D-gluconic acid, compound with N,N''-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediamidine (2:1)

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Additional information

Short description of key information:
A two generation reproduction study according to OECD Guideline 416 is not available. However, there are data which indicate that there are no effects on the reproductive organs, that there are no relevant effects in the offspring and that offspring are not more sensitive than dams:
The main observation in adult rats, i.e. the reactive histiocytosis of mesenteric lymph nodes following oral administration of chlorhexidine digluconate, has been investigated in a specially designed pre-, postnatal and weaning study. In this study, oral treatment of dams from day 15 of pregnancy until parturition or further through lactation to day 21 postpartum had no effect on maternal weight gain, length of gestation, litter size at birth, the number of dead pups per litter, or on postnatal development.
In chronic toxicity studies with chlorhexidine digluconate in adult rats, there were no treatment-related effects on the gonads of male and female rats. Also, no histopathological effects on female or male reproductive organs were observed in a carcinogenicity study with mice. In a chronic toxicity study with dogs, adverse histological effects were observed in the liver, but there were no effects in female or male reproductive organs.
Toxicokinetic studies in humans indicate that there is only minimal if any absorption of chlorhexidine after dermal single and repeated exposure. Therefore, there is very little concern for systemic effects on reproduction after dermal exposure.
From the overall evidence it is concluded that there is no concern for effects of chlorhexidine digluconate on reproduction.
It is concluded that a two generation reproductive toxicity study for chlorhexidine digluconate is not justified from a scientific viewpoint and for animal welfare reasons.

Effects on developmental toxicity

Description of key information

A peri-, postnatal and weaning study in rats provides no evidence for a developmental toxic effect of chlorhexidine digluconate. Also a developmental and fertility toxicity study gave no concern for developmental or teratogenic effects.
As there is minimal if any dermal absorption of chlorhexidine after administration to the skin, it is considered that there is no concern for a specific developmental effect.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.18 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

The results of fertility and developmental toxicity studies with chlorhexidine digluconate are summarised in the following Table:

Route of exposure	Test type Method Guideline	Species Strain Sex no/group	Exposure Period	Doses (mg/kg bw/d)	Critical effects	NO(A)EL (mg/kg bw/d)
Oral, gavage	Peri-, post-natal , weaning study	Rat Wistar female 7-10	From day 15 of gestation up to A: parturition B: day 21 pp C: a total of 50 d (dams), or from day 21 to 14 weeks of age (pups) D: day 21 pp (dams) or to 6 months of age (pups)	0, 0.18, 0.89 or 8.9 (dams) 4.5 (pups in protocols C and D)	Mild to moderate histiocytosis of mesenteric lymph nodes in dams and pups, same effect level, but effect more pronounced in dams than in pups	0.18
Oral, gavage	Teratology study	Rat CD female 25	gestation day 6‑19	0, 10, 30 or 100	Dams: laboured breath at >= 30 mg/kg bw/d no evidence of teratogenicity	dams: 10 offspring: > 100

Justification for classification or non-classification

The available studies gave no concern for adverse effects.

Therefore, there is no need for classification.