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Key value for chemical safety assessment

Effects on fertility

Description of key information

The two generation toxicity study (OECD 416) was conducted to evaluate the potential adverse effects of the test substance on reproduction in a 2-generation study. This included determining the effects of the test substance on male and female reproductive processes including gonadal function, oestrous cyclicity, mating behaviour, conception, gestation, parturition, lactation, weaning and growth and development of the offspring. One litter per dam was produced in each generation.

 

Three groups of Crl:CD(SD) rats (30/sex/group) were administered the test substance daily, by oral gavage, for at least 70 consecutive days prior to mating. Dose levels were 20, 40, and 60 mg/kg/day for the F0 and F1 generations. A concurrent control group of 30 rats/sex/group received the vehicle (deionised water). F0 animals were approximately 6 weeks of age at the initiation of test substance administration. The test substance was administered to offspring selected to become the F1 parental generation following weaning (beginning on PND 21). The F0 and F1 males received test substance throughout mating and until the day prior to euthanasia. The F0 and F1 females received the test substance throughout mating, gestation, and lactation until the day prior to euthanasia. For both generations (F1 and F2), 8 pups per litter (4 per sex, when possible) were selected on PND 4 to reduce the variability among the litters. Offspring (1/sex/litter, if possible) from the pairing of the F0 animals were selected prior to PND 21 to constitute the F1 generation. F0 males and females were dosed for 127-132 consecutive days, and F1 males and females were exposed for 135-149 and 134-149 consecutive days, respectively. All F0 and F1 females were allowed to deliver and rear their pups until weaning on lactation day 21. Clinical observations, body weights, and sexes for F1 and F2 pups were recorded at appropriate intervals. Developmental landmarks (balanopreputial separation and vaginal patency) were evaluated for the F1 rats selected to constitute the F1 generation. Nonselected F1 pups were necropsied on PND 21, and F2 pups were necropsied on PND 21. Selected organs were weighed from both F1 and F2 pups necropsied on PND 21. Each surviving F0 and F1 parental animal received a complete detailed gross necropsy following completion of weaning of the F1 and F2 pups; selected organs were weighed. Spermatogenic endpoints (sperm motility [including progressive motility]), morphology, and numbers) were recorded for all F0 and F1 males, and ovarian primordial follicle counts were recorded for all F1 females in the control and high-dose groups at the scheduled necropsy and from all F1 females in the 20 and 40 mg/kg/day groups suspected of reduced fertility. Designated tissues from all F0 and F1 parental animals were examined microscopically.

 

No test substance-related effects were noted at any dosage level in the F0 and F1generations on survival, body weights, food consumption, and reproduction or on the survival, growth, and development of F1and F2 offspring. In addition, no test substance-related macroscopic findings or changes in organ weights were noted. F0 and F1 male spermatogenesis was unaffected by test substance administration at all dose levels.

 

Nonadverse, test substance-related clinical findings, including red material around the nose and/or mouth, were noted in the F0 and F1 generations at approximately 2 hours following dose administration. Red material around the nose was noted in a dose-related manner for F0 males and females in the 20, 40, and 60 mg/kg/day groups. Red material around the mouth was noted for F0 and F1 males in the 40 (F0 only) and 60 mg/kg/day groups and for F0 and F1 females in the 60 mg/kg/day group. The apparent dose-related observation of red material around the mouth was attributable to the presence of a residual amount of dosing solution in the area following administration; the test substance is known to take on a characteristic reddish-brown colour upon exposure to air and/or light.

 

Nonadverse, test substance-related microscopic findings were noted for F1 males in the 60 mg/kg/day group. Hepatocellular vacuolation was noted for seven F1 males in the 60 mg/kg/day group. This was likely due to glycogen accumulation, and the finding was considered nonadverse and of no toxicological significance due to the low incidence (7 of 30 males) and severity (2 minimal, 5 mild) and the lack of any changes in liver weight.

 

Due to the lack of any adverse effects, a dose level of 60 mg/kg/day, the highest dose level evaluated, was considered to be the NOAEL (no-observed-adverse-effect level) for parental systemic toxicity, reproductive toxicity, and neonatal toxicity of furfural when administered orally by gavage to Crl:CD(SD) rats.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
chronic

Effects on developmental toxicity

Description of key information

The available OECD Guideline 414 developmental toxicity study in rats used the oral (gavage) route of administration for furfural (Nemec, 1997). This key study was described in the Risk Assessment Report of 2-Furaldehyde (Furfural) published as a final version by the EU in 2008.

Mated female rats were dosed with 0, 50, 100 or 150 mg/kg bw/day furfural from days 6 to 15 of gestation. The highest dose level of 150 mg/kg bw/day produced maternal lethality and was unsuitable for the evaluation of developmental toxicity. The maternal NOAEL was considered to be less than 50 mg/kg bw/day, based on clinical observations (exophthalmia and tremors) at all dose levels. The developmental NOAEL was considered to be 100 mg/kg bw/day, the highest dose level that could be evaluated; no teratogenicity was observed at this dose level.

 

The CMR Working Group concluded that furfural should not be classified for reproductive toxicity under Directive 67/548/EEC (November 2003).

 

An OECD 414 pre-natal developmental toxicity study in rabbits was conducted in 2020 in order to comply with the second species requirement:

Groups of 24 pregnant New Zealand White rabbits were dosed with furfural, via oral gavage once daily during gestation Days 6–28, at dose levels of 0 (vehicle control), 30, 100 and 300 mg/kg bw/day. Clinical signs, bodyweights, bodyweight gains, gravid uterine weights, food consumption, gross necropsy findings, intrauterine growth and survival, and foetal morphology were evaluated.

There were no test substance-related effects on survival at any dose level. No test substance-related clinical observations were noted at the daily examinations or 1–2 hours postdosing at any dose level. Initial weight loss and a lower mean bodyweight gain, with corresponding reduced mean food consumption, were noted at 300 mg/kg bw/day during the treatment period (gestation Days 6–29) compared to controls. Mean corrected bodyweight, corrected bodyweight change and gravid uterine weight at 300 mg/kg bw/day group were generally comparable to the control group. Mean maternal bodyweights, bodyweight gains, corrected bodyweights, corrected bodyweight gains, gravid uterine weights, and food consumption at 30 and 100 mg/kg bw/day were unaffected by test substance administration.

Mean foetal bodyweights (male, female, and combined sexes) at 300 mg/kg bw/day were lower than the concurrent control group and considered to be test substance-related. Intrauterine growth at 30 and 100 mg/kg bw/day and intrauterine survival at 30, 100 and 300 mg/kg bw/day were unaffected by test substance administration.

There were no test substance-related fetal malformations or developmental variations noted at any dose level.

A dose level of 100 mg/kg bw/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study based on reduced maternal bodyweight and food consumption at the highest dose tested of 300 mg/kg bw/day. Lower mean fetal bodyweights were observed at 300 mg/kg/day, and a dose level of 100 mg/kg bw/day was considered to be the NOAEL for embryo/fetal development when furfural was administered orally by gavage to time-mated New Zealand White rabbits.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Additional information

The available OECD Guideline 414 developmental toxicity study in rats used the oral (gavage) route of administration for furfural (Nemec, 1997). This key study was described in the Risk Assessment Report of 2-Furaldehyde (Furfural) published as a final version by the EU in 2008.

Mated female rats were dosed with 0, 50, 100 or 150 mg/kg bw/day furfural from days 6 to 15 of gestation. The highest dose level of 150 mg/kg bw/day produced maternal lethality and was unsuitable for the evaluation of developmental toxicity. The maternal NOAEL was considered to be less than 50 mg/kg bw/day, based on clinical observations (exophthalmia and tremors) at all dose levels. The developmental NOAEL was considered to be 100 mg/kg bw/day, the highest dose level that could be evaluated; no teratogenicity was observed at this dose level.

The CMR Working Group concluded that furfural should not be classified for reproductive toxicity under Directive 67/548/EEC (November 2003).

In the second available OECD Guideline 414 developmental toxicity study in rabbits groups of 24 pregnant New Zealand White rabbits were dosed with furfural, via oral gavage once daily during gestation Days 6–28, at dose levels of 0 (vehicle control), 30, 100 and 300 mg/kg bw/day. Clinical signs, bodyweights, bodyweight gains, gravid uterine weights, food consumption, gross necropsy findings, intrauterine growth and survival, and foetal morphology were evaluated.

There were no test substance-related effects on survival at any dose level. No test substance-related clinical observations were noted at the daily examinations or 1–2 hours postdosing at any dose level. Initial weight loss and a lower mean bodyweight gain, with corresponding reduced mean food consumption, were noted at 300 mg/kg bw/day during the treatment period (gestation Days 6–29) compared to controls. Mean corrected bodyweight, corrected bodyweight change and gravid uterine weight at 300 mg/kg bw/day group were generally comparable to the control group. Mean maternal bodyweights, bodyweight gains, corrected bodyweights, corrected bodyweight gains, gravid uterine weights, and food consumption at 30 and 100 mg/kg bw/day were unaffected by test substance administration.

Mean foetal bodyweights (male, female, and combined sexes) at 300 mg/kg bw/day were lower than the concurrent control group and considered to be test substance-related. Intrauterine growth at 30 and 100 mg/kg bw/day and intrauterine survival at 30, 100 and 300 mg/kg bw/day were unaffected by test substance administration.

There were no test substance-related fetal malformations or developmental variations noted at any dose level.

A dose level of 100 mg/kg bw/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study based on reduced maternal bodyweight and food consumption at the highest dose tested of 300 mg/kg bw/day. Lower mean fetal bodyweights were observed at 300 mg/kg/day, and a dose level of 100 mg/kg bw/day was considered to be the NOAEL for embryo/fetal development when furfural was administered orally by gavage to time-mated New Zealand White rabbits.

Toxicity to reproduction: other studies

Additional information

Toxicity to reproduction: other studies: Very limited data available from studies of 13 week oral administration of furfural to rats and to mice did not indicate the potential for the chemical to adversely affect any of the reproductive organs at dose levels that did induced lethality/toxicity and neither did the data obtained from the subsequent two year studies. However, it is recognised that the two year studies provide little relevant data for defining the potential effect of furfural on reproduction.

 

Justification for classification or non-classification

The available data provide adequate information from which to assess the potential of furfural to induce reproductive or developmental effects and to conclude that classification under the CLP is not warranted.