1,3-diphenylguanidine

Endpoint summary

Description of key information

1,3-Diphenylguanidine has an acute oral LD50 of 107-111 mg/kg b.w. for the rat. By dermal route, the dermal LD0 is >= 2,000 mg/kg b.w. in the rabbit. After oral administration, the post mortem examination revealed liver effects (dark colour) and severe irritation of the gastro-intestinal tract. On a weight-of-evidence basis, the 30-min LC0 is higher than 500 mg/m3 in rats and dogs.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Crj:CD(SD)IGS

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan Co. (Yokoyama, Kanagawa Prefecture).
- Age at study initiation: 6 weeks of age
- Weight at study initiation: 167-187g (males), 128-144g (females)
- Fasting period before study: yes, 16 hours prior to administration.
- Housing: 202 barrier system cages
- Diet (e.g. ad libitum): solid food MF (oriental Yeast Co., Tokyo), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/-3°C
- Humidity (%): 55+/-20%
- Air changes (per hr): 20
- Photoperiod (hrs dark / hrs light): 12/12 (150-300 lux, lighted at 7am, darkened at 7 pm).

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

The administration dose was 0.5mL per 100g of body weight, and the administration dose was calculated individually based on the measured body weight. A stomach probe was used between 10:00 and 11:00 for forced oral administration into thee stomach of animals who had fasted for 16 hours prior to administration of DPG.
DGP was dissolved in corn oil and prepared at the time of use.

Doses:

0, 50, 65, 85, 110 and 143 mg/kg

No. of animals per sex per dose:

5 rats/sexe/dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations : Observations on toxic symptoms and mortalities were performed at one hour intervals until six hours after administration, and then twice a day, in the morning and afternoon, until the 14th day.
- Frequency of weighing: The body weights were measured immediately before administration, and then again on the 7th and 14th days after administration.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology

Statistics:

The LD50 values and the 95% confidence interval were calculated from the mortality rate 14 days after administration, using the Probit method.

Preliminary study:

The results from the preliminary tests conducted prior to this study (Doses: 10, 50, 100, 250 and 500 mg/kg; vehicle: corn oil, administration weight: 0.5mL/100g bw) included 3 cases of mortality among 3 males at 100 mg/kg and higher, and 2 of 3 cases in the 100 and 500 mg/kg groups, as well as 3 of 3 cases in the 250 mg/kg group. Five doses from 50 to 143 mg/kg were established for this particular study (ratio 1:3), and a solvent control group was set for both sexes.

Sex:

male

Dose descriptor:

LD50

Effect level:

111 mg/kg bw

95% CL:

> 86 - < 161

Sex:

female

Dose descriptor:

LD50

Effect level:

107 mg/kg bw

95% CL:

> 78 - < 177

Mortality:

The mortality rate for the 0, 50, 65, 85, 110 and 143 mg/kg groups 0, 0, 0, 0, 40 and 60% respectively for the males and 0, 0, 0, 0, 40 and 60% respectively for the females. Most of the deaths were confirmed during 1 and 3 hours after administration.

Clinical signs:

other: All animals of both sexes in the test substance administration groups exhibited a reduction in spontaneous motor activity, lying laterally and staggered gait immediately after administration. Most of the mortalities exhibited the aforementioned symptoms b

Gross pathology:

Nothing abnormal was noted for any of the animals during pathological necropsy of mortalities during the test period as well as after completion of the period of observation.

Other findings:

no

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

With a LD50 of 107-111 mg/kg (females/males), DPG was classified in the Category 3 in accordance to the Guidance on the Application of the CLP Criteria (2008).

Executive summary:

An acute oral toxicity study of 1.3 -diphenylguanidine was conduted using Crj:CD(SD)IGS rats with five males and five females in each group.

DPG was suspended in corn oil, and single forced oral administration of 50 -143 mg/kg was conducted on both sexes. A solvent control group was established, with administration of only corn oil. The observation period was 14 days, and then observations were made on the mortality, toxicity and period of onset, changes in weight, and pathological examinations were also concluded.

The LD50 value was 111 mg/kg for males and 107 mg/kg for females.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

107 mg/kg bw

Quality of whole database:

The key study is a reliable study and has a klimish score of 1.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

No reliable study

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

Cited as Directive 92/69/EEC, B.3

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1100 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

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: Mohican Valley Rabbitry, Loudonville, Ohio, USA
- Age at study initiation: no data
- Weight at study initiation: 2.355 +/- 0.067 kg for males and 2.416 +/-0.186 kg for females
- Housing: individually in suspended stainless steel cages
- Diet (e.g. ad libitum): Agway Prolab Rabbit Feed
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

On the day prior to dosing, the fur was clipped from the dorsal area of the trunk of each animal using a small animal clipper. The clipped area measured approximately 20 cm x 12 cm and constituted approximately 10% of the animal's total body surface. Care was taken during clipping to avoid accidentai abrasion to the skin. On the following day, each rabbit was weighed and the test article was applied uniformly over the clipped area at the appropriate test article dose. Each animal's dose was contained at the area of application using an 8 ply gauze dressing taped in place which was moistened with an equivalent volume of distilled water. A plastic wrap followed by an elastic wrap was then positioned over the trunk of each animal and both secured in place using tape. After an exposure period of 24 hours, the elastic wrap, plastic wrap and gauze dressing were removed. The exposure site on each animal was rinsed with gauze moistened in distilled water to remove residual test article.

Duration of exposure:

24 hrs

Doses:

2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

The animals were observed frequently on the day of dosing and once daily thereafter for the duration of the study (day 15). Mortality checks were performed twice daily. Individual body weights were determined and recorded on days 1, 8 and 15. All animals were subjected to a gross necropsy examination at the time of scheduled sacrifice (sodium pentobarbital).

Statistics:

Not appropriate

Preliminary study:

no data

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

> 2 000 mg/kg bw

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality occurred during the study

Clinical signs:

other: The most notable clinical signs were generally limited to transient dermal irritation at the site of test article application

Gross pathology:

At necropsy on day 15, the pancreas or pancreatic lymph nodes of 4/10 animais were noted to have an abnormal red discoloration. The cause of this finding could not be determined. No significant internal abnormalities were observed in the remaining animals at necropsy

Other findings:

no

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal LD50 of 1,3-Diphenyl Guanidine was determined to be greater than 2000 mg/kg in the rabbit

Executive summary:

The acute dermal toxicity of 1,3-Diphenyl Guanidine (DPG) was evaluated in rabbits in a study performed following EU method B. 3. A limit test was performed in which one group of five male and five female rabbits received a single dermal application of DPG at a dose of 2000 mg/kg body weight. Following dosing, the rabbits were observed daily and weighed weekly. A gross necropsy examination was performed on all test animals at the time of death or scheduled euthanasia (day 15).

No mortality occurred during the study. The most notable clinical signs were generally limited to transient dermal irritation at the site of test article application. Body weight gain was exhibited by all animals during the study. At necropsy on day 15, the pancreas or pancreatic lymph nodes of 4/10 animals were noted to have an abnormal red discoloration. The cause of this finding could not be determined. No significant internai abnormalities were observed in the remaining animals at necropsy.

The acute dermal LD0 of 1,3-Diphenyl Guanidine was determined to be greater than 2000 mg/kg in the rabbit.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

The key study is a reliable study and has a klimish score of 1.

Additional information

Acute toxicity : oral

An acute oral toxicity study of DPG (1.3 -diphenylguanidine) was conducted using Crj:CD(SD)IGS rats with five males and five females in each group. DPG was suspended in corn oil, and single forced oral administration of 50 -143 mg/kg was conducted on both sexes. A solvent control group was established, with administration of only corn oil. The observation period was 14 days, and then observations were made on the mortality, toxicity and period of onset, changes in weight, and pathological examinations were also concluded. The LD50 value was 111 mg/kg for males and 107 mg/kg for females.

 

 

 

Acute toxicity : dermal

In one reliable study (OECD guideline and GLP), dermal LD0 for rabbits was higher or equal than 2000 mg/kg bw (Rush 1992). A limit test was performed in which one group of five male and five female rabbits received a single dermal application of DPG at a dose of 2000 mg/kg body weight. Following dosing, the rabbits were observed daily and weighed weekly. A gross necropsy examination was performed on all test animals at the time of death or scheduled euthanasia (day 15). No mortality occurred during the study. The most notable clinical signs were generally limited to transient dermal irritation at the site of test article application. Body weight gain was exhibited by all animals during the study. At necropsy on day 15, the pancreas or pancreatic lymph nodes of 4/10 animals were noted to have an abnormal red discoloration. The cause of this finding could not be determined. No significant internal abnormalities were observed in the remaining animals at necropsy.

Justification for classification or non-classification

Mandatory classification :

Regulation (EC) No 1272/2008 Annex VI Table 3.1: Acute Tox. 4, H 302 (Harmful if swallowed)

  

Proposed self-classification

- Regulation (EC) No 1272/2008: Acute Tox. 3, H 301 (Toxic if swallowed)

- Justification : the oral DL50 is of 107 mg/kg/day, corresponding to the category 3 [50-300 mg/kg].