: no data
- Diet (e.g. ad libitum): Ewos (Sodertalje) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: gastric intubation and intravenous
Vehicle:
other: Intralipid
Details on exposure:
none
Duration and frequency of treatment / exposure:
Single oral or iv administration
Doses / concentrations
Remarks:
Doses / Concentrations:
Autoradiographic study - 12.5 MBq/kg bw
Tissue concentration and excretion studies - 1.25 MBq/kg bw
No. of animals per sex per dose:
Autoradiograph study
MCDD - 4 (iv); 1 (oral) and 1 pregnant (iv)
PCDD I - 5 (iv); 1 (oral) and 2 pregnant (iv)
PCDD II - 3 (iv); 2 (oral) and 1 pregnant (iv)

Tissue concentration
PCDD I - 4 (oral)
PCDD II - 4 (oral)

Excretion study
MCDD - 4 (iv)
PCDD I - 4 (oral) and 4 (iv)
PCDD II - 4 (oral) and 4 (iv)
Control animals:
no
Positive control:
Autoradiographic study:
[1-14C]lauric acid given to 2 pregnant mice (iv) and to 7 non-pregnant mice (iv) and 1 (oral)

Excretion study:
[1-14C]lauric acid given to 4 mice (iv)
Details on study design:
none
Details on dosing and sampling:
Autoradiographic study
MCDD - iv dose mice killed at 4 h, 24 h, 4 days and 60 days; oral dose mouse killed at 24 h and pregnant mouse at 24 h
PCDD I - iv dose mice killed at 4 h, 24 h, 4 days, 12 days and 60 days; oral dose mouse killed at 24 h and pregnant mice at 4 h and 24h
PCDD II- iv dose mice killed at 24 h, 12 days and 30 days; oral dose mice killed at 24 h and pregnant mouse killed at 24 h
Lauric acid - iv dose mice killed at 1 h, 4 h, 24 h, 4 days, 12 days and 60 days; oral dose mouse killed at 24 h and pregnant mice killed at 4 h and 24 h

Tissue concentration study
PCDD I - mice killed at 24 h and 30 days
PCDD II - mice killed at 24 h and 30 days

Excretion study
For all test materials: 14CO2 was collected at 15 and 30 min and at 1 ,2, 3, 4, 6, 8, 10 and 12 h after dosing and urine and faeces were collected for up to 12 h
Statistics:
For tissue concentration and excretion studies values are reported as mean ± SEM for 4 animals

Results and discussion

Preliminary studies:
None
Main ADME resultsopen allclose all
Type:
absorption
Results:
Absorption of between 62 and 95% of orally administered PCDD I after 12 h, and between 12 and 79% for PCDD II. (The oral absorption is likley to be at the higher end of these ranges.)
Type:
distribution
Results:
Short times (up to 24 h) - radioactivity in high activity cells and in liver and white fat; longer times - prominent in liver, white fat. Also in gonads and CNS (not PCDD II)
Type:
excretion
Results:
Major route -CO2 (MCDD, Lauric acid); CO2/urine (PCDD I); faeces (PCDD II)

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Significant absorption, possibly about 80 and 90% of the administered dose of PCDD II and PCDD I, respectively, can occur within 12 h following single oral administration.

Details on distribution in tissues:
Injection (iv) studies
(i) short times (4-24 h): uptake of radioactivity seen in liver and fat and in tissues with high activity/cell turnover (eg intestinal mucosa, bone marrow, salivary gland, thymus), with lauric acid similar to MCDD, PCDD I less and PCDD II weak. In brown fat accumulation after PCDD II and lauric acid similar, with PCDD I and MCDD lower. Highest activity in liver and intestinal content was in PCDD II animals. Activity was prominent in bile and urine for all chlorododecanes, but not after lauric acid.
(ii) Intermediate times (4-12 days): Activity prominent in liver and white fat, and present in adrenal cortex and gonads (not PCDD II). Also present in bile and urine of chlorododecane-treated animals.
(iii) longer times (30-60 days): Activity present in liver and white fat after all chlorododecanes and in central nervous system (lauric acid , MCDD and PCDD I).

Oral studies
Tissue distribution pattern of radioactivity at 24 h similar after oral and iv administration; however concentration of radioactivity in white fat lower after oral administration.

Pregnant mice
In pregnant mice, transplacental passage of radoactivity detected for all test materials, with activity in foetal liver and white fat and in intestine (not lauric acid). Distribution pattern similar to iv at 24 h, but white fat concentration lower.
Details on excretion:
Oral dosing:
PCDD I - 33% as 14CO2 in exhaled air; 29% in urine and 5% in faeces after 12 h
PCDD II -8% as 14CO2 in exhaled air; 4% in urine and 21% in faeces after 12 h

iv dosing:
MCCD - 52% as 14CO2 in exhaled air; 18% in urine and 3% in faeces after 12 h
PCDD I - 32% as 14CO2 in exhaled air; 21% in urine and 4% in faeces after 12 h
PCDD II - 8% as 14CO2 in exhaled air; 5% in urine and 9% in faeces after 12 h
Lauric acid - 71% as 14CO2 in exhaled air; 2% in urine and 0.2% in faeces after 12 h

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
no data

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
In a good quality study, a qualitative autoradiographic investigation of the tissue distribution of radioactivity in female C57Bl mice after intravenous administration of three 14C-labelled chlorinated dodecanes (C12 chlorinated paraffins; 17, 56 or 69% chlorination) showed that accumulation of unmetabolised material apparently increased with increasing degree of chlorination. The early uptake of these materials into tissues with a high metabolic activity/high cell turnover and the extent of excretion of radioactivity in urine and as exhaled 14CO2 suggests that these materials are degraded to metabolites that can be utilised in intermediary metabolism. Overall, this study suggests that significant absorption (possibly about 80 and 90% of the administered dose of PCDD II and PCDD I, respectively) can occurr within 12 h following single oral administration.
Executive summary:

In a good quality study, the tissue distribution and excretion of three C12 chlorinated paraffins, labelled with 14C in the terminal carbon atom, has been investigated in pregnant and non-pregnant female C57Bl mice following intravenous and gavage administration. Animals were given a single dose of either a monochlorinated dodecane (MCDD; 17.4% chlorinated), a polychlorinated dodecane (PCDD I; 55.9% chlorinated) or a second polychlorinated dodecane (PCDD II; 68.5% chlorinated) and the results compared with animals given the non-chlorinated analogue, 14C-labelled lauric acid. Tissue distribution was assessed qualitatively by autoradiography at between 1 h and 60 days post injection and excretion was followed by collecting urine, faeces and expired 14CO2 up to 12 h post administration (injection and oral dosing). In addition, the nature of the radioactivity present in liver and white fat after the oral administration of PCDD I and PCDD II was examined chemically.

At early times after iv injection (up to 24 h), radioactivity was detected in liver, white fat and in tissues with a high metabolic activity/high cell turnover (eg intestinal mucosa, bone marrow, salivary glands and thymus). The accumulation was most pronounced for lauric acid and MCDD and least for PCDD II. Radioactivity was seen in urine and bile of all chlorododecane-treated animals but not in animals given lauric acid. At longer times (up to 30 days), activity was still prominent in liver, white fat, bile and urine and, except for PCDD II-treated animals, in the adrenal cortex and gonads. At 30 to 60 days post injection, radioactivity was still present in liver and white fat of chlorododecane-treated animals, but not in the fat of lauric acid treated mice. At this time, radioactivity was also seen in the central nervous system after all treatments except PCDD II. At 24 h after oral dosing, the distribution pattern of radioactivity was similar to that after iv injection. Autoradiograms from late-gestation pregnant females showed evidence for transplacental transfer of radioactivity with all treatments, the distribution within foetuses being similar to that in adult animals. The extent of labelling was greatest with MCDD and lauric acid, and weakest with PCDD II. A proportion of the radioactivity retained in the liver and fat 30 days after oral administration of the polychlorinated paraffins was heptane-extractable and probably represents unmetabolised parent compound. In fat from PCDD I-treated mice, 24% of the retained activity was heptane-extractable, whereas in PCDD II-treated animals 78% was extractable.

About 32 and 21% of the administered dose of PCDD I was recovered in the urine and 14CO2, respectively, of mice in the 12 h post intravenous administration, and about 33 and 29% following oral administration (for the corresponding values). This compares with only about 8% as 14CO2 and 4 to 5% in urine for PCDD II. Recovery in faeces at 12 h post-dosing amounted to about 4 and 5% for PCDD I after iv and oral dosing, respectively, whereas for PCDD II the corresponding values were 9 and 21%, respectively. Mice treated with MCDD intravenously excreted 52% of the dose as 14CO2, 18% in urine and 3% in faeces; the corresponding values for lauric acid-treated animals being 71, 2 and 0.2%, respectively. Overall, this study suggests that significant absorption (possibly about 80 and 90% of the administered dose of PCDD II and PCDD I, respectively) can occurr within 12 h following single oral administration.