Tetrahydrofurfuryl methacrylate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2013-08-14 to 2013-10-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study, GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (adopted on 22 March 1996)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrahydrofurfuryl methacrylate

EC Number:

219-529-5

EC Name:

Tetrahydrofurfuryl methacrylate

Cas Number:

2455-24-5

Molecular formula:

C9H14O3

IUPAC Name:

(oxolan-2-yl)methyl 2-methylprop-2-enoate

Details on test material:

- Name of test material (as cited in study report): Tetrahydrofurfuryl methacrylate

Test animals

Species:

rat

Strain:

other: Hsd: Sprague Dawley SD

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Italia SpA, Italy
- Age at study initiation: 6 to 7 weeks
- Weight at study initiation: 176 to 200 g (males), 151 to 175 g (females)
- Housing: up to 5 of one sex/cage, in polisulphone solid bottomed cages measuring 59.5x38x20 cm; nesting material was provided inside suitable bedding bags and changed at least twice a week
- During mating, animals were housed one male to one female in clear polycarbonate cages measuring approximately 43x27x19 cm with a stainless steel
mesh lid and floor, each cage tray held absorbent material which was inspected and changed daily
- After mating, the males were re-caged as they were before mating, the females were transferred to individual solid bottomed cages for the gestation period, birth and lactation; suitable nesting material was provided and changed as necessary
- Diet (e.g. ad libitum): laboratory rodent diet (4 RF 21, Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI), Italy), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C±2°C
- Humidity (%): 55%±15%
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The formulations were prepared daily.

VEHICLE
- Concentration in vehicle: 10, 24 and 60 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg body weight

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

- M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 1 of pregnancy
- The female was paired with the same male until positive identification occurred.
- After successful mating each pregnant female was transferred to individual solid bottomed cage for the gestation period, birth and lactation; suitable nesting material was provided and changed as necessary

Duration of treatment / exposure:

males: 29 d (2 consecutive weeks prior to pairing and thereafter through the day before necropsy)
females: 29 d (2 consecutive weeks prior to pairing and thereafter during pairing, post coitum and post partum periods until Day 3 post partum or the day before sacrifice)

Frequency of treatment:

daily, 7 d / week

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CLINICAL SINGS AND MORTALITY: Yes
- Time schedule: at least once daily, approximately 0.5-1 hour after dosing

DETAILED CLINICAL OBSERVATIONS: Yes (Functional Observation Battery Tests)
- Time schedule: once before commencement of treatment and at least once a week thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: weekly; females additionally on Days 0, 7, 14 and 20 post coitum, dams with live pups were also weighed on Days 1 and 4 post partum

SACRIFICE
- Male animals: All surviving animals. The males were killed after the mating of all females on Day 30 of study.
- Maternal animals: All surviving animals . The females with live pups were killed on Day 4 post partum. The females with total litter loss were killed on the day the total litter loss occurred or shortly after.
The females which did not give birth 25 days after positive identification of mating were sacrificed on Days 26, 27 or 28 post coitum.

All females were examined also for the following:
– number of visible implantation sites (pregnant animals)
– number of corpora lutea (pregnant animals)

more details are given in IUCLID section "repeated dose toxicity" and "toxicity to reproduction"

Fetal examinations:

SACRIFICE / GROSS NECROPSY
All pups found dead in the cage were examined for external and internal abnormalities. All live pups sacrificed at termination were killed and examined for external abnormalities and sex confirmation by gonadal inspection.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

120 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A combined repeated toxicity study with a reproduction and developmental toxicity study was conducted in Sprague Dawley rats in order to provide information on systemic toxicity (body weight and body weight gain, clinical signs including neurotoxicity assessment, motor activity and sensory reaction to stimuli, food consumption, clinical pathology parameters, organ weights, macroscopic and microscopic examination) as well as any possible effects of the test item on male and female reproductive performance (gonadal function, mating behaviour, conception, development of the conceptus, parturition and early lactation).The dosages were 50, 120 and 300 mg/kg bw/day.
On the basis of the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for systemic toxicity was considered 300 mg/kg bw/day for males and females.
The NOAEL for reproductive and developmental toxicity was considered to be 300 mg/kg bw/day for males and 120 mg/kg bw/day for females and their litters.

Executive summary:

In a combined repeated toxicity study with a reproduction and developmental toxicity study according to OECD Guideline 422 (adopted on 22 March 1996) Tetrahydrofurfuryl methacrylate was administered to 10 Sprague Dawley rats / sex / dose by gavage at dose levels of 0 (control), 50, 120 and 300 mg/kg bw/day in corn oil at a constant volume of 5 mL/kg bw.

 

Males were treated for a total of 29 days including 2 weeks prior to pairing and continuously thereafter, up to the day before necropsy. Females were dosed throughout the study including 2 weeks before pairing, thereafter during pairing, gestation and lactation periods until the day of necropsy or Day 3 post partum for females with live pups at Day 4 post partum.

The following parameters were evaluated in parental animals: body weight, clinical signs (including neurotoxicity assessment, motor activity and sensory reaction to stimuli), food consumption, oestrous cycle, mating performance, clinical pathology investigations (haematology and clinical chemistry), litter data, macroscopic observations, organ weights and histopathological examination. Pup weight, pup clinical signs and pup macroscopic observations were also performed.

 

No mortality occurred in the study. Observation of animals at removal from the cage and in an open arena (neurotoxicity assessment) did not reveal changes attributable to the test item. No significant clinical signs were observed.

 

A total of 5 females were found not pregnant at necropsy: 4 in the control group and 1 in the mid-dose (120 mg/kg bw/day) group. Unilateral implantation was observed in one low dose (50 mg/kg bw/day) female. In the high dose group (300 mg/kg bw/day), 3 females had total resorption and 7 females had total litter loss within 1 day of parturition.

Therefore, the number of females with live pups on Day 4 post partum was: 6 in the control, 10 in the low dose (50 mg/kg bw/day), 9 in the mid-dose (120 mg/kg bw/day) group and none in the high dose (300 mg/kg bw/day) group.

On Day 20 post coitum, a decrease in body weight and body weight gain (statistically significant) was evident in females dosed at 300 mg/kg bw/day respect to controls. Decreases in food consumption were seen in high dose females (300 mg/kg bw/day) when compared with controls during the post coitum and post partum periods with statistically significance on Days 7 and 14 post coitum and 4 post partum. Gestation length of all treated groups was higher than controls and significantly increased at statistical analysis, in the high dose group. The pre-birth loss was significantly increased at statistical analysis, in high dose females. This increase could be attributable to the prolonged gestation period which caused most probably pup suffering and the death during or shortly after the birth.

 

An increased presence of missing or dead pups was noted in females receiving 300 mg/kg bw/day. No other treatment-related findings were noted in pups. At necropsy no treatment-related findings were noted in pups which died or in pups sacrificed on Day 4 post partum. No difference in sex ratios was noted between the control and treated groups. No relevant differences in litter data were seen. Decreases in litter weights, seen in low and mid-dose groups were due to the lower number of pups in treated groups respect to control, more evident in mid-dose group in which the increased pup loss was attributed to single females.

 

On the basis of the results obtained in the study, the NOAEL (No Observed Adverse Effect Level) for systemic toxicity was considered 300 mg/kg bw/day for males and females.

The NOAEL for reproductive and developmental toxicity was considered to be 300 mg/kg bw/day for males and 120 mg/kg bw/day for females and their litters.

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