Tetrakis(hydroxymethyl)phosphonium chloride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Published experimental data (GLP) from National Technical Information Service, NTIS. Evaluated data from a reliable secondary source (US-CPSC).

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1992

Report date:

1992

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

minor deviations

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrakis(hydroxymethyl)phosphonium chloride

EC Number:

204-707-7

EC Name:

Tetrakis(hydroxymethyl)phosphonium chloride

Cas Number:

124-64-1

Molecular formula:

C4H12O4P.Cl

IUPAC Name:

tetrakis(hydroxymethyl)phosphonium chloride

Test animals

Species:

rabbit

Strain:

Wistar

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

volume: 5 ml/kg bw

Details on mating procedure:

Each female mated with 1 stud male. After coitus females injected with 10 I.U. chorionic gonadotrophin i.v. Day of insemination is taken as day 0 of gestation.

Duration of treatment / exposure:

once daily from day 7 to 19 of gestation

Frequency of treatment:

once daily

Duration of test:

Day 0 to 29 of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
2, 6, 18 or 36 mg/kg/day
Basis:
analytical conc.

Control animals:

yes, concurrent vehicle

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: reduced food consumption and body weight gain

Details on maternal toxic effects:
The observation, in five high-dose females, of changes to the nature of the mucosal lining of the gastro-intestinal tract was considered to be a result of irritation/corrosion due to the acidic nature of the test article (local toxicity). One group 3 female (6mg/kg bw/day) showed similar mucosal changes at necropsy after a 10 days recovery period.
2-4% body weight loss and decreased food consumption are considered secondary to severe local toxicity. The occurrence of anorexia in high-dose females (36 mg/kg bw/day) during the dosing and immediate post-dosing periods was considered to be treatment-related.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

>= 2 mg/kg bw/day

Based on:

act. ingr.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: eye and limb malformations

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

>= 18 mg/kg bw/day

Based on:

act. ingr.

Basis for effect level:

other: teratogenicity

2

Dose descriptor:

NOAEL

Effect level:

>= 2 mg/kg bw/day

Based on:

act. ingr.

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In the main study, pregnant animals were given 0, 2, 6, 18 or 36 mg/kg bw/day.
Maternal effects were noted at 6, 18 and 36 mg/kg bw/day and included local toxicity at the site of first contact and subsequent reduced food consumption and body weight gain. At 36 mg/kg bw/day, one female aborted and was killed; one female died during the study. In addition, two high dose females appeared not to be pregnant, resulting in 11 pregnant animals at the end of the study, versus 15/16 pregnant animals in the other dose groups.
No changes in mean litter or foetal weight were observed. An increased incidence of foetuses with slightly lower insertion of the pelvic girdle was noted at 6, 18 and 36 mg/kg bw/day. An increase in supernumerary ribs was noted in foetuses at 36 mg/kg bw/day. No clear teratogenic changes were noted in any dose level, with the exception of 3 foetuses with microphthalmia at 36 mg/kg bw/day. All three foetuses were from one litter; the maternal animal showed no clear effects on body weight gain or food consumption, and there were no specific clinical signs.
In addition, the incidence of bilateral insertion of pelvic girdle on the 2nd sacral vertebra was 3 times higher at doses 6, 18 and 36 mg/kg bw/day than in the concurrent control group. It has to be noted that the observations on records of the variations were done during the main study only.

Executive summary:

Eye and limb malformations, including microphthalmia, dysplasia of the retina, oligosyndactylyl and brachymelia were fond at maternal toxic dose level (36 mg/kg bw/day). Maternal toxicity, e.g. local irritation/corrosion in mucosal lining of the gastro-intestinal tract (limited recovery!), 2-4% body weight loss and decreased food consumption and anorexia were considered to be substance/treatment-related.

In the range-finding study a dose dependend increase of the (malformations and maternal toxicity) findings (at 60 mg/kg bw/day ) were noted. This dose level was considered not applicable for ethical reasons.

THPC may be considered a possible developmental toxicant.