N,N'-diphenylguanidine monohydrochloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The structural analogue substance, was investigated following OECD 421 guideline, at dose-levels of 5, 15 or 25 mg/kg/day. Under the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental systemic toxicity was considered to be 15 mg/kg/day, the No Observed Effect Level (NOEL) for reproductive performance (mating and fertility) was considered to be 25 mg/kg/day and the NOEL for toxic effects on progeny was 15 mg/kg/day.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

The test item (target substances, CAS 24245-27-0) is the salt of 1,3-diphenylguanidine and mono-hydrochloride. As read-across source substance the uncharged free base of 1,3-diphenylguanidine (CAS 102-06-7) is applied. This is considered appropriate since the target substance is expected to readily dissociate in contact with water such as surface water in the environment or the intestinal fluids or mucosal membranes of an organism. 1,3-diphenylguanidine is considered a weak base. Therefore, it is expected to be present as uncharged molecule at neutral and high pH solutions. However, acidic conditions will lead to protonation of the molecule and the charged ion is expected to be the main present form. Since transformation of the target to the source substance and vice versa is anticipated, kinetics and toxicological behaviour are well transferable from the source to the target substance. This applies for human health endpoints as well as for the aquatic environment.
Moreover, chloride ions are ubiquitously present in every-day nutrition and are part of numerous physiological processes. Therefore, this constituent does not require further assessment in regards to its toxicological behaviour. It is expected to be well regulated by endogenous physiological mechanisms of the organism.
Based on the considerations above, a read-across is considered appropriate and further tests, especially vertebrate studies, are not needed to adequately address this endpoint. Information Requirements are fulfilled according to REACH Annex XI Section 1.5.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

parental toxicity

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: lower body weight gain in males at 25 mg/kg/day

Key result

Dose descriptor:

NOEL

Remarks:

reproductive performance

Effect level:

>= 25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOEL

Remarks:

developmental toxicity

Generation:

F1

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Lower mean body weight gain over the lactation period and lower mean body weights on lactation day 5 at 25 mg/kg/day

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP and guideline study with a strutural analogue substance.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

OECD 421 with structural analogue substance

The objective of this study was to evaluate the potential toxic effects of 1,3-Diphenylguanidine, following daily oral administration (gavage) to male and female rats from before mating, through mating and gestation and until day 4 post-partum. This study provides initial information on possible toxicological effects likely to arise from repeated exposure on male and female reproductive performance, such as gonadal function, mating behaviour, conception, development of the conceptus and parturition. The study was conducted as a reproduction/developmental screening test according to OECD 421 guideline and GLP. Three groups of 10 male and 10 female Sprague-Dawley rats received the test item, 1,3-Diphenylguanidine, daily, by oral (gavage) administration, 4 weeks before mating, through mating and gestation and until day 4 post-partum.The dose-levels were 5, 15 or 25 mg/kg/day. Another group of 10 males and 10 females received the vehicle, 0.5% aqueous methylcellulose, alone, under the same experimental conditions and acted as a control group. The dosing volume was 5 mL/kg/day. Clinical signs and mortality were checked once or twice daily, respectively. Body weight and food consumption were recorded weekly. The animals were paired for mating after 4 weeks of treatment and the dams were allowed to litter and rear their progeny until day 5 post-partum. The total litter sizes and numbers of pups of each sex were recorded after birth. Pups were observed daily for clinical signs and pup body weights were recorded on days 1 and 5 post-partum. The males were sacrificed after a total of 10 weeks of treatment (after most of the females and litters had been sacrificed). The body and selected organs were weighed and a complete macroscopic post-mortem examination was performed. Sperm samples were taken from the left epididymis and the left testis for assessment of sperm motility, morphology and/or count. A microscopic examination was performed on the reproductive organs, liver and kidneys from the males in the control and high-dose groups and on all macroscopic lesions. The dams were sacrificed on day 5 post-partum, the body and selected organs were weighed and a complete macroscopic examination was performed. A microscopic examination was performed on the ovaries, liver and kidneys of the females in the control and high-dose groups and on all macroscopic lesions. Pups were sacrificed on day 5post-partumand, including those found dead, were carefully examined for gross external abnormalities.

 

There were no unscheduled deaths during the study. Lateral decubitus, mydriasis and staggering gait/locomotory difficulties were observed in one male and one female treated at 25 mg/kg/day on one occasion only. Salivation was observed with a dose-related incidence at 15 and 25 mg/kg/day but was considered to be non-adverse. The male group treated at 25 mg/kg/day had a statistically significantly lower mean body weight gain over the treatment period. There were no effects on the females treated at 25 mg/kg/day nor on the groups treated at 5 or 15 mg/kg/day. There were no effects on mean male food consumption. The female group treated at 25 mg/kg/day had lower mean food consumption during gestation and lactation, achieving statistical significance for the period of the last 7 days of gestation. There were no effects on the female groups treated at 5 or 15 mg/kg/day.

There were no effects on mating, fertility, gestation or delivery at any dose-level. Male and female pups from the group treated at 25 mg/kg/day had lower mean body weight gain over the lactation period and lower mean body weights on lactation day 5. Clinical signs were considered to be unrelated to treatment with the test item. There were no effects of treatment with 1,3-diphenylguanidine on sperm analysis, organ weights, macroscopic post-mortem examination and Microscopic examination

 

Based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 15 mg/kg/day, the No Observed Effect Level (NOEL) for reproductive performance (mating and fertility) was considered to be 25 mg/kg/day and the NOEL for toxic effects on progeny was 15 mg/kg/day.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on reproductive toxicity, the NOAEL for fertility was found to be the highest dose tested (i. e. 25 mg/kg bw/d) since no adverse effects on fertility were observed in the OECD 421 study. The NOAEL for developmental and systemic toxicity was determined to be 15 mg/kg bw/d. Effects seen on the progeny are considered secondarily induced by the general toxicity in the dams and not directly induced by the test item itself. Consequently, the test item is does not require classification according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.