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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Biochemical effects of manufactured gas plant residue following ingestion by B6C3F1 mice.
Author:
Weyand EH, Wu Y, Patel S, Goldstein L
Year:
1994
Bibliographic source:
J Toxicol Environ Health, 42, 89-107 (1994)
Reference Type:
publication
Title:
Urinary excretion and DNA binding of coal tar components in B6C3F1 mice following ingestion
Author:
Weyand EH, Wu Y, Patel S, Taylor BB, Mauro DM
Year:
1991
Bibliographic source:
Chem. Res. Toxicol., 4, 466-473 (1991)

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
no full examination protocol: hematology, urinalysis are lacking
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
8007-45-2
Cas Number:
8007-45-2
IUPAC Name:
8007-45-2
Constituent 2
Reference substance name:
Tar, coal
EC Number:
232-361-7
EC Name:
Tar, coal
IUPAC Name:
232-361-7
Constituent 3
Reference substance name:
Tar, coal
IUPAC Name:
Tar, coal
Details on test material:
- Name of test material (as cited in study report): Manufactured gas plant residue (MPG) [= Coal-tar sample C in Weyand et al. 1991]
- Source: Electric Power Research Institute, Palo Alto
- Production: by-product from coal gasification of East Coast coal feedstock
- Molecular formula (if other than submission substance): not applicable = complex mixture
- Substance type: organic
- Physical state: viscous liquid at room temperature
- Composition of test material, percentage of components (Weyand et al. 1991):
Component g/kg
=======================
Naphthalene 43.0
1-Methylnaphthalene 24.0
2-Methylnaphthalene 42.0
Phenanthrene 19.0
Fluoranthene 5.3
Pyrene 7.8
Benz(a)anthracene 2.6
Chrysene 2.7
Benz(b)fluoranthene 1.5
Benz(k)fluoranthene 0.7
Benz(a)pyrene 1.7
Indeno(1,2,3-cd)pyrene ND (1.1)
Dibenz(ah)anthracene ND (0.1)
Benzo(ghi)perylene ND (1.3)
===========================
ND = < detection limit of 0.3 mg/kg using GC/MS
(value) = determination by GC/FID

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Wilmington/Mass
- Age at study initiation: 49 - 56 d
- Weight at study initiation: 23 - 24 g (m); 17 - 18 g (f) (estimated from Report, Fig. 1
- Fasting period before study: none
- Housing:
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- controlled conditions: no details
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: water and gelling agent
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): 1x
- Preparation of the diet (basal gel diet): 3020 mL of boiling water was blended with 100 g of a gelling agent (not specified) for 1 min,
then 1948 g dry food added and blending continued for additionakl 2-3 min.
- Mixing appropriate amounts: Aliquots of MPG was added, followed by homogenisation (2-3 min).
The food blends were cooled down in bar molds.
- Storage temperature of food: packaged into plastic bags and stored at -20 °C
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
94 d and 185 d
Frequency of treatment:
continuous
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.05, 0.25, and 0.50 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 51, 251, or 462 mg/(kg bw*d) (males) / 0, 42, 196, or 344 mg/(kg bw*d) (females)
Basis:
actual ingested
No. of animals per sex per dose:
12 (94 d)
12 (185 d)
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: previous range finding and acceptance (palatability) testing
Positive control:
Benzo(a)pyrene (BaP): 0.005 % in diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, no details

DETAILED CLINICAL OBSERVATIONS: Yes, no details

BODY WEIGHT: Yes
- Time schedule for examinations: throughout (see Report, Fig. 1)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/mouse/day: Yes, per mouse

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No (bone marrow was examined, 94 d and 185 d)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 94 d or 185 d
- How many animals: 12 per group
- Parameters: glucose, creatine, BUN, protein, Asp-aminotransferase, ala-aminotransferase, alk. phosphatase

URINALYSIS: No data on standard parameters /
Chemical analysis of PAH metabolites in male mice over time (1-OH-pyrene + 3-OH-BaP)

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all organs after 94 d and 185 d
HISTOPATHOLOGY: Yes, in in 10 animals per sex of the 0.5% group, BaP and control group (after 94 d and 185 d)
Other examinations:
DNA adducts in lung and forestomach

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
no mortality

BODY WEIGHT AND WEIGHT GAIN (estimated from Report, Fig. 1)
Dose-related decrease, exception 0.05% (females):
0.25% (males): significant decrease in body weight of 10 - 12 % at 94 d and 185 d, respectively, as compared to the control
0.50 % (males): significant decrease in body weight of ~22 and ~15 % at 94 d and 185 d, respectively, as compared to the control
0.05% (female): significant increase in body weight of ~16 % at 94 d and 185 d, respectively, as compared to the control
0.50 % (female): significant decrease in body weight of ~20 % at 94 d and 185 d, respectively, as compared to the control


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) [Report, Tab. 1]
Dose-related decrease as compared to the untreated control / increase for the 0.05 % female group

Changes in body-weight development may be partly explained by the differences in food consumption.


HISTOPATHOLOGY: NON-NEOPLASTIC
After 94 d. lesions observed included minimally to moderate vacuolisation of hepatocytes, increased hematopoietic cell proliferation
in spleens, modest hyperplasia of granulocytic cells in the bone marrow of the femur, and cytoplasmic alteration of the olfactory epithelial cells.

After 185 d, microscopic lesions observed included irregular cytoplasmic vacuoles in hepatocytes, infiltration of lympjoid cells in various tissues,
and changes in the olfactory epithelial cells of the nose.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
After 185 d, a squamous cell carcinoma was present in the forestomach of one male (0.5 %),
one squamous papilloma was found in the forestomach of a female.

Teh effects were sporadic and not considered treatment-related.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
(highest tested dose)
Effect level:
0.5 other: % in diet
Sex:
male/female
Basis for effect level:
other: Clinical signs; mortality; clinical chemistry; gross pathology; histopathology
Dose descriptor:
NOAEL
Remarks:
(highest tested dose)
Effect level:
ca. 350 - ca. 460 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Clinical signs; mortality; clinical chemistry; gross pathology; histopathology
Dose descriptor:
NOAEL
Effect level:
0.25 other: % in diet
Sex:
male/female
Basis for effect level:
other: body weight
Dose descriptor:
NOAEL
Effect level:
ca. 200 - ca. 250 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Body weight

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion