[[(phosphonomethyl)imino]bis[hexamethylenenitrilobis(methylene)]]tetrakisphosphonic acid

Endpoint summary

Description of key information

There are no acute toxicity data available for BHMT-H. Therefore, data are read across from the structural analogue DTPMP-H (CAS 15827-60-8).

In the acute oral toxicity study for DTPMP-H (Younger Laboratories, 1971a), conducted according to a protocol similar to the now-deleted OECD Test Guideline 401, but conducted prior to GLP, the LD50 was concluded to be 7180 mg/kg bw (equivalent to 4164 mg active acid/kg bw).

In the acute dermal toxicity study for DTPMP-H (Younger Laboratories, 1971b), conducted according to a protocol similar to OECD Test Guideline 402, but conducted prior to GLP, the LD50 was concluded to be greater than 7940 mg/kg bw (equivalent to >4605 mg active acid/kg bw).

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:

Conducted prior to the adoption of OECD test guideline.

Principles of method if other than guideline:

Method: other: Insufficient detail to fully assess comparability with OECD guideline.

GLP compliance:

no

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: Males: 190-250 g. Females: 200-235 g.
- Weight at study initiation: No data
- Fasting period before study: No data
- 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: No data

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: No data

Doses:

5010, 6310, 7940 and 10000 mg/kg bw

No. of animals per sex per dose:

5010 mg/kg bw : 2 male, 3 female; 6310 mg/kg bw: 3 male, 2 female; 7940 mg/kg bw: 2 male, 3 female; 10000 mg/kg bw:  3 male, 2 female.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: yes, animals that died during the test and surviving animals (killed seven days after dosing) were necropsied.  Viscera of test animals were observed macroscopically.  
- Other examinations performed: clinical signs

Statistics:

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

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 7 180 mg/kg bw

Based on:

test mat.

95% CL:

>= 6 570 - <= 7 830

Sex:

male/female

Dose descriptor:

LD50

Remarks:

active acid

Effect level:

4 164 mg/kg bw

Based on:

act. ingr.

Mortality:

0, 2 (females), 3 (females) and 5 deaths at 5010, 6310, 7940 and 10000 mg/kg bw, respectively. Survival times were several hours to one day.

Clinical signs:

other: Toxic signs included reduced appetite and activity, slight lethargy (lasting two to seven days in survivors), rapidly increasing weakness, collapse and death.

Gross pathology:

In animals that died there was slight liver discolouration and acute gastrointestinal inflammation. Seven days after administration the viscera of surviving animals appeared normal at macroscopic examination.

Other findings:

None reported.

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study (reliability score 2) conducted prior to the adoption of OECD guidelines and GLP, the LD50 for DTPMP-H was 7180 mg/kg (previous reviewer comment: presumed equivalent to 4164 mg active acid/kg bw) in the rat.

Executive summary:

In an acute oral toxicity study (reliability score 2) conducted prior to the adoption of OECD guidelines and GLP, a single dose of DTPMP-H was administered to by oral gavage to Sprague-Dawley rats (mixed sex 5/dose). Doses of 5010, 6310, 7940 and 10000 mg/kg bw were tested. The animals were then observed for seven days, after which surviving animals were killed. All animals were examined macroscopically. There were 0, 2 (females), 3 (females) and 5 deaths at 5010, 6310, 7940 and 10000 mg/kg bw, respectively. Survival times were several hours to one day. Toxic signs included reduced appetite and activity, slight lethargy (lasting two to seven days in survivors), rapidly increasing weakness, collapse and death. Surviving female rats sustained weight loss in seven days. Males recovered initial weight loss and most showed weight gain. In animals that died there was slight liver discolouration and acute gastrointestinal inflammation. Seven days after administration the viscera of surviving animals appeared normal at macroscopic examination. The LD₅₀ was calculated to be 7180 mg/kg bw (equivalent to 4164 mg active acid/kg bw).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 164 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:

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 402 (Acute Dermal Toxicity)

Version / remarks:

Conducted prior to adoption of OECD test guidelines.

Deviations:

yes

Remarks:

Limited detail on test substance, methods and animals/conditions.

Principles of method if other than guideline:

Method: other: Insufficient detail to fully assess comparability with OECD guideline.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

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: 1.8 to 2.0 kg
- Fasting period before study: No data
- 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: No data

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: No data
- % coverage: No data
- Type of wrap if used: 'plastic strips'


REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data
- Time after start of exposure: No data


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): No data
- Constant volume or concentration used: No data

Duration of exposure:

24 hours

Doses:

3160, 5010, 7940 and 7940 mg/kg bw

No. of animals per sex per dose:

One male or female animal per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, and macroscopic examination of all animals.

Statistics:

None

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 7 940 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Remarks:

active acid

Effect level:

>= 4 605 mg/kg bw

Based on:

act. ingr.

Mortality:

No deaths occurred.

Clinical signs:

other: Clinical symptoms included reduced appetite and activity for 1-2 days. 

Gross pathology:

No adverse findings.

Other findings:

None

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute dermal toxicity study (reliability score 2), conducted prior to the adoption of OECD test guidelines and GLP, the LD50 for DTPMP-H was >7940 mg/kg bw (equivalent to >4605 mg active acid/kg bw) in the rabbit.

Executive summary:

In an acute dermal toxicity study (reliability score 2), conducted prior to the adoption of OECD test guidelines and GLP, 58% w/w solution of DTPMP-H was applied to the clipped, intact skin of four New Zealand white rabbits, under an occlusive dressing, for 24 hours. Animals were then observed for 14 days, and all animals were examined macroscopically. No animals died and the LD₅₀ was concluded to be greater than 7940 mg/kg bw (equivalent to >4605 mg active acid/kg bw). Toxic signs included reduced appetite and activity for one to two days after treatment. There were no abnormal macroscopic findings.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 605 mg/kg bw

Additional information

There are no acute toxicity data available for BHMT-H. Therefore, data are read across from the structural analogue DTPMP-H (CAS 15827-60-8).

In the acute oral toxicity study for DTPMP-H (Younger Laboratories, 1971a), conducted according to a protocol similar to the now-deleted OECD Test Guideline 401, but conducted prior to GLP, the LD50 was concluded to be 7180 mg/kg bw (equivalent to 4164 mg active acid/kg bw).

In the study single oral doses of 5010, 6310, 7940 and 10000 mg/kg bw DTPMP-H were administered by oral gavage to five Sprague-Dawley rats per group. The test material was administered as an aqueous solution containing 58% active acid by weight. The animals were then observed for seven days, after which they were examined macroscopically. There were 0, 2, 3 and 5 deaths at 5010, 6310, 7940 and 10000 mg/kg bw, respectively. Survival times were several hours to one day. Toxic signs included reduced appetite and activity, slight lethargy (lasting two to seven days in survivors), rapidly increasing weakness, collapse and death. Surviving female rats sustained weight loss over seven days. Males recovered initial weight loss and most showed weight gain. In animals that died there was slight liver discolouration and acute gastrointestinal inflammation. Seven days after administration the viscera of surviving animals appeared normal at macroscopic examination.

In the acute dermal toxicity study for DTPMP-H (Younger Laboratories, 1971b), conducted according to a protocol similar to OECD Test Guideline 402, but conducted prior to GLP, the LD50 was concluded to be equal to or greater than 7940 mg/kg bw (equivalent to >4605 mg active acid/kg bw).

In the study, doses of 3160, 5010, 7940 and 7940 mg/kg bw DTPMP-H were applied onto the clipped, intact skin of four New Zealand white rabbits, under an occlusive dressing, for 24 hours. The test material was administered as an aqueous solution containing 58% active acid by weight. Animals were then observed for 14 days, and all animals were examined macroscopically. No animals died during the study period. Toxic signs included reduced appetite and activity for one to two days after treatment. There were no abnormal macroscopic findings.

The classification decision is based on read-across data from the structural analogue DTPMP-H (CAS 15827-60-8). The registered substance, BHMT-H, and the source substance, DTPMP-H, both have the same known impurity, phosphonic acid, with similar concentration ranges.

Phosphonic acid (CAS 13598-36-2, EC 237-066-7), present at concentration 0-10 % (w/w solids) and 0-15 % (w/w solids) in BHMT-H and DTPMP-H, respectively, is classified for acute oral toxicity Cat 4 according to Annex VI of CLP Regulation (EC) No 1272/2008. The impurity does not affect the classification conclusion for BHMT-H and DTPMP-H based on the additivity approach and the read-across data, which indicate that DTPMP-H is not acutely toxic.

Another impurity present at concentration of 0-15 % (w/w solids) and 0-20 % (w/w solids) in BHMT-H and DTPMP-H, respectively, is hydrogen chloride (CAS 7647-01-0, EC 231-595-7; aqueous solution), which is classified for specific target organ toxicity following single exposure (STOT SE) Cat 3 according to Annex VI of CLP Regulation (EC) No 1272/2008. Since, the STOT SE classification is Cat 3, hydrogen chloride does not affect the no classification conclusion for BHMT-H. In addition, the read-across acute toxicity data for DTPMP-H did not demonstrate any evidence to suggest the need for STOT SE classification.

Justification for classification or non-classification

Based on the available information for the analogue substance DTPMP-H (CAS 15827-60-8), BHMT (CAS 34690-00-1) does not require classification for acute toxicity according to Regulation (EC) No 1272/2008.