The product from the burning of a combination of carbonaceous materials.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

between 19 May 2010 and 30 July 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant guideline study.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2011

Report date:

2011

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

The product from the burning of a combination of carbonaceous materials.

EC Number:

931-597-4

Molecular formula:

UVCB substance, not available. View remarks field.

IUPAC Name:

The product from the burning of a combination of carbonaceous materials.

Details on test material:

- Name of test material: Mixed ash
- Physical state: powder
- Composition range of test material (% (w/w)): Aluminium (Al) 13.07, Calcium (Ca) 45.52 , Iron (Fe) 4.15 , Magnesium (Mg) 3.49, Phosphorus (P) 0.79 , Potassium (K) 2.56, Silicon (Si) 28.07, Sodium (Na) 1.08, Sulphur (S) 1.27.
- The critical minor components examined (mg/kg d.w.): Arsenic (As) 18, Barium (Ba) 670 Cadmium (Cd) 3.6, Copper (Cu) 410, Lead (Pb) 180 and Antimony (Sb) 22.
- Purity test date: the substance is UVCB substance
- Lot/batch No.: MIXED ASH 1-01032010
- Expiration date of the lot/batch: March 2011
- Stability under test conditions: Stable
- Storage condition of test material: Room temperature under argon.
- Other: Mixed Ash is named in dossier as Ash. Mixed in the substance name has meant that there has been several (mixed) fuels when producing ash.

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, France.
- Age at study initiation: 6 - 8 weeks
- Weight at study initiation: males 151.4 g and 181.1 g, females 131.9 g and 151.6 g
- Fasting period before study: -
- Housing: 5 rats of one sex per cage
- Individual metabolism cages: no
- Diet (e.g. ad libitum): RM1 (E)-SQC SDS/DIETEX feed
- Water (e.g. ad libitum): available ad libitum in polycarbonate bottles with a stainless steel nipple
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): relative humidity between 45% and 65%
- Air changes (per hr): approximately 10 times
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours darkness with light on at 7.30 a.m.

IN-LIFE DATES: From: May 19, 2010 To: Jul. 30, 2010

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1%

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Ash was weighed in a brown glass flask previously tarred. The vehicle was added. The suspension was ground using a homogeniser without agitation until homogenisation was completed. Samples were taken under magnetic stirring. The test item formulations were prepared daily before administration.

VEHICLE
- Justification for use and choice of vehicle (if other than water): homogeneity of dosing suspensions
- Concentration in vehicle: 0, 50, 100 or 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): SIGMA-Aldrich, Batch No. 044K0101, Expiry date: Oct 2010

HOMOGENEITY AND STABILITY OF TEST MATERIAL: based on chemical analysis of Pb, Cr and Cd; dosing suspension prepared daily immediately before dosing

Duration and frequency of treatment / exposure:

Once daily for 28 days.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 500, 1000 or 2000 mg/kg bw/day

No. of animals per sex per dose / concentration:

2

Control animals:

other: 1% carboxymethyl cellulose

Positive control reference chemical:

-

Details on study design:

- Dose selection rationale: A dose range-finding study.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : blood
- Time and frequency of sampling: Day 1: predose, 1 h and 6 h; Day 14: predose; Day 28: predose, 1 h and 6 h.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, tissues, cage washes, bile

Results and discussion

Main ADME results

Type:

absorption

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Blood Pb concentrations showed dose-dependent increases and modest accumulation during the Study. Cr concentrations showed at most only very slight increases and virtually no accumulation. Cd concentrations were not affected by the treatment. Blood concentrations reflected the concentrations of Pb, Cr and Cd in Ash.

Transfer into organs

Transfer type:

other: gastrointestinal tract/blood

Observation:

slight transfer

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

See Figures 3, 6, and 9 in Appendix E of the Study Report.

Applicant's summary and conclusion

Conclusions:

Interpretation of result: low bioaccumulation potential based on study results. Systemic bioavailability of heavy metals (Pb, Cr, Cd) from Ash is very low. Blood concentrations reflected the concentrations of Pb, Cr and Cd in Ash.

Executive summary:

Concentration of 3 indicator metals (Cr, Cd, Pb) in blood were analysed in 2 male and 2 female satellite animals on study days 1, 14 and 28. Samples were taken from the same animals predose, 1h and 6h after dosing; on study day 14 only predose. Blood Pb concentrations showed dose-dependent increases and modest accumulation during the study so that the predose values on day 28 were about 1, 1, 2.5 and 4.5 µg/l in males and 1, 2, 4 and 7.5 µg/l in females at dose-levels of 0, 500, 1000 and 2000 mg/kg/day, respectively. Cr concentrations showed at most only very slight increases and virtually no accumulation. Cd concentrations were not affected by the treatment.