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Administrative data

Description of key information

There are no acute toxicity data for HEDP-xK, therefore good quality data are read-across from the category members HEDP-4Na and HEDP (2-3Na).

In an acute oral study conducted using a protocol similar to the now deleted OECD Test Guideline 401 but pre-GLP, undiluted HEDP-4Na was administered to five Sprague-Dawley rats by oral gavage at doses of 2000, 2500, 3200 or 4000 mg/kg bw (aqueous solution). The LD50 was calculated to be 2850 mg/kg bw (equivalent to 940 mg/kg/day bw active salt and 659 mg/kg bw/day active acid) (BioDynamics Inc., 1985; reliability 2).

In a well-conducted acute dermal toxicity limit test conducted according to a protocol similar to OECD Test Guideline 402 and pre-GLP, 5000 mg/kg bw of HEDP-4Na was applied to the skin of New Zealand white rabbits (5 per sex) under an occlusive dressing for 24 hours. The LD50 was determined to be >5000 mg/kg bw (equivalent to 3505 mg active acid/kg bw) (BioDynamics Inc., 1985; reliability 2).  

 

In an acute dermal toxicity study (reliability score 2), conducted prior to the adoption of OECD test guidelines and pre-GLP, the LD50 for HEDP (2-3Na) was >7940 mg/kg bw in rabbits. This was based on no observed mortality although some toxicity was observed including reduced appetite and activity for one to three days (Younger lab, 1971).

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:
12.03.1985 to 17.04.1985 (inclusive of limit, range-finder and LD50 tests)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
no post-dose fast
Principles of method if other than guideline:
Bio/dynamics protocol based on US guidelines. Broadly compatible with OECD guideline.
GLP compliance:
no
Remarks:
pre-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: Charles River Breeding Laboratories
- Age at study initiation: 9-12 weeks
- Weight at study initiation: 220-329 g
- Fasting period before study: 18 hours overnight prior to dosing
- Housing: Six per cage, suspended, stainless steel with wire mesh bottoms
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: At least 9 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 67-76 (equivalent to 19.4-24.4 °C)
- Humidity (%): 30-70 %
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hours dark /12 hours light


IN-LIFE DATES: Limit test: From: 21.03.85 To: 22.03.85
Range-finding test: From: 27.03.85 To: 03.04.85
LD50 test: From: 03.04.85 To: 17.03.85
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 3.8 mL/kg in the limit test, 1.5 mL/kg in the range-finding test, and 3.1 mL/kg in the LD50 test.
Doses:
Limit test: 5000 mg/kg bw.
Range-finding test: 50, 100, 500, 1000 or 2000 mg/kg bw
LD50 determination: 2000, 2500, 3200 or 4000 mg/kg bw
No. of animals per sex per dose:
Limit test: 5
Range-finding test: 1
LD50 determination: 5
Control animals:
no
Details on study design:
Animals used in the range-finding test were observed for viability twice daily and deaths were recorded. The following observations were made on all other animals.
Viability check: twice daily.
Clinical signs: approximately 1, 2 and 4 hours after dosing and daily thereafter for 14 days
Body weights: Pre-fasting, post-fast, just prior to dosing, and Days 7 and 14 after dosing.
Macroscopic examination: Not on range-finding test animals. A macroscopic examination was conducted on all other animals.
Statistics:
The LD50 with 95% confidence limits was calculated using the method of Miller, Lloyd C. and M.L. Tainter., Estimation of the ED50 and its error by means of Logarithmic-Probit graph paper, Proc.Soc.Exp.Bio.Med. 57: 261-264 (1944).
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 850 mg/kg bw
95% CL:
>= 2 489 - <= 3 211
Remarks on result:
other: (equivalent to 940 mg/kg bw active salt, which is equivalent to 659 mg/kg bw active acid).
Mortality:
RANGE FINDING TEST: No deaths at any dose level. 
LD50 DETERMINATION TEST/LIMIT TEST: At 2000 mg/kg, 1 animal died (day 3 after dosing) 
At 2500 mg/kg, 4 animals died (1-4 hours after dosing) 
At 3200 mg/kg, 7 animals died (1 hour - day 8 after dosing) 
At 4000 mg/kg, 8 animals died (1-4 hours after dosing) 
At 5000 mg/kg, all 10 animals died (2-7 hours after dosing)
Clinical signs:
other: LD50 determination: Observations in all groups for up to four hours post-dosing, included ataxia and/or tremors, oral and nasal discharge, hypoactivity, soft stool and faecal and/or urinary staining.
Gross pathology:
LD50 determination: Macroscopic abnormalities observed at necropsy were primarily changes to the lungs (discolouration) and gastrointestinal tract (red or black walls, or red or black fluid present, suggestive of an irritant effect). Most of the animals in the 2500, 3200 and 4000 mg/kg dose groups had enlarged kidneys at necropsy, and one animal in the 4000 mg/kg bw group had unilateral renal pallor, dilated renal pelvis and red fluid surrounding the kidney. 
Other findings:
None reported.

Table 1 Summary of deaths in LD50 determination study.

 Dose   Mortality       Time to death
 mg/kg bw  Males  Females  Combined  
 2000  1/5  0/5  1  day 3
 2500  1/5  3/5  4  1 -4 h
 3200 3/5  4/5  7  1 h to day 8
 4000  4/5  4/5  8  1 -4 h
 5000  5/5  5/5  10  2 -7 h
 LD50  3100  2500  2850  
 95% conf limit  2365 -3635  1802 -3198  2489 -3211  




Interpretation of results:
GHS criteria not met
Conclusions:
In an acute oral study, conducted using a protocol similar to the now deleted OECD Test Guideline 401 but pre-GLP, an LD50 of 2850 mg/kg was determined for HEDP-4Na in the rat. This is equivalent to 940 mg/kg/day bw active salt and 659 mg/kg bw/day active acid.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
940 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

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
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
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
Study conducted prior to the adoption OECD test guidelines.
Deviations:
yes
Remarks:
Only one animal tested and limited reporting.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
water
Duration of exposure:
At least 24 hours.
Doses:
2000, 3160, 5010, 7940 and 7940 mg/kg bw (the report gives the highest dose twice, it is assumed that the duplicated dose is the highest dose).
No. of animals per sex per dose:
One (male or female)
Control animals:
not required
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 7 940 mg/kg bw
Remarks on result:
other: No deaths.
Interpretation of results:
GHS criteria not met
Conclusions:
In an acute dermal toxicity study (reliability 2), conducted prior to the adoption of OECD test guidelines and pre-GLP, the LD50 for HEDP (2-3Na) (25% aqueous solution) was >7940 mg/kg bw in rabbits. This was based on no observed mortality although some toxicity was observed including reduced appetite and activity for one to three days.
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
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Remarks:
pre-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: Ad libitum
- Water: 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 hours dark / 12 hours light


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: 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: 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 considered 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 similar to OECD Test Guideline 402 but pre-GLP, the dermal LD50 for HEDP-4Na was >5000 mg/kg bw (presumed equivalent to 3505 mg active acid/kg bw) in the rabbit.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
> 3 505 mg/kg bw

Additional information

In an acute oral study (reliability score 2), conducted using a protocol similar to the now deleted OECD Test Guideline 401 but pre-GLP, undiluted HEDP-4Na (5000 mg/kg bw) was administered to five Sprague-Dawley rats by oral gavage in a limit test. Within seven hours, all of the animals had died. Therefore, a range-finding study and subsequently, an LD50 was determined. In the range-finding study, doses of 50, 100, 500, 1000 or 2000 mg/kg bw were administered to one male and one female Sprague-Dawley rat. Based on the findings of this study, doses of 2000, 2500, 3200 and 4000 mg/kg bw HEDP-4Na was administered to five male and five female Sprague-Dawley rats by oral gavage. Animals were observed for 14 days following dosing, and all animals were examined macroscopically. Body weights were recorded prior to dosing and on days 7 and 14. Mortality was observed in 1, 4, 7 and 8 animals, respectively. Observations in all groups for up to four hours post-dosing, included ataxia and/or tremors, oral and nasal discharge, hypoactivity, soft stool and faecal and/or urinary staining. The majority of surviving animals showed some weight loss during the first week after dosing, although all animals gained weight between days 7 and 14. Macroscopic abnormalities observed at necropsy were primarily changes to the lungs (discolouration) and gastrointestinal tract (red or black walls, or red or black fluid present, suggestive of an irritant effect). Most of the animals in the 2500, 3200 or 4000 mg/kg dose groups had enlarged kidneys at necropsy and one animal in the 4000 mg/kg bw group had unilateral renal pallor, dilated renal pelvis and red fluid surrounding the kidney. The LD50 was calculated to be 2850 mg/kg bw (equivalent to 940 mg/kg/day bw active salt and 659 mg/kg bw/day active acid) (BioDynamics Inc., 1985). As a precautionary approach this study is used as the basis of the classification and labelling conclusion for HEDP-xK.

 

In a well conducted acute oral toxicity study (reliability score 2), conducted using a protocol similar to the now deleted OECD Test Guideline 401 but pre-GLP, an LD50 of 5300 mg/kg bw (equivalent to 3715 mg active acid/kg bw) was determined in rats for HEDP-4Na. This was based on mortality occurring in two of five rats at 5300 mg/kg bw as well as some toxicity including diarrhoea, convulsions and rapid weakness with collapse in 10-30 minutes post-dosing. Some of the animals that collapsed improved within 1-2 hours and survived (Younger Laboratories, 1965).

In a well-conducted acute dermal toxicity limit test (reliability score 2), conducted according to a protocol similar to OECD Test Guideline 402 and pre-GLP, 5000 mg/kg bw of HEDP-4Na was applied to the skin of New Zealand white rabbits (5 per 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 observed for 14 days for signs of toxicity. 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 considered 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, no abnormal findings were observed in the other animals. The LD50 was determined to be >5000 mg/kg bw (equivalent to 3505 mg active acid/kg bw) (BioDynamics Inc., 1985).

In an acute oral toxicity study (reliability score 2), conducted to a protocol similar to the now deleted OECD Test Guideline 401 and pre-GLP, HEDP (2-3Na) was administered by oral gavage to ten female Wistar rats in concentrations of 2510, 3160, 3570, 3980 mg/kg bw at 20 mL/kg using water as the vehicle. The animals were individually housed and kept in three Makrolon cages. An LD50 of 3550 mg/kg bw which is equivalent to 2925 mg/kg bw active acid was concluded (Henkel KGaA, 1984).

In an acute oral toxicity study (reliability score 2), unknown if in accordance with any OECD Test Guideline and pre-GLP, an LD50 of 1340 mg/kg, equivalent to 1104 mg/kg bw active acid was determined for the 25 % active ingredient of HEDP (2-3Na) in the rat (Nixon et al., 1972).

In a well conducted acute oral toxicity study (reliability score 2), conducted using a protocol similar to the now deleted OECD 401 but pre-GLP, an LD50 of 3400 mg/kg bw was determined for HEDP (2-3Na) in the rat (Younger Laboratories, 1971).

In an acute oral toxicity study (reliability score 2), unknown if comparable to any OECD Test Guidelines and pre-GLP, HEDP (2-3Na) was tested in various gavage doses in male (immature and mature) and female (immature, mature, pregnant and non-pregnant) New Zealand white rabbits. The lowest LD50 found for mature male rabbits was 581 mg/kg bw (equivalent to 139.4 mg/kg bw/day active acid) while younger (immature) animals appeared less sensitive with an LD50 of 1140 mg/kg bw (equivalent to 939.4 mg/kg bw/day active acid) (Nixon et al., 1968).

In an acute dermal toxicity study (reliability score 2), conducted prior to the adoption of OECD test guidelines and pre-GLP, male and female New Zealand rabbits were exposed to HEDP (2-3Na) for at least 24 hours under occlusive coverage in concentrations of 2000, 3160, 5010 or 7940 mg/kg bw. The LD50 for HEDP (2-3Na) was concluded to be >7940 mg/kg bw. This was based on no observed mortality although some toxicity was observed including reduced appetite and activity for one to three days (Younger laboratories, 1971).

Justification for classification or non-classification

Based on the available acute oral toxicity studies on HEDP-4Na, HEDP-xK is classified as ‘Acute Oral Cat. 4’ in accordance with Regulation (EC) No. 1272/2008; hence 'H302: Harmful if swallowed'.