α,α,α',α'-tetramethylxylene-α,α-diol

Endpoint summary

Description of key information

Acute oral toxicity

For this endpoint, there is no data on the isomer mixture.

The acute oral toxicity of the meta isomer was evaluated in Wistar rats according to OECD N°401 guideline, but not in compliance with GLP (Wang, 2012a). Groups of 5 male and 5 female Sprague Dawley rats were given a,a,a’,a’-tetramethyl-m-xylene-a,a’-diol in corn oil by oral exposure at doses of 464, 1000, 2150 and 4640 mg/kg for female and 1000, 2150, 4640 and 10000 mg/kg for male. Following treatment, rats were observed daily and weighted on days 3, 7 and 14. A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14). The signs such as activity decreased, limb weakness, side position, dyspnea, issued open mouth breathing were observed in the higher dose groups (21500 and 10000 mg/kg) about 10 minutes after treatment. Death occurred within 4 hour after exposure (mortality was observed from 4640 mg/kg both in males and in females). The rats in the 4640 mg/kg dose group showed slighter signs and the number of deaths was less than the higher dose groups above. No toxic signs and death occurred in the 2150 and 1000 mg/kg dose groups. The survival animals recovered within 24 hours after exposure. At necropsy, pulmonary hemorrhage and congestion of the liver were observed in dead animals only. The LD50 was 4300  mg/kg for female rats and 5010 mg/kg for male rats, and around 4655 mg/kg for both males in females.

 

The oral LD50 of the meta and para isomers was evaluated using QSAR models. In the Danish QSAR database, the estimated LD50 was 3700 mg/kg for both isomers. Using the Toxicity Estimation Software Tool (T.E.S.T), LD50 3761 and 3326 mg/kg were estimated for the meta and para isomers, respectively. Globally, the acute oral LD0 of m/p-DIOL is estimated to be higher than 2000 mg/kg.

 

Acute dermal toxicity

The acute dermal toxicity of m/p-DIOL was assessed in Sprague-Dawley rats, following the OECD 402 guideline and in compliance with GLP (Silvano, 2012). The test item was applied in its original form (pre-moistened) to the skin of five female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours. Each animal was observed at least once a day for mortality and clinical signs for 15 days. From day 2, any local reactions at the treatment site were also noted. Body weight was recorded on day 1 and then on days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. No tissues were preserved. No unscheduled deaths and no clinical signs indicative of systemic toxicity were observed in any animals. No cutaneous reactions were observed in any animals. When compared to historical control data, a lower body weight gain was noted in all females between day 1 and day 8. Their body weight gain returned to normal thereafter. Body weight of males was unaffected by the test item treatment. There were no macroscopic findings in any animals. In conclusion the dermal LD0 of m/p-DIOL is higher than 2000 mg/kg in rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

09 June 2011 - 20 August 2011

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study has deviations and the information in the report is incomplete. Nevertheless it is sufficient for assessment of acute oral toxicity.

Qualifier:

according to guideline

Guideline:

other: The Guidelines for the Testing of Chemicals (State Environmental Protection Administration of China, 2004.5, 401, Acute Oral Toxicity Test)

Deviations:

no

GLP compliance:

no

Remarks:

The laboratory has no GLP accreditation (nevertheless the project plan and the report were audited by the Quality Assurance Unit)

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

- 135-156g Wistar rats, SPF grade, were supplied by Vital River Lab Animal Technology Co., Ltd
- 12-h light/dark cycle
- temperature of 20-23°C
- relative humidity of 40-70%
- All animals had free access to sterilized drinking water and irradiation sterilized commercial pellet diets except during exposure
- Animals were acclimatized to the laboratory conditions for at least 3 days prior to the test.
- Fasting period: 12 hours before esposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

1000, 2150, 4640 and 10000 mg/kg bw for female, and 2150, 4640, 10000 and 21500 mg/kg bw for male, respectively.

No. of animals per sex per dose:

5

Control animals:

no

Sex:

female

Dose descriptor:

LD50

Effect level:

4 300 mg/kg bw

Based on:

test mat.

95% CL:

2 950 - 6 260

Sex:

male

Dose descriptor:

LD50

Effect level:

5 010 mg/kg bw

Based on:

test mat.

95% CL:

3 440 - 7 300

Clinical signs:

other: The signs such as, activity decreased, limb weakness, side position, dyspnea, issued open mouth breathing were observed in the higher dose groups (21500 and 10000 mg/kg) about 10 minutes after treatment. Death occurred within 4 hour after exposure. The r

Gross pathology:

At 10000 mg/kg, pulmonary hemorrhage and congestion of the liver were observed in 5/5 females; and at 4640 they were observed in 3/5 females.At 21500 mg/kg and 10000 mg/kg, pulmonary hemorrhage and congestion of the liver were observed in 5/5 males; and at 4640 they were observed in 2/5 males.
No gross pathological changes were observed at necropsy at 2150 mg/kg and 1000 mg/kg dose groups.

Sex	Dose (mg/kg)	Mortality
Female	10000	5/5
	4640	3/5
	2150	0/5
	1000	0/5
Male	21500	5/5
	10000	5/5
	4640	2/5
	2150	0/5

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute oral LD50 (95% confidence limits): The oral LD50 (95% confidence limits) of the test substance is 4300 (2950-6260) mg/kg for female rats and 5010 (3440-7300) mg/kg for male rats, respectively.Taking into consideration both males and females, the LD 50 is aoproximately 4655 mg/kg.

Executive summary:

The acute oral toxicity of a,a,a',a'-tetramethyl-m-xylene-a,a'-diol was evaluated in Wistar rats according to OECD N°401 guideline (Acute Toxic Standard Method), but not in compliance with GLP. Groups of 5 male and 5 female Sprague Dawley rats were given a,a,a',a'-tetramethyl-m-xylene-a,a'-diol in corn oil by oral exposure at doses of 464, 1000, 2150 and 4640 mg/kg for female and 1000, 2150, 4640 and 10000 mg/kg for male . Following treatment, rats were observed daily and weighted on days 3, 7 and 14 . A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14).

 

The signs such as activity decreased, limb weakness, side position, dyspnea, issued open mouth breathing were observed in the higher dose groups (21500 and 10000 mg/kg) about 10 minutes after treatment. Death occurred within 4 hour after exposure (mortality was observed from 4640 mg/kg both in males and in females). The rats in the 4640 mg/kg dose group showed slighter signs and the number of deaths was less than the higher dose groups above. No toxic signs and death occurred in the 2150 and 1000 mg/kg dose groups. The survival animals recovered within 24 hours after exposure.

At necropsy, pulmonary hemorrhage and congestion of the liver were observed in dead animals only.

 

The results indicate that the oral LD50 (95% confidence limits) of the test substance is 4300 (2950-6260) mg/kg for female rats and 5010 (3440-7300) mg/kg for male rats, respectively. Taking into consideration both males and females, the LD 50 is aoproximately 4655 mg/kg.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Guideline:

other: REACH Guidance on QSARs R.6

Version / remarks:

May 2008

Guideline:

other: Commercial ACD/Labs model for acute toxicity (LD50) in rats, oral administration, Danish QSAR Group at DTU Food

Version / remarks:

ACD/Labs Tox Suite version 2.95.1.

Specific details on test material used for the study:

Smiles:
1999-85-5: OC(c1cccc(C(O)(C)C)c1)(C)C
2948-46-1: C(C)(C)(O)c1ccc(C(C)(C)O)cc1

Species:

rat

Route of administration:

oral: unspecified

Dose descriptor:

LD50

Effect level:

3 700 mg/kg bw

Remarks on result:

other: QSAR predicted value

Remarks:

Reliability Index: 0.62

Interpretation of results:

Category 5 based on GHS criteria

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Qualifier:

according to guideline

Guideline:

other: REACH guidance. Chapter R.6: QSARs and grouping of chemicals

Version / remarks:

May 2008

Principles of method if other than guideline:

T.E.S.T allows to estimate the value for oral rat LD50 (amount of chemical in mg/kg body weight that causes 50% of rats to die after oral ingestion)

Specific details on test material used for the study:

Smiles:
1999-85-5: OC(c1cccc(C(O)(C)C)c1)(C)C
2948-46-1: C(C)(C)(O)c1ccc(C(C)(C)O)cc1

Species:

rat

Route of administration:

oral: unspecified

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 761 mg/kg bw

Based on:

other: m-DIOL

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 326 mg/kg bw

Based on:

other: p-DIOL

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

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:

01 June 2012 - 05 July 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France.
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: the males had a mean body weight of 350 g (range: 336 g to 359 g) and the females had a mean body weight of 238 g (range: 231 g to 245 g).
- Fasting period before study: yes, during the night before treatment
- Housing: the animals were housed by five from the same sex and group in polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 or 8 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h.

IN-LIFE DATES: 12 June 2012 to 29 June 2012.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Remarks:

but premoistened

Details on dermal exposure:

TEST SITE
- Area of exposure: 10% of body surface, dorsal site
- Type of wrap if used: hydrophilic gauze pad + adhesive hypoallergenic aerated semi-occlusive dressing + restraining bandage

REMOVAL OF TEST SUBSTANCE
- Removal of dressing: 24h post-exposure
- Washing: at 24h post-exposure, with a moistened cotton pad

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume: no
- For solids, paste formed: no

Duration of exposure:

24 hours

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 anmals per sex.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

other: No clinical signs indicative of systemic toxicity were observed in any animals. No cutaneous reactions were observed in any animals.

Gross pathology:

No gross findings were observed.

see Executive summary

Interpretation of results:

not classified

Remarks:

Migrated information CLP Criteria used for interpretation of results: other:

Conclusions:

The dermal LD50 of the test item was higher than 2000 mg/kg in rats.
Therefore, the test item is not classified as toxic by dermal route according to the criteria of CLP Regulation.

Executive summary:

The objective of this study was to evaluate the potential toxicity of the test item following a single dermal application to rats, following the OECD 402 guideline. This study was conducted in compliance with the principles of Good Laboratory Practice.

 

Methods

The test item was applied in its original form (pre-moistened) to the skin of five female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered by a semi-occlusive dressing for 24 hours. Each animal was observed at least once a day for mortality and clinical signs for 15 days. From day 2, any local reactions at the treatment site were also noted. Body weight was recorded on day 1 and then on days 8 and 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. No tissues were preserved.

 

Results

No unscheduled deaths and no clinical signs indicative of systemic toxicity were observed in any animals. No cutaneous reactions were observed in any animals. When compared to CiToxLAB historical control data, a lower body weight gain was noted in all females between day 1 and day 8. Their body weight gain returned to normal thereafter. Body weight of males was unaffected by the test item treatment. There were no macroscopic findings in any animals.

Conclusion

The dermal LD₅₀of the test item was higher than 2000 mg/kg in rats. Therefore, the test item is not classified as toxic by dermal route according to the criteria of CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

Klimisch 1, GLP compliant.

Justification for classification or non-classification

According to EU Regulation (EC) N0. 1272/2008 (CLP), the test item is not classified for acute toxicity.