3-hydroxy-2-methyl-4-pyrone

Endpoint summary

Description of key information

Acute oral toxicity: LD50 (male) = 1440 mg/kg bw with 95% CI 1274-1627 mg/kg bw (Equivalent or similar to OECD 401)

Acute dermal toxicity: LD50 (female) = >2000 mg/kg bw (OECD 402/GLP)

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:

supporting study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reliability has been presented as 2 because similar to OECD Guideline protocol has been follo wed but not GLP.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

RIFM standard protocol but limitedly reported for each report

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
No details.

ENVIRONMENTAL CONDITIONS
No details.

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No details.

Doses:

670, 1310, 1640, 2560 and 5000 mg/kg bw

No. of animals per sex per dose:

10 (no sex specified)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: No data

Statistics:

Not performed, calculated LD50 value with 95% CL.

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 330 mg/kg bw

95% CL:

>= 1 570 - <= 3 090

Mortality:

At 1310 mg/kg bw 2 animals died, at 1640 and 2560 mg/kg bw 5 animals died and at 5000 mg/kg bw all animals died.

Clinical signs:

other: At 1640 mg/kg bw slight lethargy was observed and at 2560 mg/kg bw lethargy was observed. At 5000 mg/kg bw lethargy and loss of righting reflex was observed.

Dose mg/kg	No. of deaths	Observation day
		1	2	3	4	5	6	7	8	9	10	11	12	13	14
670	0/10	0	0	0	0	0	0	0	0	0	0	0	0	0	0
1310	2/10	2	0	0	0	0	0	0	0	0	0	0	0	0	0
1640	5/10	3	0	2	0	0	0	0	0	0	0	0	0	0	0
2560	5/10	5	0	0	0	0	0	0	0	0	0	0	0	0	0
5000	10/10	10	0	0	0	0	0	0	0	0	0	0	0	0	0

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Not classified according to CLP.

Conclusions:

An LD50 of 2330 mg/kg bw (with 95% CL 1570 - 3090 mg/kg bw) was calculated in the acute oral toxicity study with rats.

Executive summary:

In an acute oral toxicity test (RIFM, 1974), 10 rats/group were administered Maltol orally at doses of 670, 1310, 1640, 2560 and 5000 mg/kg bw and observed for 7 days.

At 1310 mg/kg bw 2 animals died, at 1640 and 2560 mg/kg bw 5 animals died and at 5000 mg/kg bw all animals died. At 1640 mg/kg bw slight lethargy was observed and at 2560 mg/kg bw lethargy was observed. At 5000 mg/kg bw lethargy and loss of righting reflex was observed. The LD50 was 2330 mg/kg bw (with 95% CL 1570 - 3090 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 440 mg/kg bw

Quality of whole database:

The acute oral toxicity result used for classification and labelling is of sufficient quality and adequate for this dossier.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 April 2019 - 18 September 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

2017

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: ANHUI JINHE INDUSTRIAL CO., LTD., 201902271
- Expiration date of the lot/batch: 26 February 2021
- Purity: 99.96%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Controlled room temperature (15-25oC), protected from light and humidity (beside silica)

OTHER SPECIFICS:
- measurement of pH: If the pH is 2 or less or 11.5 or greater, a study cannot be conducted, unless there is evidence that the test item is not severely irritating or corrosive to the skin. The pH of the test item in this study was determined prior to the initiation of the experiment and it was found to be 5.0, therefore the experiment could be started.

Species:

rat

Strain:

other: Crl:WIWistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: ~8 weeks old
- Weight at study initiation: Between 205 g and 223 g
- Housing: Individual and group caging (Type II. polypropylene/polycarbonate). Rodents were housed with deep wood sawdust bedding (SAFE 3/4 S certified wooden chips) to allow digging and other normal rodent activities.
- Diet: Animals received ssniff SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494, Soest, Germany, ad libitum
- Water: tap water from the municipal supply ad libitum
- Acclimation period: 6 or 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.1–24.9°C
- Humidity (%): 29–78%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: The back of each animal
- % coverage: approximately 10% area of the total body surface
- Type of wrap if used: Sterile gauze pads were placed on the skin of rats to cover the test item. These gauze pads were kept in contact with the skin using a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was then wrapped with semi occlusive plastic wrap for 24 hours.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the exposure period, the treated area of skin with the test item was washed with water at body temperature.
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.45 g (DRF); 0.43g and 0.41g (main study)
- For solids, paste formed: Sufficient amount of water was used to moisten the test item to ensure good contact with the skin.

Duration of exposure:

24 hrs

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

1 female (DRF)
2 females (main study)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Clinical observations were performed on the day of treatment at 30 minutes, 1, 2 and 5 hours after application of the test item and once each day for 14 days thereafter. Observations included the skin and fur, eyes and mucous membranes, the respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day). The body weights were recorded on Day 0 (before the test item administration) and on Days 7 and 14 (before necropsy).

- Necropsy of survivors performed: Yes; Macroscopic examination was performed on all animals. All animals were anaesthetised with sodium pentobarbital and exsanguinated. Following confirmation of death, after examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed. All macroscopic changes were recorded.

- Other examinations performed: Adverse skin reactions at the site of application were recorded daily following the removal of the dressing.

Statistics:

The method used was not intended to allow the calculation of a precise LD50 value so statistical analysis was not performed.

Preliminary study:

Initially one animal was dosed at the selected limit dose (2000 mg/kg bw). As the animal survived, the second and third animals received the same dose (Tables 1, 2, 3).

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

The test item did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical signs:

other: There were no systemic clinical signs noted in any animal throughout the study (Table 1).

Gross pathology:

There was no evidence of any gross macroscopic changes at a dose level of 2000 mg/kg bw (Table 3, Appendix 1)

Other findings:

- Other observations: No adverse local dermal signs were observed after treatment with the test item or during the 14-day observation period.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute dermal toxicity study in Crl:WI Wistar rats, the LD50 (female) of Maltol was >2000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study (19/080-002P), 3 Wistar Crl: WI female rats were dermally exposed (10% total body area; semi-occlusive) to the test item Maltol (99.96%) in sterile water for 24 hours at doses of 2000 mg/kg bw. At the end of the exposure period the residual test item was removed using sterile water.

The LD50 (female) was >2000 mg/kg bw.

Initially one animal was dosed at the selected limit dose (2000 mg/kg bw). As the animal survived, the second and third animals received the same dose. The test item did not cause mortality at a dose level of 2000 mg/kg bw in the main study. There were no systemic clinical signs noted in any animal throughout the study. There were no test item related effects on body weight or body weight gain during the observation period. There was no evidence of any gross macroscopic changes at a dose level of 2000 mg/kg bw. No adverse local dermal signs were observed after treatment with the test item or during the 14-day observation period.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

There is one acute dermal toxicity available and it is an OECD 402/GLP study with a Klimisch score of 1.

Additional information

Acute oral toxicity

Two acute oral toxicity studies in the rat are available. The key study (Gralla et al., 1969) was selected as it is just sufficiently documented and has the lower acute oral toxicity LD50 value.

In the acute oral toxicity key study (equivalent or similar to OECD 401), male Charles River CD rats (8/group) were administered Maltol by oral gavage (no doses specified) and observed for 7 days. The LD50 was 1440 mg/kg bw (with 95% CI 1274-1627 mg/kg bw).

In the acute oral toxicity supporting study (equivalent or similar to OECD 401), 10 rats/group were administered Maltol orally at doses of 670, 1310, 1640, 2560 and 5000 mg/kg bw and observed for 7 days. At 1310 mg/kg bw 2 animals died, at 1640 and 2560 mg/kg bw 5 animals died and at 5000 mg/kg bw all animals died. At 1640 mg/kg bw slight lethargy was observed and at 2560 mg/kg bw lethargy was observed. At 5000 mg/kg bw lethargy and loss of righting reflex was observed. The LD50 was 2330 mg/kg bw (with 95% CL 1570 - 3090 mg/kg bw).

Acute dermal toxicity

There is one acute dermal toxicity in rats available.

In an acute dermal toxicity study (OECD 402/GLP), 3 Wistar Crl: WI female rats were dermally exposed (10% total body area; semi-occlusive) to the test item Maltol (99.96%) in sterile water for 24 hours at doses of 2000 mg/kg bw. At the end of the exposure period the residual test item was removed using sterile water. Initially one animal was dosed at the selected limit dose (2000 mg/kg bw). As the animal survived, the second and third animals received the same dose. The test item did not cause mortality at a dose level of 2000 mg/kg bw in the main study. There were no systemic clinical signs noted in any animal throughout the study. There were no test item related effects on body weight or body weight gain during the observation period. There was no evidence of any gross macroscopic changes at a dose level of 2000 mg/kg bw. No adverse local dermal signs were observed after treatment with the test item or during the 14-day observation period. The LD50 (female) was >2000 mg/kg bw.

The results from the studies are acceptable to use in the human health assessment.

Justification for classification or non-classification

Based on the available information in the dossier, the substance Maltol (CAS No. 118-71-8) is classified for acute oral toxicity (Category 4) and is not classified for acute dermal toxicity, when the criteria outlined in Annex I of 1272/2008/EC are applied.