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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Up to 52 day dosing period, extending to day 4 lactation
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
Research working closely in line with OECD 415
Testing performed on major metabolite tetrahydrofurfuryl alcohol which is considered a suitable substitute for the ether.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across: supporting information
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Assessment made on result of testing to support registration of this substance and using test data from key metabolites
See report attached
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
no guideline followed
Principles of method if other than guideline:
Assessment made on result of testing to support registration of this substance and using test data from key metabolites
GLP compliance:
not specified
Radiolabelling:
no
Species:
other: Not applicable
Route of administration:
not specified
Preliminary studies:
The substance is soluble in water and is considered rapidly biodegradable (although along with other ethers and glycols, the results will depend on the type of method performed). A hydrolysis study has been performed and although apparently stable under environmental conditions, ethers will hydrolyse under gastric conditions to corresponding alcohols and aldehydes.

In view of the metabolic route being to tetrahydrofurfuryl alcohol (plus acetylaldehyde) and then on to hydroxybutanoic acid, date from these metabolites can be used to assess the potential toxicity of the ether.
Type:
absorption
Results:
Yes, oral
Type:
distribution
Results:
Yes, target organs identified
Type:
metabolism
Results:
Yes, key metabolites estimated
Type:
excretion
Results:
No evidence of excretion, but metabolism is to substances found in nature
Details on absorption:
There was evidence of systemic effects reported for oral toxicity studies, with the repeat oral study and reproduction toxicity screening tests showing adverse effects at higher dose levels. Effects for both the ethyl ether and the alcohol include effects on liver function and organ weights, including testes.

There is no evidence of absorption following dermal or inhalation exposure, but in view of the low molecular weight, polarity and similarity to other ethers and alcohols, dermal absorption is considered likely.
Details on distribution in tissues:
The impact on organs following oral ingestion and changes in chemistry parameters confirms distribution to key organs, even though some of the reported changes are possibly adaptive (ie metabolic processes) and not toxic adverse effects.

The low molecular weight and solubility in biological media would suggest transport of the substance and primary metabolites.
Details on excretion:
There is limited evidence that furans and linear ethers are directly excreted, but in view of the potentially rapid metabolism to substances found naturally in the body, it is not expected that there will be excretion of the substance itself.

The ultimate metabolisms is to water and carbon dioxide that are excreted as part of natural biological systems.
Metabolites identified:
yes
Details on metabolites:
Furans and linear ethers are well document for metabolic processes in biotic and in acidic media. The route of metabolism is illustrated below.

This route of degradation is the basis for validating the read-across between the ethyl ether and alcohol. Although the impact of acetaldehyde cannot be ignored, the reaction kinetics is thought to result in further degradation to acetate at a sufficiently high rate to ensure low levels of acetaldehyde. However, the slight, but significant, mutagenic potential from in-vitro gene mutation testing is consistent with low levels of acetaldehyde and furan.

In human metabolism, acetaldehyde forms naturally as part of the metabolism of ethanol.
Conclusions:
Considered to be readily adsorbed and metabolised to alcohols, aldhehydes and acid salts.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Principles of method if other than guideline:
Rats were given tetrahydrofurfuryl alcohol (THFA) by gavage.
Males were dosed for 47 days, beginning 14 days before mating, and females were dosed for 42–52 days beginning 14 days before mating to day 4 of lactation
throughout the mating and gestation period
GLP compliance:
not specified
Limit test:
no
Justification for study design:
Follows accepted scientific principles

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrahydrofurfuryl alcohol
EC Number:
202-625-6
EC Name:
Tetrahydrofurfuryl alcohol
Cas Number:
97-99-4
Molecular formula:
C5H10O2
IUPAC Name:
Tetrahydrofurfuryl alcohol
Specific details on test material used for the study:
99.5% purity

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
21.9–22.4 C,
Relative humidity of 49–57%,
12-h light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
Twelve male and female rats per group were given tetrahydrofurfuryl alcohol (THFA) by gavage at 0, 15, 50, 150 or 500 mg/kg/day. Males were
dosed for 47 days, beginning 14 days before mating, and females were dosed for 42–52 days beginning 14 days before mating to day 4 of lactation
throughout the mating and gestation period
Details on mating procedure:
After 14 days pre-,ating exposure, male and female rats (1:1) were placed in seperate cages
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations in the formulations were confirmed to be 97.7–103.0% of nominal (gas chromatography).
Duration of treatment / exposure:
14 days prior to mating (males and females) and up to 4 days after birth (females)
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Vehicle only
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12 males and 12 females
Control animals:
yes, concurrent vehicle
Positive control:
No

Examinations

Parental animals: Observations and examinations:
All animals were observed for clinical signs at least twice a day.
The body weight was recorded at least once a week
Oestrous cyclicity (parental animals):
Yes
Sperm parameters (parental animals):
Yes
Litter observations:
Yes
Postmortem examinations (parental animals):
Gross necropsy and more detailed pathology on reproductive organs
Postmortem examinations (offspring):
Viabilty, weight and gross necropsy
Reproductive indices:
Yes
Offspring viability indices:
Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Reduced activity in higher dose groups
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male died on Day 15 in a mid group. Not considered to be treatment related.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced bodyweight gain at 500 mg/kg/day
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced food consumptionin higher treatment levels
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Reduced activity in higher groups
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Significant increases in the incidence of seminiferous tubular atrophy and hyperplasia of interstitial cells in the testes, and cell debris and decreased sperm at 500 mg/kg/day
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
Oestrous cycle at 500 mg/kg prolonged
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
Reduced sperm parameters at 500 mg/kg/day
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
No young from highest doese goup and reduced at 150 mg/kg/day

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
gross pathology
reproductive function (sperm measures)
reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:
yes
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
System:
male reproductive system
Organ:
kidney
spleen
testes
Treatment related:
yes
Dose response relationship:
yes

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Description (incidence and severity):
Live pups survived until termination
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed

Effect levels (F1)

Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
yes
Lowest effective dose / conc.:
150 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
The research demonstrated a NOAEL for parental and reproductive/developmental toxicity to be 50 mg/kg/day.
The impact on testes and sperm parameters is consistent with other repeat dose toxicity studies in rats and dogs, suggesting reproductive toxicty
This result is consistent with furan (cyclic ether)