Etidronic acid

Endpoint summary

Description of key information

In a well conducted study (Younger Laboratories, 1965) 60% HEDP-H was administered to Sprague-Dawley rats (two or three per sex depending on dose; five total) as aqueous solutions at doses of 2000, 2510, 3160 and 3980 mg/kg bw, by oral gavage. Observations were made for clinical signs and the viscera of the animals that died were examined macroscopically. There were 0, 1, 3 and 4 deaths, respectively. Survival time was 1 -8 hours with most deaths occurring in 1 to 2 hours. At macroscopic examination, inflammation of the gastric mucosa and haemorrhagic areas in the lungs were observed. Toxic symptoms included weakness followed by dyspnoea and collapse. The LD50 for the test substance was calculated to be 3130 mg/kg bw (reviewer of IUCLID comment: presumed equivalent to 1878 mg/kg bw of 100% active acid).

No data were available for HEDP acid for acute dermal toxicity. Therefore, data were read across from HEDP salts.

In an acute dermal toxicity limit test (Biodynamics Inc., 1985) 5000 mg/kg bw of HEDP-4Na (as 31% active salt) was applied to the skin of rabbits (5/sex, occlusive dressing, 24 hours). Animals were then observed for 14 days. One female died on Day 13 (not test-related). Most animals had severe dermal effects at the dose site (necrosis followed by eschar formation and/or exfoliation of the eschar tissue), which persisted throughout the observation period. The LD50 was determined to be >5000 mg/kg bw as test material (subsequently calculated to be equivalent to >3500 mg active acid/kg bw). 

 

The test substance was tested at pH 11.5. The above local irritation effects in the oral study and severe dermal effects in the dermal study may not be directly comparable to the registration substance. The deaths are possibly secondary to the local effects and therefore using this study as read-across is a conservative or worst-case approach.

 

There are no acute inhalation data.

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:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Study conducted prior to the adoption of OECD test guidelines.

Deviations:

yes

Remarks:

Level of report detail does not meet current standards.

GLP compliance:

no

Remarks:

Study was conducted prior to GLP.

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: Not specified
- Females (if applicable) nulliparous and non-pregnant: Not specified
- Age at study initiation: Not specified
- Weight at study initiation: from 225 to 270 g
- Fasting period before study: Not specified
- Housing: Not specified
- Diet (e.g. ad libitum): Not specified
- Water (e.g. ad libitum): Not specified
- Acclimation period: Not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not specified
- Humidity (%): Not specified
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): Not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

The test substance was administered by gavage (dosing volumes not stated, as a 50% aqueous solution).   No details about the range-finding study, test conditions or observation schedule are provided.  

Doses:

2000, 2510, 3160 and 3980 mg/kg bw

No. of animals per sex per dose:

3 females and 2 males at 2000 mg/kg bw
3 females and 2 males at 2510 mg/kg bw
2 females and 3 males at 3160 mg/kg bw
2 females and 3 males at 3980 mg/kg bw

Control animals:

no

Details on study design:

- Duration of observation period following administration: Clinical signs of toxicity observed for, but duration not stated.
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopic examination of the viscera of animals that died.

Statistics:

LD50 calculated by a modification of the method of E.J. de Beer (no further details).  Calculation was not presented in study report.

Preliminary study:

No data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 130 mg/kg bw

Based on:

test mat.

95% CL:

> 2 660 - < 3 665

Remarks on result:

other: presumed equivalent to 1878 mg active acid/kg bw

Mortality:

No death was observed at 2000 mg/kg bw. One female died at 2510 mg/kg bw. Two male and one female rats died at 3160 mg/kg bw. Two male and two female rats died at 3980 mg/kg bw. Survival time was one to eight hours with most deaths occurring in one to two hours.

Clinical signs:

other: Toxic symptoms included weakness followed by dyspnoea and collapse.

Gross pathology:

At autopsy there was inflammation of the gastric mucosa and haemorrhagic areas in the lungs.

Other findings:

No data

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In a well conducted acute oral study (reliability score 2), conducted using a protocol similar to the now deleted OECD 401, but not to GLP, an LD50 of 3130 mg/kg bw was determined for the test substance (60% HEDP-H) in the rat (reviewer of IUCLID comment: presumed equivalent to 1878 mg active acid/kg bw) .

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

1 878 mg/kg bw

Quality of whole database:

(active acid)

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:

04.03.1985 to 02.04.1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Remarks:

Conducted prior to adoption of GLP

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton-Dutchland Laboratory animals
- Age at study initiation: 8 weeks
- Weight at study initiation: Males: 2.2-2.7 kg. Females: 2.5-2.7 kg
- Fasting period before study: No
- Housing: Individually, in suspended stainless steel cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 60-70
- Humidity (%): 30-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 19.03.85 To: 02.04.85

Type of coverage:

occlusive

Vehicle:

other: aqueous solution, administered undiluted.

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal area of the trunk
- % coverage: 10% of body surface area
- Type of wrap if used: Impervious plastic sleeve


REMOVAL OF TEST SUBSTANCE
- Washing (if done): test sites wiped free of excess test substance
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 3.8 ml/kg

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

Five

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Viability: Twice daily. Clinical signs: 1, 2, and 4 hours after dosing and then daily for 14 days. Body weights: Pretest, immediately prior to dosing and days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: Macroscopic examination of all animals.

Statistics:

None

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Remarks on result:

other: Presumed equivalent to 3505 mg active acid/kg bw

Mortality:

One female died on Day 13. However, macroscopic examination revealed signs of intestinal disease that was not thought to be related to the test substance. All other animals survived to the end of the observation period.

Clinical signs:

other: In all surviving animals there were some occurrences of oral and nasal discharge. Most animals had severe dermal effects at the dose site (necrosis followed by eschar formation and/or exfoliation of the eschar tissue), which persisted throughout the obse

Gross pathology:

The female that was found dead had gross abnormalities suggestive of mucoid enteritis. Apart from the presence of dermal lesions, there were no abnormal findings in the other animals.

Other findings:

None reported.

Interpretation of results:

GHS criteria not met

Conclusions:

In a well-conducted acute dermal toxicity limit test, conducted according to a protocol that was similar to OECD 402, but not to GLP, the dermal LD50 for Dequest 2016 was >5000 mg/kg bw (IUCLID 4 reviewer comment: presumed equivalent to 3505 mg active acid/kg bw) in the rabbit.

Executive summary:

In a well-conducted acute dermal toxicity limit test, conducted according to a protocol that was similar to OECD 402, but not to GLP, 5000 mg/kg bw of Dequest 2016 was applied to the skin of New Zealand white rabbits (5/sex) under an occlusive dressing, for 24 hours. After the 24 hour exposure period excess test substance was wiped off the test site. Animals were then observed for 14 days for signs of toxicity, and body weights were measured prior to dosing and on days 7 and 14. All animals were examined macroscopically. One female died on Day 13. However, macroscopic examination revealed signs of intestinal disease that was not thought to be related to the test substance. All other animals survived to the end of the observation period. In all surviving animals there were some occurrences of oral and nasal discharge. Most animals had severe dermal effects at the dose site (necrosis followed by eschar formation and/or exfoliation of the eschar tissue), which persisted throughout the observation period. Most animals had slight weight losses at Days 7 and/or 14. The female that was found dead had gross abnormalities suggestive of mucoid enteritis. Apart from the presence of dermal lesions, there were no abnormal findings in the other animals. The LD₅₀ was determined to be >5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 500 mg/kg bw

Quality of whole database:

(active acid)

Additional information

The most recent reliable studies were selected as key for both the acute oral and acute dermal endpoints.

 

Justification for classification or non-classification

Based on the available data, it is proposed that HEDP acid is classified as Acute Oral Cat. 4 H302: Harmful if swallowed' according to Regulation (EC) No 1272/2008. There is no requirement to classify HEDP acid for acute dermal toxicity.