1,2,3,6-tetrahydromethyl-3,6-methanophthalic anhydride

Endpoint summary

Description of key information

Acute toxicity - Oral LD50: 1300mg/kg; Inhalation: LC50 < 0.75 mg/L; Dermal LD50: 4920mg/kg

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:

July - September 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well conducted study in accordance with methods regarded as similar/equivalent to current OECD guidelines

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Study pre-dates introduction of OECD test methods. Study design similar/equivalent to OECD test methods

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: 99 - 133 g
- Fasting period before study: Overnight
- Housing: No data
- Diet (e.g. ad libitum): No data
- Water (e.g. ad libitum): No data
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: July 1980 To: September 1980

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 4.0mL/kg body weight

Doses:

0.0, 0.5, 1.0, 1.6, 2.5, 5.0 g/kg body weight

No. of animals per sex per dose:

5 male / 5 female

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed daily, weighed weekly
- Necropsy of survivors performed: yes

Statistics:

Probit analysis by method of Finney

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 300 mg/kg bw

Based on:

test mat.

95% CL:

1 100 - 1 600

Mortality:

0.0 g/kg - 0/5 males: 0/5 females
0.5 g/kg - 0/5 males: 0/5 females
1.0 g/kg - 1/5 males: 0/5 females
1.6 g/kg - 3/5 males: 5/5 females
2.5 g/kg - 5/5 males: 5/5 females
5.0 g/kg - 5/5 males: 5/5 females

Clinical signs:

other: Signs of reaction to treatment, observed shortly after dosing in all treated animals included piloerection, abnormal body carriage (hunched posture) and abnormal gait (waddling). These were accompanied by: lethargy, a decreased respiratory rate, pallor of

Gross pathology:

Autopsy revealed congestion and haemorrhages in the lungs and pallor of the liver, spleen and kidneys. These findings were accompanied by: congestion of the intestinal blood vessels amongst rats treated at 1.6 g/kg and above; a creamy-coloured film on the liver in one male and female treated at 2.5 g/kg and three males and females at 5.0 g/kg; haemorrhage of the large intestine and discolouration of its contents in one male treated at 5.0 g/kg; discolouration of the large intestinal contents in one female treated at 5.0 g/kg. Terminal autopsy findings (those animals surviving treatment) were within normal limits.

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Acute toxicity has been determined in the rat following administration of a single oral dose. The median lethal dose (LD50) was determined to be 1300 mg/kg body weight.

Executive summary:

Acute toxicity has been determined in the rat following administration of a single oral dose using method regarded a similar or equivalent to OECD test methods. The median lethal dose (LD50) was determined to be 1300 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 300 mg/kg bw

Quality of whole database:

A total of 4 studies are available, the outcome of which are all similar.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Experimental data with study designed according to standard methods

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes

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:

No data
TEST ANIMALS
- Source: Blue Spruce Farms Inc.
- Fasting period before study: None
- Housing: During acclimatisation group caged, 5 same sex/cage. During study Individually caged in wire mesh cages
- Diet (e.g. ad libitum): ad libitum except during 4 hour exposure period
- Water (e.g. ad libitum): ad libitum except during 4 hour exposure period
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS - No data

IN-LIFE DATES: From: 1981-2-12 To: 1981-2-26

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: ethanol

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel and glass cylindrical chamber
- Exposure chamber volume: 361 L
- Method of holding animals in test chamber: Whole body exposure with animals in wire mesh cages within exposure chamber
- Source and rate of air: Room air drawn into chamber by Vortex transvector jet at flow rate of 70 L/minute
- Method of conditioning air: Not applicable
- System of generating particulates/aerosols: Fluid metering pump feeding an atomiser
- Method of particle size determination: Cascade impactor
- Treatment of exhaust air: Vented to extraction hood
- Temperature, humidity, pressure in air chamber: 21-22 deg C; 41-57% RH; no data on pressure

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric analysis - 5L of chamber air drawn through glass fibre filter. Weight of trapped material used to calculate chamber concentration. Samples taken twice/hour and time weighted average concentration calculated for the 4 hour exposure period
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): Ethanol
- Concentration of test material in vehicle (if applicable): 90% w/w
- Justification of choice of vehicle: No data

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: Particles <10 micron - 93%
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 3.2 / 2.1 micron

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Nominal - 4.9 mg/L
Achieved - 0.75 mg/L

No. of animals per sex per dose:

5 males / 5 female

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations at intervals on day of exposure and daily thereafter. Body weight recorded Prior to exposure (Day 1) and on Days 3, 4, 5, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: Whole head with nasal passages, trachea, bronchi, lungs, liver and kidneys preserved in buffed formalin

Statistics:

No data

Sex:

male/female

Dose descriptor:

LC50

Effect level:

< 4.9 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

< 0.75 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

3/5 males and 5/5 females

Clinical signs:

other: Laboured breathing, nasal discharge and wet coat noted in all animals during exposure. Urinary incontinence, bloody urine, bloody discharge around ano-genital region and film covered appearance of eyes seen in individual animals following exposure.

Body weight:

Weight loss occurred in all animals following exposure. Only 1 of the 2 surviving animals re-gained its original body weight.

Gross pathology:

No unusual findings

Interpretation of results:

toxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Acute toxicity has been determined in the rat following 4 hours inhalation exposure. A single group of rats were exposed to a nominal concentration of 4.9 mg/L (achieved concentration was 0.75 mg/L) and 80% mortality occurred. The median lethal concentration (LC50) is therefore less than the concentration investigated.

Executive summary:

Acute toxicity has been determined in the rat following 4 hours inhalation exposure. A single group of rats were exposed to a nominal concentration of 4.9 mg/L (achieved concentration was 0.75 mg/L) and 80% mortality occurred. The median lethal concentration (LC50) is therefore less than the concentration investigated.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

discriminating conc.

Value:

750 mg/m³ air

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Although the study pre-dates current test guidelines and GLP regulations, the design follows standard methods for the determination of acute toxicity.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Remarks:

Study pre-dates implementation of GLP regulations

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Tif: RAIf

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: In-house breeding colony
- Age at study initiation: No data
- Weight at study initiation: 155 - 208 g
- Fasting period before study: Overnight
- Housing: Group caged (5 same sex / cage)
- Diet (e.g. ad libitum): Standard rodent diet pellets (Nafag Gossau SG), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23 deg C
- Humidity (%): 50-60%
- Photoperiod (hrs dark / hrs light): 10 hours dark / 14 hour light

IN-LIFE DATES: From: March 1977 To: May 1977

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 100 cm2 / kg body weight
- Type of wrap if used: Occlusive dressing held in place by adhesive elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes - warm water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000, 3000, 4000 and 5000 mg/kg body weight
- Constant concentration used: yes (undiluted)

Duration of exposure:

24 hours

Doses:

2000, 3000, 4000 and 5000 mg/kg body weight

No. of animals per sex per dose:

5 males / 5 females / dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 24, 48 and 72 hours and 14 days after dosing; Body weights recorded at test start and termination
- Necropsy of survivors performed: yes

Statistics:

Probit analysis

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 920 mg/kg bw

Based on:

test mat.

95% CL:

3 670 - 6 590

Mortality:

2000 mg/kg - 0/5 males, 0/5 females
3000 mg/kg - 1/5 males, 1/5 females
4000 mg/kg - 2/5 males, 1/5 females
5000 mg/kg - 2/5 males, 3/5 females

Clinical signs:

other: 2000 mg/kg - Reduced activity and ataxia seen after 60 minutes. After 3 hours palpebral closure apparent. After 6 hours ventricumbency occurred Palpebral closure and humpbacked posture lasted 2 days. 3000 mg/kg - Reduced activity and ataxia seen after 60

Gross pathology:

2000 mg/kg - No gross organ changes seen
3000 mg/kg – Decedent animals not examined due to cannibalism by cage mates. No gross organ changes seen in surviving animals.
4000 mg/kg – Examination of decedent animals revealed congestion of the lungs, bloody stomach content and petechial haemorrhage on the stomach mucosa. Surviving animals showed no pathology.
5000 mg/kg – As above

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Acute toxicity has been determined in the rat following administration of a single dose to the skin for a 24 hour period. The median lethal dose (LD50) was determined to be 4920 mg/kg body weight.

Executive summary:

Acute toxicity has been determined in the rat following administration of a single dose to the skin for a 24 hour period. The median lethal dose (LD50) was determined to be 4920 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

4 920 mg/kg bw

Quality of whole database:

A total of 2 studies are available, the outcome of which are similar.

Additional information

Acute toxicity has been determined in the rat following administration of a single oral dose. The median lethal dose (LD50) was determined to be 1300 mg/kg body weight. A second study resulted in a LD50 of 1580 mg/kg. A third study, in which the undiluted substance was administered to rats, resulted in a LD50 of 958.4 mg/kg body weight. A fourth, poorly documented study, reports a LD50 of 914 mg/kg.

Acute inhalation toxicity has been investigated using methods similar to those described by OECD test guidelines. Exposure to a respirable atmosphere for 4 hours at a concentration of 0.75 mg/L resulted in 80% mortality. The median lethal concentration (LC50) is therefore less than 0.75 mg/L.

Acute dermal toxicity has been investigated using methods similar to those described by OECD test guidelines. Toxicity in the rat, following administration of a single dose to the skin for a 24 hour period, resulted in a median lethal dose (LD50) of 4920 mg/kg body weight. A similar study in the rabbit, in which a single dose of 2000 mg/kg was investigated, resulted in no mortality. The median lethal dose (LD50) was therefore in excess of 2000 mg/kg.

Justification for selection of acute toxicity – oral endpoint
Best documented study

Justification for selection of acute toxicity – inhalation endpoint
Single study available

Justification for selection of acute toxicity – dermal endpoint
Best documented study

Justification for classification or non-classification

Based on the results obtained in the acute toxicity studies (oral LD50 1580 mg/kg bw; inhalation LC50 < 0.75 mg/L, dermal LD50 > 2000 mg/kg bw and taking into account the provisions laid down in Council Directive 67/548/EEC and CLP (1272/2008/EC), the substance should be classified regarding acute oral toxicity (harmful / Category 4) and acute inhalation toxicity (toxic / Category 3).