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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: prenatal developmental toxicity study
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The center has been assessed by China National Accreditation Services for Conformity Assessment (CNAS) and proved to be in compliance with CNAS/CL01:2006 'Accreditation Criteria for Testing and Calibration Laboratories (Identical to ISO/IEC17025: 2005 General Requirements for the competence of Testing Calibration Laboratories). The accreditation certificate number is CNAS L0238.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 414
GLP compliance:
not specified
Remarks:
China National Accreditation Services for Conformity Assessment (CNAS) and proved to be in compliance with CNAS/CL01:2006 'Accreditation Criteria for Testing and Calibration Laboratories
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Sample No: ZL0902374
- Supplied by: Thomas Swan & Co,. Ltd
- Physical appearance: Clear colourless liquid, soluble in water and plant oil
- Storage - test substance was stored in its original container that supplied by Thomas Swan & Co,. Ltd at toom temperature
- Handling - The test substance was handled with necessary protective methods and all recommended safety measures were followed.
-

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
- Supplier: Guangdong Medical Laboratory Animal Center [certified animal number SCXK (Guangdong) 2008-0002].
- Number of animals used: 200 male and 200 female
- Number of groups: 5 groups ( a negative control, a positive control, a low-dose, a medium-dise, a high-dose)
- Number of animal in each group: 145 young adult nulliparous female rats were successfully mated with the males of the same species and strain, and then they were randomly divided into 5 groups (29 mated females in each group).
- Body weight at start of experiment: 200 ~ 290g before mating
- Identification of animals: Tags marked with animal group number and treatment detaisl were attached to cages. Each animal was given a unique number.
- Acclimatisation: 5 days prior to the experiment in the test room
- Randomisation: Animals were randomly assigned to 5 groups based on their body weights.

- Test Room: SPF animal lab in the Center.
- Animal house condition: The SPF test facility was an air-conditioned room with 12 hours artifical fluorescent light and 12 hours dark
- Temp range: 20~25°C
- Humidity Range: 40~70%
- Caging: Stainless steel cages were used at first. when animals were mated, the females were housed in plastic cages in small numbers.
- Water bottle: Each cage was supplied with a polypropylene water bottle with a stainless steel nozzle.
- Sanitation: Sterilised bedding material was changed 3 times a week. Corncob Laboratory Animal Bedding was supplied by Guangzhou Sebiona Bio-Tech Co,. Ltd.
- Food and Water: Standard pellet feed supplied by Guangdong Medical Laboratory Animal Center and ultra-pure filtered sterilized water were provided to the animals freely.
-Freq. of providing feed and drinking water: Both drinking water and feed were provided ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on study schedule:
Test Animals:Healthy young animals were acclimatized to the laboratory conditions for 5 days prior to the test. Each animal was assigned a unique identification number. The females were mated with males of the same species and strain (one female and one male stayed together overnight). For the rats day 0 of gestation was the day on which a vaginal plug and/or sperm were observed. Mated females were then assigned in an unbiased manner to the negative control, the positive control and 3-treatment groups.
Dose levels:The low-, medium- and high-dose groups were conducted respectively at the dose levels of 25.28 mg/kg, 126.4 mg/kg and 632.0 mg/kg, while the negative control group was given distilled water instead of the test substance, and the positive group was given 1 mg/kg of N,N'-Methylene bis -(2 -amino -1,3,4 -thiadiazole) (CAS 26907-37-9] by gavage. Animals were weighed on the first day of dosing, and then every 3 days during the dosing period. The dose to each animal was normally based on the most recent individual body weight determination.

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
> 2 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: please refer to comments in any "other information on results"
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Results: P1 (second parental generation)

Effect levels (P1)

Dose descriptor:
NOAEL
Effect level:
126.4 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: please refer to comments in any "other information on results"
Remarks on result:
other: Basically Non-Teratogenic

Target system / organ toxicity (P1)

Critical effects observed:
not specified

Results: F1 generation

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
126.4 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Compared with those of the negative control group, some indexes in the high dose group were significantly increased (including enlarged fontanels, abnormal upper occipital, dysostosis of parietal bones and os incae, bipartite ossification of cervical arch and sternum, and abnormal metacarpal ossification). Growth indexes (body weight, body length and tail length) were significantly decreased. The embryonic resorptions in low-, medium- and high-level groups were significantly increased, while the viable foetuses were decreased (P<0.05 or P<0.01). In medium- and high-dose groups, the foetal deaths were observed to be higher than that of the control (P<0.01). Other indexes, including body weight of the dams, sex ratio of the foetuses, external alterations and soft tissue alterations of the foetuses, did not show any obvious difference with those of the controls. The results are concluded as follows:

(1) No obvious maternal toxic response was observed under designed dose levels

(2)  Definte embryonic toxic responses were observed at the low-, medium- and high-dose groups under existing test conditions.


(3)        ethyl tetrahydrofurfuryl etherelicited the increase of skeletal malformations. The minimum teratogenic dose was 632.0mg/kg and theNo Observed Adverse Effect Level (NOAEL)ofethyl tetrahydrofurfuryl ether(supplied by Thomas Swan&Co. Ltd.) was 126.4mg/kg. Based onThe Guidelines for the Testing of Chemicals (No. 414’ Teratogenicity)of the State Environmental Protection Administration of China, the Teratogenicity Index was calculated to be5,indicatingJjigjtest material was categorized as "Basically Non-teratogenic".


Applicant's summary and conclusion

Conclusions:
The minimum teratogenic dose was 632.0mg/kg and the No Observed Adverse Effect Level (NOAEL) of theyl tetrahydrofurfuryl ether (supplied by Thomas Swan & Co. ltd) was 126.4mg/kg on SPF SD rats.