Reaction mass of rel-(2S,4R,6S)-2,4,6-trimethyl-4-phenyl-1,3-dioxane and rel-(2S,4S,6S)-2,4,6-trimethyl-4-phenyl-1,3-dioxane

Endpoint summary

Description of key information

Oral (OECD 401), rat: LD50: 1.24 mL/kg bw (equivalent to 1.265 g/kg bw)

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

No information on purity was given.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1981

Deviations:

yes

Remarks:

no information on purity, no constant dose volume applied

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

SPF-WIstar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 150 - 180 g
- Fasting period before study: 16 h
- Housing: individually
- Diet: Standard diet (Ssniff/Intermast), ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 45 - 55
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25%

DOSE VOLUMES APPLIED:
0.794 mL/kg bw: 0.49 - 0.51 mL
1.0 mL/kg bw: 0.60 - 0.72 mL
1.26 mL/kg bw: 0.78 - 0.83 mL
1.59 mL/kg bw: 0.96 - 1.1 mL

Doses:

0.794, 1.0, 1.26 and 1.59 mL/kg bw equivalent to 0.810, 1.02, 1.29 and 1.62 g/kg bw (based on a relative density of 1.02)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs were noted 20 min, 1, 3 and 24 hours after dosing and on Days 7 and 14. Body weight was determined before the application (Day 0) and on Day 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Statistics:

LD50 was calculated by Probit analysis (Finney, 1971).

Sex:

male/female

Dose descriptor:

LD50

Remarks:

calc.

Effect level:

1.24 mL/kg bw

Based on:

test mat.

95% CL:

>= 1.16 - <= 1.32

Remarks on result:

other: equivalent to 1.26 g/kg bw

Mortality:

0.794 mL/kg bw dose group: no mortality occurred
1.0 mL/kg bw dose group: 3 females died
1.26 mL/kg bw dose group: 4 females died within 4 days
1.59 mL/kg bw dose group: 4 males and 5 females within 3 days

Clinical signs:

other: Coordination disorder, attitude and positon anomaly, reduced or lack of the righting-reflex, grip reduction, hyperaemia, piloerection, decreased respiratory frequency and ptosis were detected 10 min after application and persisted partly longer than 24 ho

Gross pathology:

Reddening of the intestinal mucosa and the stomach lining was found in the moribund animals. In the surviving animals no pathological findings were noted.

Interpretation of results:

other: Acute Tox. Cat. 4

Remarks:

according to Regulation (EC) No 1272/2008

Conclusions:

In this acute oral toxicity study in male and female rats a LD50 value of 1.24 mL/kg bw was found.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 265 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:

21 Sep - 06 Oct 1999

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:

1987

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

1997

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Shoe:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 204 - 262 g
- Fasting period before study: no
- Housing: two or three animals per sex in transparent polycarbonate cages (Macrolone type III, floor area 810 cm²), individually during 24 h exposure period, pinewood sawdust "Lignocel-Fasern" (Altromin, Lage, Germany) was used as bedding
- Diet: Altromin 1314 (Altromin GmbH, Lage, Germany), ad libitum
- Water: domestic quality drinking water acidified with hydrochloric acid to pH 2.5, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3
- Humidity (%): 55 ± 15
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back and flanks (5 x 6 cm)
- Type of wrap if used: 4-layer gauze pack fixed with Micropore tape

REMOVAL OF TEST SUBSTANCE
- Washing: Skin and surrounding hair were sponged with lukewarm water.
- Time after start of exposure: 24 h

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Each rat was observed 1, 3 and 6 h after dosing and subsequently once daily for fourteen days. The body weight was recorded on Days 0, 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Preliminary study:

In a pilot study, one male was treated with 2000 mg/kg bw. No mortality was observed. Very slight signs of toxicity and a normal body weight gain were noted.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalitiy was noted until the end of the observation period.

Clinical signs:

other: One hour after application all males and 1 and 3 h after application all females showed piloerection. All further observations until the end of the observation period revealed no abnormalities.

Gross pathology:

No abnormalities were noted at necropsy.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Conclusions:

In this acute dermal toxicity study a LD50 value > 2000 mg/kg bw in male and female rats was found.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

The acute oral toxicity of the test substance was assessed in a study similar to OECD Guideline 401 (1979). The test substance was applied via gavage as 25% dilution in arachis oil. Doses of 0.794, 1.0, 1.26 and 1.59 mL/kg bw equivalent to 0.810, 1.02, 1.29 and 1.62 g/kg bw (based on a relative density of 1.02) were given to 5 male and 5 female Wistar rats per dose group. No mortality occurred in the low dose group during the 14-day observation period. In the 1.0 and 1.26 mL/kg bw dose groups 3 females and 4 females died, respectively. In the high dose group 4 males and 5 females were found dead within 4 days. Coordination disorder, attitude and position anomaly, reduced or lack of the righting-reflex, grip reduction, hyperaemia, piloerection, decreased respiratory frequency and ptosis were detected 10 min after application and persisted partly longer than 24 hours. Afterwards all surviving animals appeared normal and showed the expected gains in body weight. At gross pathology reddening of the intestinal mucosa and the stomach lining was found in the moribund animals. In the surviving animals no pathological findings were noted. Using Probit analysis, the LD50 for male and female rats was calculated to be 1.24 mL/kg bw (equivalent to 1265 mg/kg bw).

In a non-guideline study with methodological deficiencies single oral doses of 2.15, 2.61 and 3.16 mL/kg bw equivalent to 2.19, 2.66 and 3.22 g/kg bw (based on a relative density of 1.02) were given each to 2 male NMRI mice (1979). The graphically determined LD50 value was 2.61 mL/kg bw. This study was not taken into account for hazard assessment.

 

Dermal

The acute dermal toxicity of the test substance was assessed in a limit test performed in 5 male and 5 female Wistar rats according to OECD Guideline 402 and in compliance with GLP (1999). A single dose of 2000 mg/kg bw of the test substance was applied to the clipped skin of rats under semi-occlusive conditions for 24 hours. There was no mortality and no effects on body weight gain during the 14-day observation period. One hour after application all males and one and three hours after application all females showed piloerection. All further observations until the end of the observation period revealed no abnormalities. The post-mortem inspection revealed no findings. The LD50 value for dermal toxicity is considered to be > 2000 mg/kg bw.

Justification for classification or non-classification

The available data on acute oral toxicity of the test substance meet the criteria for Acute Tox. 4 (H302) according to Regulation (EC) 1272/2008.

The available data on acute dermal toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.