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Key value for chemical safety assessment

Effects on developmental toxicity

Description of key information
LOAEL for developmental toxicity in laboratory rabbits exceeds the no-effect level for (maternal) local toxicity by factor 20. Teratogenicity cannot be excluded based on the foetuses with microphthalmia at 36 mg/kg bw/day. Given animal data considering only the oral route of exposure. 
Link to relevant study records
Reference
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).
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
minor deviations
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
Wistar
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
Remarks:
Doses / Concentrations:
2, 6, 18 or 36 mg/kg/day
Basis:
analytical conc.
Control animals:
yes, concurrent vehicle
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.
Dose descriptor:
NOAEL
Effect level:
>= 2 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: eye and limb malformations
Dose descriptor:
NOAEL
Effect level:
>= 18 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
>= 2 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
other: embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
36 mg/kg bw/day
Species:
rabbit
Additional information

The NOAEL for maternal toxicity in rabbits was 2 mg/kg bw/day based on local effects.

The NOAEL for developmental toxicity in rabbits was 18 mg/kg bw/day.

Justification for classification or non-classification

1) Teratogenicity was found at maternal toxic dose levels in rabbits. Classification of THPC with Repr.Tox Cat. 1B H360 is concerned on basis of hazard. With respect to the severe local toxicity of the substance "exposure/risk for" an developmental effect in men is unlikely. Avoiding local toxicity (and subsequent maternal toxicity) will give a large margin of safety for the endpoint teratogenicity.

2) In view of the application/life cycle of the substance the exposure to men is limited and the oral route is not relevant.

3) When considering a dermal teratogenicity test, repeated exposure to the skin of test animals would be limited according to the inherent corrosivity of THPC.

4) The inhalation route of exposure is not relevant because THPC is an organic salt which cannot evaporate without decomposition. During its life cycle, which takes place in industrial settings exclusively, aerosol formation does not occur.

Overall, there is evidence that in men systemic toxicity is rather unlikely for THPC, which is a cytotoxic, electrophilically reactive substance. THPC causes primary local toxicity. Exposure, like in teratogenicity studies (gavage), is not relevant with regard to the anticipated human exposure. No human data are available.

Classification of THPC with Repr.Tox Cat 2, H361 "Suspected of damaging the unborn child" is justified.

Additional information