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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
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: see 'Remark'
Remarks:
Guideline study, tested with the source substance Methylparaben. According to the ECHA guidance document β€œPractical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1974
Report Date:
1974

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test)
Deviations:
no
GLP compliance:
no
Remarks:
study performed before
Type of assay:
rodent dominant lethal assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Methylparaben, Lot No. 1674K, as supplied by the Food and Drug Administration

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
10 to 12 week old, male, albino rats obtained from a closed colony (random-bred) were used.
Body weight: 280 to 350 g (400 g in case of high dose group rats)
The animals were fed a commercial 4% fat diet water ad libitum until they were put on experiment. Periodic tests to verify the absence of coliforms, Salmonella and Pseudomonas sp. were performed.
Acclimatisation period: 4 to 11 days
Housing: 5/cage
Identification: Ear punch
Sanitary cages and bedding used, and changed 2 times per week, at which time water containers were cleaned, sanitised and filled. Once a week, cages were repositioned on racks; racks were repositioned within rooms monthly.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
0.85% saline
Details on exposure:
Dose levels employed for Methylparaben:
- acute (single dose): 5, 50, 500, 5,000 mg/kg bw
- subacute (5 doses on 5 consecutive days): 5, 50, 500, 5,000 mg/kg bw
Duration of treatment / exposure:
n.a. (gavage study)
Frequency of treatment:
acute: 1 single oral administration
subacute: once a day for 5 consecutive days (24 hours apart)
Post exposure period:
8 weeks (sequential matings)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
5
Basis:
actual ingested
mg/kg body weight
Remarks:
Doses / Concentrations:
50
Basis:
actual ingested
mg/kg body weight
Remarks:
Doses / Concentrations:
500
Basis:
actual ingested
mg/kg body weight
Remarks:
Doses / Concentrations:
5000
Basis:
actual ingested
mg/kg body weight
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Positive control(s):
0.3 mg/kg bw Triethylene Melamine intraperitoneally

Examinations

Tissues and cell types examined:
determination of fertility index
Necropsy of the uteri of mated females
- early deaths (deciduomata)
- absorptions
- dead implatations
- total implantations
- Number of Corpora lutea
Details of tissue and slide preparation:
Following treatment, the males were sequentially mated to 2 females per week for 8 weeks (7 weeks in the subacute study). Females were killed using CO2 at 14 days after separating from the male, and at necropsy the uterus was examined for deciduodimata, late fetal deaths and total implantations.
Corpora lutea, early fetal deaths, late fetal deaths and total implantations per uterine horn were recorded.
Evaluation criteria:
Each male was mated with 2 females per week, and this provided for an adequate number of implantations per group per week (200 minimum) for negative controls, even if there was a 4-fold reduction in fertility of implantations.
Statistics:
yes, please refer to "any other information..." below

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Remarks:
100 and 500 mg/kg: no effects
Vehicle controls validity:
valid
Negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
Toxicity:
Test I
1000 mg/kg: 1 of 5 animals dead; reddened stomach lining, lung congested (day 3)
2000 mg/kg: 2 of 5 animals dead, reddened stomach lining, lung congested (day 2)
3000 mg/kg: 4 of 5 animals dead, reddened stomach lining, lung congested (day 1: 3 animals, day 2: 1 animal)
4000 mg/kg: 4 of 5 animals dead, reddened stomach lining, lung congested (day 1: 4 animals)
5000 mg/kg: 10 of 10 animals dead, reddened stomach lining, lung congested (day 1: 10 animals)
=> LD50 2,100 mg/kg (Litchfield-Wilcoxon method)

Test II
A single dose of 5000 mg/kg bw Methylparaben was administered to 10 male rats (average body weight: 262 g). No signs of toxicity or abnormal behavior were observed in the 7-day observation period. No deaths occured. At termination all animals were killed and on necropsy no gross findings were observed.
=> LD50 > 5000 mg/kg

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Methylparaben is considered to be non-mutagenic in rats in the Dominant Lethal Assy applying dosages up to 5000 mg/kg bw (at single dose or 5 dosages on 5 consecutive days).
Executive summary:

Methylparaben was tested in the dominant lethal assay in rats. The test item was suspended in 0.85% saline and dosed at 5, 50, 500 and 5000 mg/kg bodyweight to male rats (acute: single dose; subacute: 5 doses at 5 consecutive days), upon the results of the previously conducted dose range finding study. According to the test procedure the animals were sequentially mated to 2 females per week for 8 weeks (7 weeks in the subacute study). Females were killed at 14 days after mating and at necropsy the uterus was examined for the number of Corpora lutea, early deaths, late fetal deaths and total implantations.

Triethylene Melamine (TEM) was used as positive control substance and administered intraperitoneally at a dose of 0.3 mg/kg bodyweight. TEM caused significant preimplantation loss and embryo resorption during the first 5 weeks.Saline was used as negative control.

Methylparaben is considered to be non-mutagenic in rats in this dominant lethal assay when using dosages of 5, 50, 500 and 5000 mg/kg bw/d since no dose response or time trend patterns, which would suggest an effect, were observed.