Dibenzyl ether

Toxicity to reproduction

Administrative data

Endpoint:

multi-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Maximum reliability for read across-studies Critical study in OECD risk assessment, 2004: Meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Reference

Reference 1

Reference Type:

publication

Title:

No information

Author:

Kieckebusch W & Lang K

Year:

1960

Bibliographic source:

Arzneim.-Forsch. 10: 1001-1003

Reference 2

Reference Type:

publication

Title:

SIDS Initial Assessment Report for 13th SIAM (Bern, 7th – 9th November 2001) on Benzoates: Benzoic acid, Sodium benzoate, Potassium benzoate, Benzyl alcohol, CAS Nos. 65-85-0, 532-32-1, 582-25-2, and 100-51-6

Author:

OECD

Year:

2004

Bibliographic source:

http://webnet.oecd.org/HPV/UI/SIDS_Details.aspx?key=9d081a2b-4582-464a-99d7-27749e8b324a&idx=0

Materials and methods

Principles of method if other than guideline:

4-generation diet-study. Cited from OECD risk assessment: "A robust protocol, according to standards at that time, was used. Taking into account the reputation of the investigators a high quality has to be assumed."

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Benzoic acid

EC Number:

200-618-2

EC Name:

Benzoic acid

Cas Number:

65-85-0

Molecular formula:

C7H6O2

IUPAC Name:

benzoic acid

Details on test material:

benzoic acid, purity not noted

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

initial body weight:40-50 g

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

Oral feed (first 8 weeks paired feed technique; afterwards ad libitum)

Duration of treatment / exposure:

Exposure period: generation 1 and 2: lifelong; generation 3: 16 weeks; generation 4: until breeding

Frequency of treatment:

Continuously in diet

Details on study schedule:

Lifelong (4-generations)

Doses / concentrations

Remarks:

Doses / Concentrations:
approx. 375 and 750 mg/kg bw (0.5 and 1 % in diet)
Basis:

No. of animals per sex per dose:

20

Control animals:

yes

Details on study design:

The mean compound consumption was calculated according to Lehman, A.J., Assoc. Food Drug Off. Q. Bull. 18, 66 (1954).

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

>= 750 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: No indications for parental toxicity at highest dose of 750 mg/kg; reference: OECD risk assessment, 2004

Results: F1 generation

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 750 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: No indications for fetal toxicity at highest dose of 750 mg/kg; reference: OECD risk assessment, 2004

Results: F2 generation

Effect levels (F2)

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

>= 750 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: No indications for fetal toxicity at highest dose of 750 mg/kg; reference: OECD risk assessment, 2004

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

"In all 4 generations no influence on growth (weight, weight gain and food efficiency (measured by protein efficiency) and organ weights was found. In all 4 generations, no effects on fertility ("Fortpflanzung") and lactation ("Aufzucht der Jungen") was found. The animals of the 3rd generation were sacrificed and examined histopathologically after 16 weeks (after lactation of the pups). No remarkable histopathological findings were found.

In the paper no information is given on the organs investigated, however the robustness of the total study, the reputation of the investigators, as well as the reputation of the Professor who did the histopathologic investigation, a high quality has to be assumed.

From other parameters it can be assumed that as a minimum the brains, heart, liver, kidney, testis and were examined.

Feeding of 0.5 % led to prolongation of survival compared to controls. In addition a so called "Alters-Paarung" after 48 weeks gave no influence on start of menopause."

Applicant's summary and conclusion

Executive summary:

Cited from OECD 2004: "In a 4-generation study 20 rats/sex/group were dosed continuously by diet with 375 or 750 mg/kg/day benzoic acid. In all 4 generations, no effects on fertility (“Fortpflanzung”) and lactation (“Aufzucht der Jungen”) were found. In addition a so-called “Alters-Paarung” after 48 weeks gave no influence on start of menopauze. NOAEL (Parental) > 750 mg/kg/day, NOAEL (F1 Offspring) > 750 mg/kg/day, NOAEL (F2 Offspring) > 750 mg/kg/day."

(Kieckebusch & Lang, 1960, OECD 2004)