Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Based on the overall read-across approach that benzaldehyde is rapidly metabolised to benzoic acid, and therefore the reproductive and developmental potential of benzaldehyde has been evaluated (and the data requirements fulfilled) as part of the "Benzoates" group, the following summary of the studies presented for IUCLID Section 7.8 for benzoic acid is presented for completeness.

The key study evaluating effects on fertility were by Kieckebusch and Lang (1960), which evaluated the effects of benzoic acid over 4 generations in rats via feeding. While this study does have some limitations when compared to the current OECD 443 EOGRTS, when supplemented by information on reproductive organs/tissues (sperm parameters, including epididymis/cauda epididimys/testis weights, sperm motility/density/abnormal sperm; Estrous cyclicity in females) from a 13 -week repeated dose study of benzyl acetate (a substances that is metabolized completely to benzoic acid), the apparent gaps in data from the current OECD 443 study design are filled.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
2 (reliable with restrictions)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In 1-generation study (Sporn 1967) with the test substance no effects reproduction were reported at a dose level of 5 mg/kg bw/day (limited report). From the studies that are available on repeated dose and carcinogenicity no report on effects on the reproductive organs/tissues in both male and female laboratory animals are reported.

Again, because this dossier relies on the same data presented for benzoic acid, the following information from the benzoic acid dossier is included for completeness.

From the attached "Review of Developmental Toxicology Data for Benzoic Acid":

Kiekebusch and Lang (1960) describes an experiment where 0, 0.5 and 1% benzoic acid was mixed into the feed and fed to rats (groups of 20 males and females/group) for a period of 11-12 weeks prior to breeding. The dietary concentrations were selected based upon a previous probe study where rats consuming 5% benzoic acid in the diet died within three weeks due to lack of palatability of the diet and corrosive effects of the free acid on the digestive tract. The weight range of the animals at the start of the four generation study was 40 -50 grams. Based on the mean value of the feed consumed, the authors reported that the rats in the 1% dietary group received “150 mg of benzoic acid/day”. Based upon the starting body weights and the mean body weight increases reported in Table 1 of the paper, the starting dose level in the males and female animals was in the range of 3750 mg/kg/day for the 1% dose level. After four weeks of feeding, the dose level decreased to 1304 and 1485 mg/kg/day in the male and female rats, respectively. At eight weeks, the dose levels decreased further to 802 and 867 mg/kg/day in the male and female rats, respectively (as the rats grew and consumed roughly the same amount of feed, the effective dose level decreased with the increase in body weight). At 12 weeks of age, the dose level in the male animals was 542 mg/kg/day. The dose level for the female animals was not calculated as they were pregnant by 12 weeks and not included in the body weight gain table. Overall, the dose level for the entire premating period was approximately 900 and 1176 mg/kg/day for male and female rats, respectively. This pattern of feed consumption, body weight gain and corresponding dose levels repeated itself over the four generations of rats consuming these diets within this study. These premating exposure intervals and dose levels are generally comparable to the ten week premating exposure period and limit dose level of 1000 mg/kg/day required under the current EOGRTS test guideline.

Body weights and feed consumption data were collected throughout the exposure periods over the four generations. The body weight data within this publication is presented as body weight “increase” (Table 1) and the feed consumption data is presented as “Protein efficiency (weight increase per gram of dietary protein)” in Table 2. There was no effect of feeding 0.5 or 1% benzoic acid in the diet on feed consumption (efficiency), body weight gain or body weights over the four generations of rats tested in this study.

Effects of benzoic acid on sexual maturity and fertility were determined by pairing male and female animals for 14 days in the 11th and 12th weeks of exposure. Unsuccessful matings were repeated eight weeks later to determine if sexual maturity was delayed or if the mating pairs were infertile. Finally, during the 48thweek of exposure, mating trials were again conducted to evaluate the onset of reproductive senescence in the older animals. Litter data was collected on postnatal days 1, 2 and 21 in each of the four generations. Since there was no demonstrable effect of benzoic acid on reproduction and since the data from all four generations was similar, the data from all four generations was combined into a single table (Table 3). There was no difference between the groups with benzoic acid exposure and the control group for fertility measures, delayed sexual maturity, total number of pups born, pup survival, onset of reproductive senescence or litter size.

The Kiekebusch and Lang paper also evaluated the effect of feeding 0.5 or 1.0% benzoic acid on the lifespan of rats. There was no difference between the 1.0% group and the control animals in terms of lifespan, while the incorporation of 0.5% benzoic acid in the diet appeared to lengthen the lifespan of the rats consuming this dietary concentration. The third generation of animals was necropsied after 16 weeks of exposure and organ weights of the brain, heart, liver, spleen kidneys and testes were collected. Tissues were saved and histopathological examination of the tissues did not reveal any difference between the control and two treated groups for either the organ weights or the histopathology findings.

While the design of this four-generation study for reproductive toxicity does not exactly match the endpoints included within the EOGRTS, it does include almost all of the endpoints associated with the OECD Guideline 416 – two generation reproductive toxicity that was previously considered adequate to satisfy the reproductive toxicity endpoint under the REACh regulation. The only missing reproductive endpoints within the Kiekebusch and Lang publication are collection of sperm parameters or estrous cyclicity data. However, the endpoints that are missing from the four-generation study with benzoic acid are available for benzyl acetate, a chemical that is metabolized completely to benzoic acid. In the National Toxicology Program (Morrissey et al., 1988) 13-week feeding benzyl acetate studies in rats and mice, both sperm parameters (epididymis, cauda epididymis, testis weights, and sperm motility, density and percent abnormal sperm) and estrus cyclicity measurements were collected. Dose levels of 2000 to 3000 mg/kg/day did not affect any endpoints of male reproduction. Estrus cycles were lengthened in female mice receiving >3000 mg/kg/day but this only occurred at a dose levels also causing significant decreases in growth (body weights and body weight gain). Therefore, it appears that all of the reproductive toxicity endpoints have been collected, albeit in two separate studies on benzoic acid and benzyl acetate. Based upon the recent information that has become available following receipt of the English translation of the Kiekebusch and Lang publication, the reproductive toxicity endpoint for benzoic acid should be satisfied based upon the available study data. Shortcomings of the Kiekebusch and Lang 1960 study can be addressed using the data from the 13-week feeding study with benzyl acetate (Morrissey et al., 1988). For these reasons, ECHA should consider the reproductive toxicity endpoint for benzoic acid to be satisfied with the available study data. Overall, taking into consideration both the Kieckebusch and Lang (1960), and Morrissey et al. (1988) studies, no effects on reproductive performance and off-spring were reported at 1% the test substance in feed (500 mg/kg bw). Therefore, the NOAEL for toxicity to reproduction is set at 500 mg/kg bw.

Effects on developmental toxicity

Description of key information

Again, because the overall read-across approach relies on the data for benzoic acid, the following information is presented for completeness.

Sodium benzoate is the sodium salt of benzoic acid, and is completely metabolized to benzoic acid prior to excretion via the hippuric acid pathway. The developmental toxicity database for benzoic acid includes data for both benzoic acid and its salts (primarily sodium benzoate). The available studies include Onodera, et al., (1978),FDA (1972), Kimmel, et al., (1971) and Jelinek, et al., (1985). The Kimmel et al., (1971) publication administered benzoic acid on a single day of gestation (GD 9) at a single dose level (510 mg/kg) as a negative control substance. The Jelinek et al., (1985) reference used chick embryos as a screening method for developmental toxicity endpoints. Since both the Kimmel, et al., (1971) and Jelinek, et al., (1985) references used methods with significant deficiencies when compared to the preferred methods described within the OECD 414 test guidelines for developmental toxicity, they should not be used as the primary studies necessary to satisfy the REACH requirements for the developmental toxicity endpoints. However, in the context of a Weight of Evidence approach, they can still provide supporting information regarding the reproductive and developmental potential of benzoic acid and/or its sodium salt. For the purposes of this endpoint, the focus will be on the Onodera study.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
175 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
2 (reliable with restrictions)
Additional information

Studies with sodium benzoate are available in rats, mice, hamsters and rabbits. Dose levels applied showed no evidence of maternal toxicity. No effects on foetal development were reported. The NOAEL is based on the rat and mouse studies and set at >= 175 mg/kg bw. This level is considered to be very conservative and rats and mice seem to be the most sensitive species.

From the toxicokinetic assessment, it was concluded that the test substance after oral dosing will be metabolised to benzoic acid (see also above). Therefore it is considered acceptable to use the data from developmental study in rats and mice with the structural analogue of benzoic acid, sodium benzoate, to set the NOAEL. The NOAEL for toxicity to reproduction is set at 175 mg/kg bw.


Justification for selection of Effect on developmental toxicity: via oral route:
This study is read-across from sodium benzoate. It was carried out according to a reliable method which similar to OECD 414 using rats.

Justification for classification or non-classification

Developmental toxicity studies, subacute, subchronic, chronic studies and 4-generation study performed with the benzoate group substances (benzyl acetate, benzyl alcohol, benzaldehyde and sodium benzoate) indicate that these compounds are not reprotoxic or developmental toxicants.

Taking into account the available data on reprotoxicity and developmental toxicity of the members of this category it is considered likely that benzaldehyde is not a significant reprotoxicant and should not be classified as such under CLP EU Regulation 1272/2008.

Additional information