Commiphora myrrha, ext.

Endpoint summary

Description of key information

LD50 > 2000 mg/kg bw based on a WoE:

- LD50 (Rats) > 5000 mg/ kg bw (similar to OECD 401, Rel. 4)

- LD50 (Mice) > 3000 mg/kg bw (similar to OECD 401, Rel. 4)

- No mortality up to 1000 mg/kg bw/day in a 28 -day repeated dose toxicity study (similar to OECD 407, Rel.4)

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

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Remarks:

study conducted similarly to OECD Guideline 401 but with a limited observation period (24 hours only)

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1987

Deviations:

yes

Remarks:

2 test groups, sex allocation per groups is not known, 24h observation period, no details on composition of the test substance

GLP compliance:

not specified

Remarks:

this information is not reported in the publication

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

"Wister albino rats"

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not reported
- Females (if applicable) nulliparous and non-pregnant: not reported
- Age at study initiation: 3-4 months
- Weight at study initiation: 150-250 g, The mean weight of rats have been estimated from 10 randomly selected rats and was found to be 198.0 g
- Fasting period before study: not reported
- Housing: Rats were divided into five individuals for each group and allocated randomly in separate clean and well ventilated cages.
- Diet : standard pellet diet purchased from ARASCObCompany, KSA.
- Water : The drinking water
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C.
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark cycle

IN-LIFE DATES: no reported

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

distilled water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: not reported. The required doses of the plant’s resins were suspended in 5 ml distilled water and administered orally using long-mouth syringe.
- Amount of vehicle (if gavage): 5 mL
- Justification for choice of vehicle: not reported

MAXIMUM DOSE VOLUME APPLIED: not reported

Doses:

1000 and 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 24h
- Frequency of observations and weighing: observations at least after 6h and 24h
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight: once before treatment and thereafter at termination, other: hematological and biochemical analysis

Statistics:

Results were presented as mean ± S.E.M. One way analysis of variance (ANOVA) was used to determine significance between tests and controls. P-values less than 0.05 were considered significant.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

other: test material in suspension

Mortality:

none reported

Clinical signs:

other: - 1000 and 5000 mg/kg bw: after 6h, a symptom of weakness and decrease in moving activity is observed. These symptoms increased on the next day. Reduction in motion activity and weakness observed may be due to the fragrant resins and volatile oils and oth

Other findings:

The hematological and biochemical parameters of the rat groups that administered high-dose oral single dose of either C. molmol suspensions exhibited serous significant variations. It is known that at higher concentrations, the toxic effects become manifest owing to the physiopharmacological interactions. Animals that administered C. molmol suspension showed significant increase in MCH and MCHC. While RDW and MPV showed significant decrease, while other hematological parameters were insignificant. As well, the biochemical analysis results revealed significant increase in BUN and K+ ions, beside significant decrease in Na+ and Ca+2 ions, whereas other biochemical parameters were insignificant in comparison with the control group.

Table 7.2.1/1: Hematological studies on rats after single dose treatment

Plant	Dose mg/kg/day	WBC (×10^3/µl)	RBC (×10^6/µl)	HGB (g/dl)	HCT (%)	MCV (fl)	MCH (pg)	MCHC (g/dl)	RDW (%)	PLT (x10^3/µl)	MPV (fl)
C. molmol	1000	9.9±0.9	8.7± 0.4	15.7± 0.5	48.8± 1.9	55.0± 0.6	18.0± 0.2	32.2± 0.2	15.4± 0.9	876.8± 119.1	6.9± 0.1
	5000	8.4± 1.0	8.8± 0.1	16.7± 0.2	50.6± 0.9	58.0± 0.3	19.4± 0.1	33.5± 0.2	12.3± 0.4	924.0± 95.3	6.3± 0.1
control	0	12.2± 0.7	7.8± 0.4	14.8± 0.6	45.3± 1.7	58.0± 1.3	19.0± 0.3	32.7± 0.3	14.7± 0.3	757.0± 58.3	9.4± 0.5

Data presented as mean ± S.E.M., n = 5, significantly different from control: P < 0.05.

Table 7.2.1/2: Biochemical studies on rats after single dose treatment

Plant	Dose mg/kg/day	GLU mmol/l	BUN mmol/l	CRE Umol/l	AST U/l	ALT U/l	ALP U/l	Na^+ mmol/l	K^+ mmol/l	CA^2+ mmol/l	Cl^- mmol/l
C. molmol	1000	10.3±1.6	9.8± 1.5	43.2± 2.9	184.4± 9.8	70.6± 16.2	247.4± 38.0	126.2± 2.5	19.4± 1.6	2.67± 0.02	92.8± 1.3
	5000	13.6± 2.6	11.5± 3.0	49.2± 5.1	162.5± 17.3	84.0± 14.8	357.2± 44.1	127.0± 3.0	21.5± 2.3	2.81± 0.05	94.2± 1.1
control	0	15.0± 1.9	6.6± 0.6	55.2± 2.2	150.2± 15.8	72.6± 9.2	319.2± 12.5	143.2± 0.9	9.75± 0.9	3.3± 0.04	95.0± 0.6

Data presented as mean ± S.E.M., n = 5, significantly different from control: P < 0.05.

Interpretation of results:

GHS criteria not met

Conclusions:

Oral LD50 > 5000 mg/kg bw

Executive summary:

In an acute oral toxicity study performed similarly to OECD Guideline 401, groups of Wister albino rats (5/dose) were administered a single oral dose of aqueous suspensions of the resin of Commiphora molmol at 1000 or 5000 mg/kg bw/day. Animal were then observed for mortality, clinical signs, body weights, hematological and biochemical analysis for one day.

No mortality was reported during the 24h observation period. Weakness and decrease in motion activity were observed at 5000 mg/kg bw in addition to significant variations in some hematological and biochemical parameters compared to the control group.

The acute oral LD50 is considered to be higher than 5000 mg/kg bw.

Under the test conditions, the substance is not classified for acute oral toxicity according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Remarks:

study conducted similarly to OECD Guideline 401 but with a limited observation period (24 hours only)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1987

Deviations:

yes

Remarks:

mice, the sex of the animals is not defined, 24h observation period, no details on composition of the test substance

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

Swiss

Remarks:

Swiss albino mice

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: home bred (Central Laboratory for Drug & Food Analysis, Ministry of Health)
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 24-28 g
- Fasting period before study: not reported
- Housing: not reported
- Diet : Purina Chow diet
- Water : ad labium
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controled. no details
- Humidity (%): controled. no details
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 h light / 12 h dark cycle

IN-LIFE DATES: no reported

Route of administration:

oral: unspecified

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: not reported. It was crushed and suspended in water at room temperature according to the dose required
- Justification for choice of vehicle: not reported

MAXIMUM DOSE VOLUME APPLIED: not reported

Doses:

500, 1000 and 3000 mg/kg bw

No. of animals per sex per dose:

5 animals per group

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 24h
- Frequency of observations and weighing: not specified
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 000 mg/kg bw

Based on:

other: test material in suspension

Mortality:

none

Clinical signs:

other: No visible signs of toxicity was observed up to 3 g/kg dose level. However, some decrease in locomotor activity at a dose of 3 g/kg was noticed.

Interpretation of results:

GHS criteria not met

Conclusions:

Oral LD50 > 3000 mg/kg bw

Executive summary:

In an acute oral toxicity study performed similarly to OECD Guideline 401, groups of albino mice (5/group) were administered a single oral dose of an aqueous suspensions of the resin of Commiphora molmol at 500, 1000 or 3000 mg/kg bw. Animals were then observed for mortality and clinical signs for 1 day.

No mortality and no visible signs of toxicity was observed during the 24h observation period up to 3000 mg/kg bw. However, some decrease in locomotor activity at a dose of 3000 mg/kg bw was noticed, which may be attributed to the presence of high contents of volatile oils in C.molmol. In general, volatile oil are known to have depressant action on the central nervous system.

The acute oral LD50 is considered to be higher than 3000 mg/kg bw.

Under the test conditions, the substance is not classfifed for acute oral toxicity according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

A weight-of-evidence approach was used to conclude on the acute oral toxicity of the substance.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Not required for an Annex VII dossier

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Not required for an Annex VII dossier

Additional information

A weight-of-evidence approach was used to conclude on the acute oral toxicity of the substance:

- In the study of Abdallah (2009, rel.4), rats (5/dose) were administered a single oral dose of aqueous suspensions of the test item at 1000 or 5000 mg/kg bw/day. Animal were then observed for mortality, clinical signs, body weights, hematological and biochemical analysis for one day. No mortality was reported during the 24h observation period. Weakness and decrease in motion activity were observed in addition to significant variations in some hematological and biochemical parameters in the high dose group compared to the control group.

The acute oral LD50 is considered to be higher than 5000 mg/kg bw in rats.

- In the study of Rao (2011, Rel.4), mice (5/dose) were administered a single oral dose of an aqueous suspensions of the test item at 500, 1000 or 3000 mg/kg bw. Animals were then observed for mortality and clinical signs for 1 day. No mortality and no visible signs of toxicity was observed during the 24h observation period up to 3000 mg/kg bw. However, some decrease in locomotor activity at a dose of 3000 mg/kg bw was noticed, which may be attributed to the presence of high contents of volatile oils in the test item. In general, volatile oil are known to have depressant action on the central nervous system.

The acute oral LD50 is considered to be higher than 3000 mg/kg bw in mice.

- In the study of Abdallah (2009, rel. 4), rats (6/dose) were administered aqueous suspensions of the test item at 250, 500 or 1000 mg/kg bw/day during 28 days. Significant decrease in mean body weights was observed. However, no toxic symptoms or deaths were found and the rats were active and healthy up to the end of the treatment.

Taking into account all the available elements of evidence, it is concluded that the substance is not classified for acute oral toxicity according to CLP criteria (i.e. LD50 > 2000 mg/kg bw).

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity via Oral route:

Based on the available data the substance is not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw.

Acute toxicity via Dermal route:

No data was available.

Acute toxicity (Inhalation):

No data was available.

Specific target organ toxicity: single exposure (Oral):

Based on the available data, the classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 and to the GHS as specific target organ toxicant (STOT) – single exposure,

oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

No data was available

Specific target organ toxicity: single exposure (Inhalation):

No data was available.