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Key value for chemical safety assessment

Effects on fertility

Description of key information

The reproduction toxicity of formamide was thoroughly investigated in a Reproductive Assessment in mice by Continuous Breed (RACB) protocol which includes several tasks (continuous breed; crossover breed trial, 2 -generation study). The study was conducted according to EPA guidelines and under GLP conditions.

Formamide was a reproduction toxicant in female mice, as evidenced by reduced fertility, litter size, and number of viable pups. The reproduction NOAEL was 85-110 mg/kg bw/day in females. The NOAEL for generalized toxicity was 144 to 226 mg/kg bw/day for the male and female F0 generation.

Effect on fertility: via oral route
Dose descriptor:
NOAEL
85 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
Quality of whole database:
Reliable without restrictions. The study was conducted according to EPA guidelines and under GLP conditions.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The reproduction toxicity of formamide was thoroughly investigated in a Reproductive Assessment by Continuous Breed (RACB) protocol which includes several tasks (continuous breed; crossover breed trial, 2 -generation study) (Key study). The study was conducted according to EPA guidelines and under GLP conditions. Formamide was examined in a continuous breeding study in mice with the substance in drinking water at concentrations of 0, 100, 350, and 750 ppm reproductive toxicity was observed at 750 ppm in drinking water (144-226 mg/kg bw/day) in the parental and offspring generation, mainly decrease in fertility rate and reduction in live litter size. In a crossover experiment, this was shown to be mainly due to impairment of reproduction in females. At 750 ppm (approx. 210 mg/kg/day) a prolongation of the time to litter from 22 to 26 days was seen. The estrous cycle of F0 and F1 mice at 750 ppm was extended (F1: 6.5 vs. 4.8 days in controls), and the high-dose group tended to be in estrous for a shorter time than controls, and to be longer in diestrous. At necropsy, histopathological examinations revealed no treatment related effect on the non-reproductive tissues. In the reproductive tissues a significant increase in relative corpus and caput epididymis and testis weight was noted, and a decrease in relative seminal vesicle weight at the high dose level. The evaluation of sperm parameters (sperm concentration, motility, morphology, spermatid head count) revealed no treatment-related changes. The absolute and relative ovarian weight was reduced at the mid- and high-dose level.

The NOAEL for generalized toxicity was 144 to 226 mg/kg bw/day for the F0 generation. The NOAEL for reproductive toxicity was 152 - 220 mg/kg bw/day for males and 85 - 110 mg/kg bw/day for females of both generations.


Short description of key information:
Formamide was a reproduction toxicant in female mice, as evidenced by reduced fertility, litter size, and number of viable pups. The reproduction NOAEL was 85-110 mg/kg bw/day in females. The NOAEL for generalized toxicity was 144 to 226 mg/kg bw/day for the male and female F0 generation
.

Effects on developmental toxicity

Description of key information

In a developmental toxicity study conducted similar to OECD guideline 414 and under GLP conditions, time-pregnant Sprague-Dawley (25 females/dose) were dosed by gavage with formamide. Overall, the maternal toxicity NOAEL was 100 mg/kg bw/day in this study, based on a decrease in gravid uterine weight at the top dose.The developmental NOAEL was 50 mg/kg bw/d was established, based on decreases in fetal body weight. Teratogenicity was not seen, the NOAEL was therefore 200 mg/kg bw/day (Key 1 study).    

In a developmental toxicity study conducted similar to OECD guideline 414 and under GLP conditions, naturally-mated New Zealand White rabbits (24 females/dose) were dosed by gavage with formamide . In this toxicity study, the maternal toxicity NOAEL was 70 mg formamide/kg/day. The NOAEL for developmental toxicity in this study was also 70 mg formamide/kg bw/day administered on GD 6 through 29 (Key 2 study).

Other than in some older studies summarized under this endpoint, the test animals were exposed over the entire gestation period in the key studies, and the test material was of analytical grade. In the key studies, developmental toxicity was seen at a lower dose level. Teratogenicity was not observed other than in the older studies. The NOAEL values obtained in the older studies are omitted because of their methodological deficiencis (low analytical purity, no exposure over the entire gestation period).

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Reliable without restrictions. The study was conducted similar to OECD guidelines and under GLP conditions.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Additional information

Rats:

In a developmental toxicity study conducted similar to OECD guideline 414 and under GLP conditions, time-pregnant Sprague-Dawley (25 females/dose) were dosed by gavage with formamide (0, 50, 100 or 200 mg/kgbw and day; dose selection based on results of a range finding study) on GD 6 through 19 (Key 1 study). Maternal toxicity was low and limited to statistically significant body weight gain reduction during gestation (GD 6-19), reduced body weight on GD 18-20, and reduced gravid uterine weight at 200 mg/kgbw and day. The body weight corrected for the gravid uterus weight was not affected and comparable between all groups. Liver weight (absolute and relative) was unaffected by treatment with formamide.

The average male and female fetal weight was statistically significantly reduced at 100 and 200 mg/kgbwand day. The number of fetuses per litter and fetal viability were not affected. The sex distribution was not changed. The incidence of external, skeletal or visceral malformations and variations was not increased at any dose. In this study, the ratconceptuswas more sensitive than the adult to the adverse effects of formamide administered orally throughout the embryo/fetal period of gestation.    

Overall, the maternal toxicity NOAEL was 100 mg/kg bw/day in this study, based on a decrease in gravid uterine weight at the top dose.The developmental NOAEL was 50 mg/kg bw/d was established, based on decreases in fetal body weight. Teratogenicity was not seen, the NOAEL was therefore 200 mg/kg bw/day (Key 1 study).   

Rabbits:

In a developmental toxicity study conducted similar to OECD guideline 414 and under GLP conditions, naturally-mated New Zealand White rabbits (24 females/dose) were dosed by gavage with formamide (0, 35, 70 or 140 mg/kg bw/day) on GD 6 through 29 (Key 2 study). Maternal clinical signs of toxicity were limited to the reduction in or absence of fecal output, primarily at the high dose. Maternal mortality was increased at the high dose (4/24). Maternal body weight and weight gain, relative maternal feed consumption, and gravid uterine weight were also decreased at the high dose. The terminal body weight, corrected for the uterus weight, was, however, comparable between all groups. Liver weight (absolute and relative) was unaffected by treatment with formamide.

Formamide decreased fetal viability (66% of control) and male fetal body weight at the high dose, but did not affect the incidence of fetal malformations (external, visceral or skeletal) at any dose.

In this study, the rabbit conceptus is not more sensitive than the adult to the adverse effects of formamide administered orally throughout the embryo/fetal period of gestation.  

In this toxicity study, the maternal toxicity NOAEL was 70 mg formamide/kg/day. The NOAEL for developmental toxicity in this study was also 70 mg formamide/kg bw/day administered on GD 6 through 29 (Key 2 study).

Other than in some older studies summarized under this endpoint, the test animals were exposed over the entire gestation period in the key studies, and the test material was of analytical grade. In the key studies, developmental toxicity was seen at a lower dose level. Teratogenicity was not observed other than in the older studies. The NOAEL values obtained in the older studies are omitted because of their methodological deficiencis (low analytical purity, no exposure over the entire gestation period).

Justification for classification or non-classification

Considering the results of the reproductive- and developmental toxicity studies with the registered substance, the registered substance meets the criteria for classification and labelling for reproductive toxicity Category 1B; H360FD: May damage fertility and the unborn child, in accordance with Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.