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Description of key information

The key study for acute oral toxicity reports an LD50 value of >2000 mg/kg bw  in a reliable study conducted according to current OECD guideline, but not in compliance with GLP (RIASBT, no date).

The key study for acute inhalation toxicity reports an LC50 value of (4 hours) >751 ppm (equivalent to >3.1 mg/l) in a reliable study, conducted according to the appropriate OECD guideline and in compliance with GLP (WIL 1994). In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the inhalation route (required in Section 8.5.2) does not need to be conducted as reliable data via the oral and dermal routes are available.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not reported
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Principles of method if other than guideline:
Reviewers' note: The Japanese relevant authority have stated clearly in secondary summaries that this study was conducted in compliance with GLP. However, some pages, which may contain the confirmation of GLP compliance, are missing from the published study report."
Reviewer's note: The study report is a translation from Japanese and does not include the date of the study. However, the OECD SIDS references the study year as 2004.
GLP compliance:
yes
Remarks:
(Certificate is not included in the study report.
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan Inc. (795 Shimofurusawa, Atsugi-shi, Kanagawa)
- Age at study initiation: 10 weeks old
- Weight at study initiation: Step 1: mean bodyweight; 214 g (205-225 g)
Step 2: mean bodyweight; 215 g (207-219 g)
- Fasting period before study: No feeding performed from PM 5 on previous day of treatment to 3-hours after treatment.
- Housing: Test animals were bred in a stenless metal mesh cage (260W x 380D x 180H mm) in a barrier system animal room (No.8).
- Diet (e.g. ad libitum): Solid feed, labo MR stock, Nosan Corporation, Lot. No. 020765, ad libitum
- Water (e.g. ad libitum): Tap water sterilized by filteration with 1 µm diameter carteidge filter and UV radiation. ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10 times per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
(purified water)
Details on oral exposure:
VEHICLE;
The test substance is soluble in water, therefore, pharmacopoeia purified water was selected as vehicle.
Pharmacopoeia purified water: Kyoei Pharmaceutical Co., Ltd. Lot. No. 181376
- Concentration in vehicle: 20w/v%
- Amount of vehicle (if gavage): 10 mL per 1 kg of body weight
DOSAGE PREPARATION;
The test solution was prepared immediately before treatment.
Starting dose;
Fixed dose level was adopted according to OECD guideline 423 and dose level was set as 2000 mg/kg in accordance with the report that LD50 value by oral treatment of the test substance in rat was reported as 1.6 to 3.2 g/kg.
Doses:
2000 mg/kg bw Step 1
2000 mg/kg bw Step 2
No. of animals per sex per dose:
Step 1; 3 animals
Step 2; 3 animals
Control animals:
no
Details on study design:
Observation period was for 14 days following administration. Observation of clinical signs and confirmation of death were performed at least once an hour after the administration between 1 and 3 hours, and between 3 and 6 hours after administration on Day 1 (the day of administration). Observation was performed once each in the morning and in the afternoon on Day 2, once in the morning from Day 3 and later. Body weight was measured on Day 1 (immediately before administration), 4, 8 and 15. After observation on Day 15, animals were anesthetized by ether and euthanized and gross necropsy was performed on internal organs. Clinical sings only was observed daily on animals that were not administered.
Statistics:
No statistical analysis was carried out.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortalities occurred in response to treatment.
Clinical signs:
Mild hyptoni and a severe decrease in locomotor activity was observed on all animals within 1 hour after treatment. These findings disappeared on day-2 and no clinical signs were observed thereafter.
(see: Table 2)
Body weight:
Normal body weight gain took place during the observation period.
Gross pathology:
No gross change was observed at necropsy at end of the observation period.
Other findings:
There were no other findings.

Table 1: Mortality of female rates treated with tetrahydorfurfuryl alcohol

       In the single dose oral toxicity test

Step

Dose

(mg/kg)

Number of

animals treated

Number of animals that died

Mortality

Category

(GHS)

1 – 15 (days)

1

2000

3

0

0* / 3**

5

2

2000

3

0

0 / 3

*: Number of animals that died

**: Number of animals treated

GHS: Globally Harmonized Classification System

Table 2: Clinical signs of female rats treated with tetrahydrofurfuryl alcohol

in the single dose oral toxicity test

Step

Dose

(mg/kg)

Findings

Grade

Day

1

2

3

4 - 15

1

3

6(hrs)

1

2000

Number of animals examined

3

3

3

3

3

3

(A)

1

3

0

0

0

0

0

3

0

3

3

0

0

0

(B)

1

0

3

3

0

0

0

2

2000

Number of animals examined

3

3

3

3

3

3

(A)

1

3

0

0

0

0

0

3

0

3

3

0

0

0

(B)

1

0

3

3

0

0

0

A: Decreased locomotor activity

B: Hypeotonia

Interpretation of results:
GHS criteria not met
Conclusions:
An LD50 value of >2000 mg/kg bw is reported in a reliable study conducted according to current OECD guideline, but not in compliance with GLP.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
29 December 1992 - 12 january 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Qualifier:
according to guideline
Guideline:
EPA OPP 81-3 (Acute inhalation toxicity)
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF 59 NohSan No. 4200
GLP compliance:
yes (incl. QA statement)
Limit test:
yes
Species:
rat
Strain:
other: Crl:CD BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Michigan
- Age at study initiation: Young adult
- Weight at study initiation: 217 to 283 grams
- Fasting period before study:
- Housing: Individual suspended wire mesh cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Minimum of 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 28-62
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure chamber volume: Animals were exposed to test vapour in a 100 litre plexiglass whole body inhalation chamber.
- Method of holding animals in test chamber: The animals were housed in wire mesh cages during exposure; cage position was arbitrarily assigned.
- Source and rate of air: A stainless steel J-tube vapour generator was supplied with filtered, compressed air that was heated to ca. 93°C (200°F). An infusion pump was set to deliver test material at ca. 0.68 ml/min.
- System of generating particulates/aerosols: Sufficient test material was dispensed into a aluminium foil wrapped Erlenmeyer flask prior to atmosphere generation. The flask was maintained on a stir plate for the duration of the exposure to ensure even distribution of the test material. Fifty millilitre glass syringes were filled from this flask as needed.
- Method of particle size determination:
- Treatment of exhaust air: the air was drawn through an activated carbon bed, a HEPA filter and a water-spray fume scrubber
- Temperature, humidity, pressure in air chamber: A solomat probe and transmitter was used to monitor temperature and relative humidity.

TEST ATMOSPHERE
- Brief description of analytical method used: The test material was analyzed by infrared spectrometry with a gas analyzer. Atmosphere concentration was determined by by recording and reading an infrared absorbance value at a given time and entering this valve into the linear regression routine to determine the concentration of the test atmosphere in ppm.
- Samples taken from breathing zone: yes
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Saturated vapour with a mean concentration of 751 ppm
No. of animals per sex per dose:
10
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The rats were observed continuously for mortality and clinical signs during exposure, at approximately 1 hour after completion of exposure on day 0 and twice daily thereafter for 14 days.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: The major organ systems of the cranial, thoracic and abdominal cavities were examined for all animals.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 751 ppm
Based on:
other: mean value for saturated vapour
Remarks on result:
other: Calculated by the reviewer to be equivalent to 3.1 mg/l
Mortality:
There were no deaths during the study.
Clinical signs:
other: Eight of the ten rats assumed a prostrate position during exposure and one of these animals had lacrimation from both eyes. At one hour after completion of exposure, 4/10 rats had wet yellow matting of the urogenital area and the entire dorsel surface was
Body weight:
Eight of ten rats lost 1 to 13 grams (less than 1% to ca. 5%) of body weight from the day of exposure (day 0) to day 3 (maximum individual loss of 5%). All but two females had recovered to exceed their initial body weight by day 14. There were no other remarkable weight changes during the study.
Gross pathology:
An enlarged lymph node and mottled areas in all lobes of the lungs were noted for one animal each. There were no changes observed for all other tissues at the terminal necropsy.
Other findings:
None reported.

751 ppm x MW 102.13

-------------------------

24.45

=

3136.99 mg/m3

----------------

1000

= 3.1 mg/l

Interpretation of results:
GHS criteria not met
Conclusions:
An LC50 value of >751 ppm (equivalent to >3.1 mg/l) was found in a reliable study, conducted according to the appropriate OECD guideline and in compliance with GLP.
Executive summary:

There were no deaths or remarkable body weight changes during the study. Transitory slight body weight losses and inhibition of body weight gain were observed, however, no remarkable effects associated with these changes were observed with regard to the general health of the rats.

The majority of the clinical findings were observed on the day of exposure. Eight of ten rats were prostrated during the exposure and this was considered to be a test material related effect. The ataxia, lacrimation, wet yellow urogenital staining and hypoactivity observed during exposure or at one hour post-exposure were also potentially related to the test material. Other clinical findings noted at low incidence included exophthalmia, dried red material around the nose or eyes and salivation. There were no significant clinical signs after day 1 and for the remainder of the study.

At the terminal necropsy, there were no test material related findings. Although one rat had mottled lungs, this finding is often spontaneous in rats and its occurrence in only one of ten animals is not indicative of a test material related effects.

The LC50 of THFA was found to be >751 ppm (equivalent to 3.1 mg/l) when male and female rats were exposed for a single four hour period under the conditions of this study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
3 100 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study need not be conducted because (i) inhalation of the substance is likely and (ii) skin contact in production and/or use is not likely and (iii) the physicochemical and toxicological properties suggest no potential for a significant rate of absorption
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

An acute oral LD50 value of >2000 mg/kg bw in rats is reported in a reliable study conducted according to current OECD guideline, but not in compliance with GLP (RIASBT, no date). No mortalities occurred in response to treatment. Mild hypotonia and a severe decrease in locomotor activity was observed in all animals within 1 hour after treatment. The clinical signs attenuated on Day 2 and none were observed thereafter. Normal body weight gain took place during the observation period. No gross changes were observed at necropsy at end of the observation period.

An acute inhalation LC50 value (4 hours) of >751 ppm (equivalent to >3.1 mg/l) in rats was found in a reliable study, conducted according to the appropriate OECD guideline and in compliance with GLP (WIL 1994). There were no deaths or remarkable body weight changes during the study. Transitory slight body weight losses and inhibition of body weight gain were observed, however, no remarkable effects associated with these changes were observed with regard to the general health of the rats. The majority of the clinical findings were observed on the day of exposure. Eight of ten rats were prostrated during the exposure and this was considered to be a test material related effect. The ataxia, lacrimation, wet yellow urogenital staining and hypoactivity observed during exposure or at one hour post-exposure were also potentially related to the test material. Other clinical findings noted at low incidence included exophthalmia, dried red material around the nose or eyes and salivation. There were no significant clinical signs after Day 1 and for the remainder of the study. At the terminal necropsy, there were no test material related findings. Although one rat had mottled lungs, this finding is often spontaneous in rats and its occurrence in only one of ten animals is not indicative of a test material related effects.

In accordance with Column 2 of REACH Annex VIII, the acute toxicity study via the dermal route (required in Section 8.5.2) does not need to be conducted as reliable data via the oral and inhalation routes are available.


Justification for classification or non-classification

Based on the available information, no classification is required for THFA for acute toxicity in accordance with EC Regulation No. 1272/2008.