Registration Dossier

Administrative data

Description of key information

The oral LD50 of 5809-08-5 is 1045 mg/kg, the dermal LD50 is >2000 mg/kg, and the inhalation LC50 is >2.85 mg/l (480 ppm v/v).

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:
June, 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
There are only limited details in study report, but this is consistent with other reports of this type from this period. Study was done before standardized test guidelines and GLP but was conducted using a standard and documented method at a reputable facility.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Remarks:
Study performed before GLP regulations
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Young adult albino rats (Wistar-derived) from the Institute's colony were used. The body weights of males varied from 194 to 373 g, those of femals from 157 to 220 g.
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
After some preliminary observations, the test material was give by gavage, as a 10% (v/v) dilution in propylen (sic) glycol.
Doses:
Single doses of 6.0, 7.2, 8.6, 10.3 or 12.4 ml per kg body weight.
No. of animals per sex per dose:
Five males and five females
Control animals:
no
Details on study design:
After treatment the rats received stock diet and tap water ad libitum. They were observed for signs of intoxication during a 14-day period, after which autopsies were carried out on the survivors. The LD50 was calculated according to the method of Weil (Biometrics 8 [1952] 249-263).
Statistics:
none
Key result
Dose descriptor:
LD50
Effect level:
0.92 mL/kg bw
95% CL:
>= 0.87 - <= 0.96
Clinical signs:
Within a few hours after dosing the rats showed sluggishness and decreased activity. Thereafter, most of the rats lost consciousness. deaths occurred between 8 hours and 3 days after treatment. Thereafter, the survivors recovered gradually and looked quite healthy again at the end of the observation period.
Body weight:
no data
Gross pathology:
Macroscopic examination of the survivors at autopsy revealed rounded edges of the livers in some of the rats. No other treatment-related gross alterations were seen.

  Dose     Mortality    
  dilution (ml/kg)   test material (ml/kg)   number    %
   males  females  
   6.0   0.60  0/5  0/5  0

7.2

 0.72  1/5  0/5 10 
 8.6  0.86  1/5  0/5 10
 10.3  1.03  5/5  5/5  100
 12.4  1.24  5/5  5/5  100
         
Interpretation of results:
sligthly toxic
Remarks:
Migrated information Criteria used for interpretation of results: other: conclusion in report
Conclusions:
From the mortality-figures the LD50 of TMPH was calculated to be 0.92 ml per kg body weight with 0.87 and 0.96 as the 95% confidence limits. Therefore, the material can be classified as slightly toxic.
Executive summary:

The acute oral toxicity of TMPH was determined by administration of graded doses of the test material. Young adult albino rats (Wistar-derived) from the Institute's colony were used. The body weights of males varied from 194 to 373 g, those of femals from 157 to 220 g.

After some preliminary observations, the test material was given by gavage, as a 10% (v/v) dilution in propylen (sic) glycol to groups of five male and five female rats in single doses of 6.0, 7.2, 8.6, 10.3 or 12.4 ml/kg body weight.

Within a few hours after dosing the rats showed sluggishness and decreased activity. Thereafter, most of the rats lost consciousness. deaths occurred between 8 hours and 3 days after treatment. Thereafter, the survivors recovered gradually and looked quite healthy again at the end of the observation period.

Macroscopic examination of the survivors at autopsy revealed rounded edges of the livers in some of the rats. No other treatment-related gross alterations were seen.

From the mortality-figures the LD50 of TMPH was calculated to be 0.92 ml per kg body weight with 0.87 and 0.96 as the 95% confidence limits. Therefore, the material can be classified as slightly toxic.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 045 mg/kg bw
Quality of whole database:
Adequate.

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
Study period:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
There are only limited details in study report, but this is consistent with other reports of this type from this period. Study was done before standardized test guidelines and GLP but was conducted using a standard and documented method at a reputable facility.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 433 draft (Acute Inhalation Toxicity: Fixed Concentration Procedure) (not officially approved)
Deviations:
not applicable
GLP compliance:
no
Test type:
fixed concentration procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Young rats (Wistar-derived, and reared under S.P.F. conditions) were used for this experiment. The weight of the males varied from 189 to 192 g, that of the females from 133 to 138 g. The animals were obtained from the Central Institute for the Breeding of Laboratory Animals, TNO-Zeist, The Netherlands.
Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Remarks:
Although not stated, exposure was probably whole-body.
Vehicle:
air
Details on inhalation exposure:
The exposure chamber consists of a horizontally placed glass cylinder (0.90 x 0.15 m) with sampling ports at both ends and contains a perforated stainless steel frame-work for separate accomodation of the rats.

Samples were analysed by means of gas-liquid chromatography, using an Intersmat gas-chromatograph loaded with a SE30 column (0.70 m, ø 1/2 cm), and detected with a flame ionisation detector.

Column-detection and injection temperatures were 75, 85 and 90 °C respectively.

The test compound was gauged by using a 4% solution in acetone.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
480 ppm (2.85 mg/l).
No. of animals per sex per dose:
five
Control animals:
no
Details on study design:
The dynamic atmosphere for the inhalation experiment was formed by passing air (relative humidity 50%) through various columns - airflow per column 1 l/min - containing chromosorb W, AW, saturated with the test substance. Five columns were used in parallel, giving an eventual airfow of 5 l/min (the minimum quantity required to prevent condensation of vapou (H2O)) through the exposure chamber. The temperature inside the cylinder was 24 °C.

A group of five male and five females rats was exposed to an atmosphere saturated with T.M.P.H. for four hours. After the exposure the rats were returned to their living-cages and provided with food and tap water ad libitum during an observation period of 14 days.
Statistics:
None
Key result
Sex:
male
Dose descriptor:
LC0
Effect level:
2.85 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Key result
Sex:
female
Dose descriptor:
LC0
Effect level:
2.85 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
None.
Clinical signs:
From the start of the exposure the animals were restless. After half an hour they closed their eyes and had wet noses. The severity of the effects increased during the exposure period. After two hours mouth breathing was observed as well as some incoordination of movement. The female rats have been recovered one day after the exposure; the males however, needed about two days before they behaved normally again.
Body weight:
No data.
Gross pathology:
No data.
Other findings:
The intoxication signs observed at 480 ppm, seem to justify the expectation that the 4-hour LC50 will not be very far above this level.
Interpretation of results:
Toxicity Category III
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
From the results of the present study it can be concluded that the 4-hour LC50 of T.M.P.H. exceeds 480 ppm (2.85 mg/l) but is expected to be less than 10 mg/L.
Executive summary:

The acute inhalation toxicity of T.M.P.H. was studied in rats, by exposing them to an atmosphere saturated with the test material for a period of four hours.

The dynamic atmosphere for the inhalation experiment was formed by passing air (relative humidity 50%) through various columns - airflow per column 1 l/min - containing chromosorb W, AW, saturated with the test substance. Five columns were used in parallel, giving an eventual airfow of 5 l/min (the minimum quantity required to prevent condensation of vapou (H2O)) through the exposure chamber. The temperature inside the cylinder was 24 °C.

A group of five male and five females rats was exposed to an atmosphere saturated with T.M.P.H. for four hours. After the exposure the rats were returned to their living-cages and provided with food and tap water ad libitum during an observation period of 14 days.

Exposure of the rats to an atmosphere saturated with T.M.P.H. - viz. 480 ppm (2.85 mg/l) under the experimental conditions - caused no mortality. From the start of the exposure the animals were restless. After half an hour they closed their eyes and had wet noses. The severity of the effects increased during the exposure period. After two hours mouth breathing was observed as well as some incoordination of movement. The female rats have been recovered one day after the exposure; the males however, needed about two days before they behaved normally again.

Since no mortality occurred during the subsequent observation period of 14 days, no LD50 value could be determined. From the results of the present study it can be concluded that the 4-hour LC50 of T.M.P.H. exceeds 480 ppm (2.85 mg/l) but is expected to be less than 10 mg/L.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating conc.
2.85 mg/m³
Quality of whole database:
Adequate.

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:
Between 12 September 2012 and 03 October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
equivalent or similar to
Guideline:
other: in order to minimise the number of animals required, the study design was based on the OECD 423 Acute Oral Toxicity Study in the Rat – Acute Toxic Class Method, using three animals for each required step.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Three male and three female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatisation period of at least five days the animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200 g, and were eight to twelve weeks of age. The weight variation did not exceed ±20% of the mean weight for each sex.
The animals were housed in suspended solid floor polypropylene cages furnished with wood flakes. The animals were housed individually during the 24 hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The calculated volume of test item, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe.

Duration of exposure:
24 hours
Doses:
2000 mg /kg body weight
No. of animals per sex per dose:
3 female
3 male
Control animals:
not required
Details on study design:
On the day before treatment the back and flanks of each animal were clipped free of hair.
Using available information on the toxicity of the test item, a single group of animals was treated as follows:
Dose Level(mg/kg) Specific Gravity Dose Volume(ml/kg) Number of Rats (Female)
2000 0.889 2.25 3
The calculated volume of test item, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.
After the 24 hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item.
As no mortalities were noted a further group of three males was similarly treated with the test item at a dose level of 2000 mg/kg bodyweight to give a total of three males and three females. The animals were caged individually for the 24 hour exposure period. After the 24 hour contact period the bandages were carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item.
The animals were housed in groups of three by sex for the remainder of the test period.
The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31:

EVALUATION OF SKIN REACTIONS
Erythema and Eschar Formation Value

No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) to slight eschar formation (injuries in depth) 4

Oedema Formation

No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4

Any other skin reactions, if present were also recorded.
Individual bodyweights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 95% confidence limits not reported.
Mortality:
Individual mortality data are given in Table 1.
There were no deaths.
Clinical signs:
Individual clinical observations data are given in Table 1.
Red/brown staining around the snout was noted thirty minutes after dosing in one male. No other signs of systemic toxicity were noted.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Table 3.
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in Table 4.
No abnormalities were noted at necropsy.
Other findings:
Dermal Reactions
Individual dermal reactions are given in Table 2.
Very slight erythema was noted at the test sites of all females. Signs of dermal irritation noted at the test sites of both groups were haemorrhage of dermal capillaries, small superficial scattered scabs and crust formation. Other signs of dermal irritation noted at the test sites of females were blanching of the skin, hardened light brown coloured scab, glossy skin and scab lifting to reveal glossy skin.

Evaluation of Data

Data evaluations included the relationship, if any, between the exposure of the animal to the test item and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects.

Using the mortality data obtained, an estimate of the acute dermal median lethal dose (LD50) of the test item was made.

Table 1              Individual Clinical Observations and Mortality Data

Dose Level

mg/kg

Animal Number and Sex

Effects Noted After Initiation of Exposure (Hours)

Effects Noted After Initiation of Exposure (Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2

Male

Ss

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0= No signs of systemic toxicity

Ss = Red/brown staining around the snout

Table 2              Individual Dermal Reactions

Dose Level mg/kg

Animal Number and Sex

Observation

Effects Noted After Initiation of Exposure (Days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Female

Erythema

1

1

1

1

1

1

1

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

Bl

0

0

Hd

Cf

Cf

Cf

0

0

0

0

0

0

0

1-1

Female

Erythema

1

1

1

1

1

1

1

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

Bl

0

0

Hd

Cf

CfSs

CfSs

Sp

Sp

Sp

Sp

Sp

Sp

SpSg

1-2

Female

Erythema

1

1

1

1

1

1

1

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

Bl

0

0

Hd

HdCf

CfSs

CfSs

Ss

G

G

0

0

0

0

2-0

Male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

Cf

CfSs

CfSs

CfSs

CfSs

CfSs

Ss

Ss

Ss

Ss

2-1

Male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

Cf

CfSs

CfSs

CfSs

Cf

Cf

Cf

Cf

Cf

Cf

2-2

Male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

CfHd

CfSs

CfSs

CfSs

CfSs

CfSs

CfSs

CfSs

CfSs

Ss

0= No reactions           Bl = Blanching of the skin         Hd = Haemorrhage of dermal capillaries                       Cf = Crust formation         G = Glossy skin

Ss = Small superficial scattered scabs                         Sp = Hardened light brown coloured scab        Sg = Scab lifting to reveal glossy skin

Table 3              Individual Bodyweights and Weekly Bodyweight Changes

Dose Level mg/kg

Animal Number and Sex

Bodyweight (g) at Day

Bodyweight Change (g) During Week

0

7

14

1

2

2000

1-0 Female

209

217

222

8

5

1-1 Female

201

219

230

18

11

1-2 Female

223

225

232

2

7

2-0 Male

338

358

380

20

22

2-1 Male

336

340

360

4

20

2-2 Male

330

353

379

23

26

Table 4              Individual Necropsy Findings

Dose Level

mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

1-0 Female

Killed Day 14

No abnormalities detected

1-1 Female

Killed Day 14

No abnormalities detected

1-2 Female

Killed Day 14

No abnormalities detected

2-0 Male

Killed Day 14

No abnormalities detected

2-1 Male

Killed Day 14

No abnormalities detected

2-2 Male

Killed Day 14

No abnormalities detected

Interpretation of results:
other: The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

Introduction. The study was performed to assess the acute dermal toxicity of the test item in the Wistar strain rat. At the request of the Sponsor, for ethical reasons and in order to minimise the number of animals required, the study design was based on the OECD 423 Acute Oral Toxicity Study in the Rat – Acute Toxic Class Method, using three animals for each required step.

Method. A group of three females was given a single, 24-hour, semi‑occluded dermal application of the undiluted test item to intact skin at a dose level of 2000 mg/kg bodyweight. Based on the results of the initial test a further group of three males was similarly treated. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. There were no deaths.

Clinical Observations. Red/brown staining around the snout was noted thirty minutes after dosing in one male. No other signs of systemic toxicity were noted.

Dermal Irritation. Signs of dermal irritation noted were very slight erythema, blanching of the skin, haemorrhage of dermal capillaries, crust formation, scabbing, glossy skin and scab lifting to reveal glossy skin.

Bodyweight. All animals showed expected gains in bodyweight over the study period.

Necropsy. No abnormalities were noted at necropsy.

Conclusion. The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
Adequate.

Additional information

The oral LD50 of 5809-08-5 is 1045 mg/kg, the dermal LD50 is >2000 mg/kg, and the inhalation LC50 is >2.85 mg/l (480 ppm v/v) < 10 mg/L.


Justification for selection of acute toxicity – oral endpoint
Acceptable study for this endpoint.

Justification for selection of acute toxicity – inhalation endpoint
Acceptable study for this endpoint.

Justification for selection of acute toxicity – dermal endpoint
Acceptable study for this endpoint.

Justification for classification or non-classification

The product was classified as R22 (harmful if swallowed) based on the oral LD50 of 1045 mg/kg. The GHS classification for acute toxicity is Category 4, H302 (harmful if swallowed).

The product was classified as R20 (harmful by inhalation) based on the inhalation LC50 of > 2.85 mg/l but less than 10 mg/L. The GHS classification for acute toxicity is Category 3, H331 (toxic if inhaled).

The acute dermal LD50 of >2000 mg/kg does not require classification.